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1. A novel viewpoint in glaucoma therapeutics: enriched environment

Author: María F González Fleitas, Damián Dorfman, and Ruth E Rosenstein
Subjects: brain-derived neurotrophic factor, chondroitin sulfate, enriched environment, glaucoma, optic nerve axons, optic nerve glia, retinal ganglion cells, visual stimulation, Neurology. Diseases of the nervous system, RC346-429
Abstract: Glaucoma is one of the world’s most frequent visual impairment causes and leads to selective damage to retinal ganglion cells and their axons. Despite glaucoma’s most accepted risk factor is increased intraocular pressure (IOP), the mechanisms behind the disease have not been fully elucidated. To date, IOP lowering remains the gold standard; however, glaucoma patients may still lose vision regardless of effective IOP management. Therefore, the exclusive IOP control apparently is not enough to stop the disease progression, and developing new resources to protect the retina and optic nerve against glaucoma is a goal of vast clinical importance. Besides pharmacological treatments, environmental conditions have been shown to prevent neurodegeneration in the central nervous system. In this review, we discuss current concepts on key pathogenic mechanisms involved in glaucoma, the effect of enriched environment on these mechanisms in different experimental models, as well as recent evidence supporting the preventive and therapeutic effect of enriched environment exposure against experimental glaucomatous damage. Finally, we postulate that stimulating vision may become a non-invasive and rehabilitative therapy that could be eventually translated to the human disease, preventing glaucoma-induced terrible sequelae resulting in permanent visual disability.
Published: 2022
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2. Enriched environment and visual stimuli protect the retinal pigment epithelium and photoreceptors in a mouse model of non-exudative age-related macular degeneration

Author: Hernán H. Dieguez, Juan S. Calanni, Horacio E. Romeo, Agustina Alaimo, María F. González Fleitas, Agustina Iaquinandi, Mónica S. Chianelli, María I. Keller Sarmiento, Pablo H. Sande, Ruth E. Rosenstein, and Damián Dorfman
Subjects: Cytology, QH573-671
Abstract: Abstract Non-exudative age-related macular degeneration (NE-AMD), the main cause of blindness in people above 50 years old, lacks effective treatments at the moment. We have developed a new NE-AMD model through unilateral superior cervical ganglionectomy (SCGx), which elicits the disease main features in C57Bl/6J mice. The involvement of oxidative stress in the damage induced by NE-AMD to the retinal pigment epithelium (RPE) and outer retina has been strongly supported by evidence. We analysed the effect of enriched environment (EE) and visual stimulation (VS) in the RPE/outer retina damage within experimental NE-AMD. Exposure to EE starting 48 h post-SCGx, which had no effect on the choriocapillaris ubiquitous thickness increase, protected visual functions, prevented the thickness increase of the Bruch’s membrane, and the loss of the melanin of the RPE, number of melanosomes, and retinoid isomerohydrolase (RPE65) immunoreactivity, as well as the ultrastructural damage of the RPE and photoreceptors, exclusively circumscribed to the central temporal (but not nasal) region, induced by experimental NE-AMD. EE also prevented the increase in outer retina/RPE oxidative stress markers and decrease in mitochondrial mass at 6 weeks post-SCGx. Moreover, EE increased RPE and retinal brain-derived neurotrophic factor (BDNF) levels, particularly in Müller cells. When EE exposure was delayed (dEE), starting at 4 weeks post-SCGx, it restored visual functions, reversed the RPE melanin content and RPE65-immunoreactivity decrease. Exposing animals to VS protected visual functions and prevented the decrease in RPE melanin content and RPE65 immunoreactivity. These findings suggest that EE housing and VS could become an NE-AMD promising therapeutic strategy.
Published: 2021
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3. Superior cervical gangliectomy induces non-exudative age-related macular degeneration in mice

Author: Hernán H. Dieguez, Horacio E. Romeo, María F. González Fleitas, Marcos L. Aranda, Georgia A. Milne, Ruth E. Rosenstein, and Damián Dorfman
Subjects: Age-related macular degeneration, Superior cervical ganglion, Choroid, Retinal pigment epithelium, Photoreceptors, Experimental model, Medicine, Pathology, RB1-214
Abstract: Non-exudative age-related macular degeneration, a prevalent cause of blindness, is a progressive and degenerative disease characterized by alterations in Bruch's membrane, retinal pigment epithelium, and photoreceptors exclusively localized in the macula. Although experimental murine models exist, the vast majority take a long time to develop retinal alterations and, in general, these alterations are ubiquitous, with many resulting from non-eye-specific genetic manipulations; additionally, most do not always reproduce the hallmarks of human age-related macular degeneration. Choroid vessels receive sympathetic innervation from the superior cervical ganglion, which, together with the parasympathetic system, regulates blood flow into the choroid. Choroid blood flow changes have been involved in age-related macular degeneration development and progression. At present, no experimental models take this factor into account. The aim of this work was to analyze the effect of superior cervical gangliectomy (also known as ganglionectomy) on the choroid, Bruch's membrane, retinal pigment epithelium and retina. Adult male C57BL/6J mice underwent unilateral superior cervical gangliectomy and a contralateral sham procedure. Although superior cervical gangliectomy induced ubiquitous choroid and choriocapillaris changes, it induced Bruch's membrane thickening, loss of retinal pigment epithelium melanin content and retinoid isomerohydrolase, the appearance of drusen-like deposits, and retinal pigment epithelium and photoreceptor atrophy, exclusively localized in the temporal side. Moreover, superior cervical gangliectomy provoked a localized increase in retinal pigment epithelium and photoreceptor apoptosis, and a decline in photoreceptor electroretinographic function. Therefore, superior cervical gangliectomy recapitulated the main features of human non-exudative age-related macular degeneration, and could become a new experimental model of dry age-related macular degeneration, and a useful platform for developing new therapies.
Published: 2018
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4. Enriched Environment Protects the Optic Nerve from Early Diabetes-Induced Damage in Adult Rats.

Author: Damián Dorfman, Marcos L Aranda, and Ruth E Rosenstein
Subjects: Medicine, Science
Abstract: Diabetic retinopathy is a leading cause of reduced visual acuity and acquired blindness. Axoglial alterations of the distal (close to the chiasm) optic nerve (ON) could be the first structural change of the visual pathway in streptozotocin (STZ)-induced diabetes in rats. We analyzed the effect of environmental enrichment on axoglial alterations of the ON provoked by experimental diabetes. For this purpose, three days after vehicle or STZ injection, animals were housed in enriched environment (EE) or remained in a standard environment (SE) for 6 weeks. Anterograde transport, retinal morphology, optic nerve axons (toluidine blue staining and phosphorylated neurofilament heavy immunoreactivity), microglia/macrophages (ionized calcium binding adaptor molecule 1 (Iba-1) immunoreactivity), astrocyte reactivity (glial fibrillary acid protein-immunostaining), myelin (myelin basic protein immunoreactivity), ultrastructure, and brain derived neurotrophic factor (BDNF) levels were assessed in non-diabetic and diabetic animals housed in SE or EE. No differences in retinal morphology or retinal ganglion cell number were observed among groups. EE housing which did not affect the STZ-induced weight loss and hyperglycemia, prevented a decrease in the anterograde transport from the retina to the superior colliculus, ON axon number, and phosphorylated neurofilament heavy immunoreactivity. Moreover, EE housing prevented an increase in Iba-1 immunoreactivity, and astrocyte reactivity, as well as ultrastructural myelin alterations in the ON distal portion at early stages of diabetes. In addition, EE housing avoided a decrease in BDNF levels induced by experimental diabetes. These results suggest that EE induced neuroprotection in the diabetic visual pathway.
Published: 2015
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5. Environmental enrichment protects the retina from early diabetic damage in adult rats.

Author: Damián Dorfman, Marcos L Aranda, María Florencia González Fleitas, Mónica S Chianelli, Diego C Fernandez, Pablo H Sande, and Ruth E Rosenstein
Subjects: Medicine, Science
Abstract: Diabetic retinopathy is a leading cause of reduced visual acuity and acquired blindness. Available treatments are not completely effective. We analyzed the effect of environmental enrichment on retinal damage induced by experimental diabetes in adult Wistar rats. Diabetes was induced by an intraperitoneal injection of streptozotocin. Three days after vehicle or streptozotocin injection, animals were housed in enriched environment or remained in a standard environment. Retinal function (electroretinogram, and oscillatory potentials), retinal morphology, blood-retinal barrier integrity, synaptophysin, astrocyte and Müller cell glial fibrillary acidic protein, vascular endothelial growth factor, tumor necrosis factor-α, and brain-derived neurotrophic factor levels, as well as lipid peroxidation were assessed in retina from diabetic animals housed in standard or enriched environment. Environmental enrichment preserved scotopic electroretinogram a-wave, b-wave and oscillatory potential amplitude, avoided albumin-Evan's blue leakage, prevented the decrease in retinal synaptophysin and astrocyte glial fibrillary acidic protein levels, the increase in Müller cell glial fibrillary acidic protein, vascular endothelial growth factor and tumor necrosis factor-α levels, as well as oxidative stress induced by diabetes. In addition, enriched environment prevented the decrease in retinal brain-derived neurotrophic factor levels induced by experimental diabetes. When environmental enrichment started 7 weeks after diabetes onset, retinal function was significantly preserved. These results indicate that enriched environment could attenuate the early diabetic damage in the retina from adult rats.
Published: 2014
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6. Global and ocular hypothermic preconditioning protect the rat retina from ischemic damage.

Author: Ezequiel M Salido, Damián Dorfman, Melina Bordone, Mónica Chianelli, María Florencia González Fleitas, and Ruth E Rosenstein
Subjects: Medicine, Science
Abstract: Retinal ischemia could provoke blindness. At present, there is no effective treatment against retinal ischemic damage. Strong evidence supports that glutamate is implicated in retinal ischemic damage. We investigated whether a brief period of global or ocular hypothermia applied 24 h before ischemia (i.e. hypothermic preconditioning, HPC) protects the retina from ischemia/reperfusion damage, and the involvement of glutamate in the retinal protection induced by HPC. For this purpose, ischemia was induced by increasing intraocular pressure to 120 mm Hg for 40 min. One day before ischemia, animals were submitted to global or ocular hypothermia (33°C and 32°C for 20 min, respectively) and fourteen days after ischemia, animals were subjected to electroretinography and histological analysis. Global or ocular HPC afforded significant functional (electroretinographic) protection in eyes exposed to ischemia/reperfusion injury. A marked alteration of the retinal structure and a decrease in retinal ganglion cell number were observed in ischemic retinas, whereas global or ocular HPC significantly preserved retinal structure and ganglion cell count. Three days after ischemia, a significant decrease in retinal glutamate uptake and glutamine synthetase activity was observed, whereas ocular HPC prevented the effect of ischemia on these parameters. The intravitreal injection of supraphysiological levels of glutamate induced alterations in retinal function and histology which were significantly prevented by ocular HPC. These results support that global or ocular HPC significantly protected retinal function and histology from ischemia/reperfusion injury, probably through a glutamate-dependent mechanism.
Published: 2013
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7. Therapeutic benefit of radial optic neurotomy in a rat model of glaucoma.

Author: Nicolás Belforte, Pablo H Sande, Nuria de Zavalía, Damián Dorfman, and Ruth E Rosenstein
Subjects: Medicine, Science
Abstract: Radial optic neurotomy (RON) has been proposed as a surgical treatment to alleviate the neurovascular compression and to improve the venous outflow in patients with central retinal vein occlusion. Glaucoma is characterized by specific visual field defects due to the loss of retinal ganglion cells and damage to the optic nerve head (ONH). One of the clinical hallmarks of glaucomatous neuropathy is the excavation of the ONH. The aim of this work was to analyze the effect of RON in an experimental model of glaucoma in rats induced by intracameral injections of chondroitin sulfate (CS). For this purpose, Wistar rats were bilaterally injected with vehicle or CS in the eye anterior chamber, once a week, for 10 weeks. At 3 or 6 weeks of a treatment with vehicle or CS, RON was performed by a single incision in the edge of the neuro-retinal ring at the nasal hemisphere of the optic disk in one eye, while the contralateral eye was submitted to a sham procedure. Electroretinograms (ERGs) were registered under scotopic conditions and visual evoked potentials (VEPs) were registered with skull-implanted electrodes. Retinal and optic nerve morphology was examined by optical microscopy. RON did not affect the ocular hypertension induced by CS. In eyes injected with CS, a significant decrease of retinal (ERG a- and b-wave amplitude) and visual pathway (VEP N2-P2 component amplitude) function was observed, whereas RON reduced these functional alterations in hypertensive eyes. Moreover, a significant loss of cells in the ganglion cell layer, and Thy-1-, NeuN- and Brn3a- positive cells was observed in eyes injected with CS, whereas RON significantly preserved these parameters. In addition, RON preserved the optic nerve structure in eyes with chronic ocular hypertension. These results indicate that RON reduces functional and histological alterations induced by experimental chronic ocular hypertension.
Published: 2012
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8. Ischemic conditioning protects from axoglial alterations of the optic pathway induced by experimental diabetes in rats.

Author: Diego C Fernandez, Laura A Pasquini, Damián Dorfman, Hernán J Aldana Marcos, and Ruth E Rosenstein
Subjects: Medicine, Science
Abstract: Diabetic retinopathy is a leading cause of blindness. Visual function disorders have been demonstrated in diabetics even before the onset of retinopathy. At early stages of experimental diabetes, axoglial alterations occur at the distal portion of the optic nerve. Although ischemic conditioning can protect neurons and synaptic terminals against ischemic damage, there is no information on its ability to protect axons. We analyzed the effect of ischemic conditioning on the early axoglial alterations in the distal portion of the optic nerve induced by experimental diabetes. Diabetes was induced in Wistar rats by an intraperitoneal injection of streptozotocin. Retinal ischemia was induced by increasing intraocular pressure to 120 mm Hg for 5 min; this maneuver started 3 days after streptozotocin injection and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. The application of ischemia pulses prevented a deficit in the anterograde transport from the retina to the superior colliculus, as well as an increase in astrocyte reactivity, ultraestructural myelin alterations, and altered morphology of oligodendrocyte lineage in the optic nerve distal portion at early stages of experimental diabetes. Ischemia tolerance prevented a significant decrease of retinal glutamine synthetase activity induced by diabetes. These results suggest that early vision loss in diabetes could be abated by ischemic conditioning which preserved axonal function and structure.
Published: 2012
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9. Melatonin Prevents Non-image-Forming Visual System Alterations Induced by Experimental Glaucoma in Rats

Author: Ruth E. Rosenstein, Marcos L. Aranda, María Florencia González Fleitas, Pablo H. Sande, Agustina Iaquinandi, Julián Daniel Devouassoux, Hernán H. Dieguez, Juan Salvador Calanni, and Damián Dorfman
Subjects: 0301 basic medicine, Melanopsin, medicine.medical_specialty, genetic structures, Neuroscience (miscellaneous), Glaucoma, Biology, Retinal ganglion, Melatonin, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Circadian rhythm, Pupillary light reflex, Pretectal area, Retina, medicine.disease, eye diseases, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Neurology, sense organs, 030217 neurology & neurosurgery, medicine.drug
Abstract: Glaucoma is a blindness-causing disease that involves selective damage to retinal ganglion cells (RGCs) and their axons. A subset of RGCs expressing the photopigment melanopsin regulates non-image-forming visual system functions, such as pupillary light reflex and circadian rhythms. We analyzed the effect of melatonin on the non-image-forming visual system alterations induced by experimental glaucoma. For this purpose, male Wistar rats were weekly injected with vehicle or chondroitin sulfate into the eye anterior chamber. The non-image-forming visual system was analyzed in terms of (1) melanopsin-expressing RGC number, (2) anterograde transport from the retina to the olivary pretectal nucleus and the suprachiasmatic nuclei, (3) blue- and white light-induced pupillary light reflex, (4) light-induced c-Fos expression in the suprachiasmatic nuclei, (5) daily rhythm of locomotor activity, and (6) mitochondria in melanopsin-expressing RGC cells. Melatonin prevented the effect of experimental glaucoma on melanopsin-expressing RGC number, blue- and white light-induced pupil constriction, retina-olivary pretectal nucleus, and retina- suprachiasmatic nuclei communication, light-induced c-Fos expression in the suprachiasmatic nuclei, and alterations in the locomotor activity daily rhythm. In addition, melatonin prevented the effect of glaucoma on melanopsin-expressing RGC mitochondrial alterations. These results support that melatonin protected the non-image-forming visual system against glaucoma, probably through a mitochondrial protective mechanism.
Published: 2021
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10. An ethologically relevant paradigm to assess defensive response to looming visual contrast stimuli

Author: Juan S. Calanni, Marcos L. Aranda, Hernán H. Dieguez, Damian Dorfman, Tiffany M. Schmidt, and Ruth E. Rosenstein
Subjects: Looming test in rodents, Contrast-dependent behavior, Contrast sensitivity, Medicine, Science
Abstract: Abstract In the animal kingdom, threat information is perceived mainly through vision. The subcortical visual pathway plays a critical role in the rapid processing of visual information-induced fear, and triggers a response. Looming-evoked behavior in rodents, mimicking response to aerial predators, allowed identify the neural circuitry underlying instinctive defensive behaviors; however, the influence of disk/background contrast on the looming-induced behavioral response has not been examined, either in rats or mice. We studied the influence of the dark disk/gray background contrast in the type of rat and mouse defensive behavior in the looming arena, and we showed that rat and mouse response as a function of disk/background contrast adjusted to a sigmoid-like relationship. Both sex and age biased the contrast-dependent response, which was dampened in rats submitted to retinal unilateral or bilateral ischemia. Moreover, using genetically manipulated mice, we showed that the three type of photoresponsive retinal cells (i.e., cones, rods, and intrinsically photoresponsive retinal ganglion cells (ipRGCs)), participate in the contrast-dependent response, following this hierarchy: cones > > rods > > > ipRGCs. The cone and rod involvement was confirmed using a mouse model of unilateral non-exudative age-related macular degeneration, which only damages canonical photoreceptors and significantly decreased the contrast sensitivity in the looming arena.
Published: 2024
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11. Melatonin Prevents Non-image-Forming Visual System Alterations Induced by Experimental Glaucoma in Rats

Author: María F, González Fleitas, Julián, Devouassoux, Marcos L, Aranda, Hernán H, Dieguez, Juan S, Calanni, Agustina, Iaquinandi, Pablo H, Sande, Damián, Dorfman, and Ruth E, Rosenstein
Subjects: Male, Retinal Ganglion Cells, Light, Rod Opsins, Animals, Glaucoma, Suprachiasmatic Nucleus, Rats, Wistar, Antioxidants, Vision, Ocular, Melatonin, Rats
Abstract: Glaucoma is a blindness-causing disease that involves selective damage to retinal ganglion cells (RGCs) and their axons. A subset of RGCs expressing the photopigment melanopsin regulates non-image-forming visual system functions, such as pupillary light reflex and circadian rhythms. We analyzed the effect of melatonin on the non-image-forming visual system alterations induced by experimental glaucoma. For this purpose, male Wistar rats were weekly injected with vehicle or chondroitin sulfate into the eye anterior chamber. The non-image-forming visual system was analyzed in terms of (1) melanopsin-expressing RGC number, (2) anterograde transport from the retina to the olivary pretectal nucleus and the suprachiasmatic nuclei, (3) blue- and white light-induced pupillary light reflex, (4) light-induced c-Fos expression in the suprachiasmatic nuclei, (5) daily rhythm of locomotor activity, and (6) mitochondria in melanopsin-expressing RGC cells. Melatonin prevented the effect of experimental glaucoma on melanopsin-expressing RGC number, blue- and white light-induced pupil constriction, retina-olivary pretectal nucleus, and retina- suprachiasmatic nuclei communication, light-induced c-Fos expression in the suprachiasmatic nuclei, and alterations in the locomotor activity daily rhythm. In addition, melatonin prevented the effect of glaucoma on melanopsin-expressing RGC mitochondrial alterations. These results support that melatonin protected the non-image-forming visual system against glaucoma, probably through a mitochondrial protective mechanism.
Published: 2020

12. Pre-ischemic enriched environment increases retinal resilience to acute ischemic damage in adult rats

Author: Ruth E. Rosenstein, Marcos L. Aranda, María Florencia González Fleitas, Hernán H. Dieguez, Julián Daniel Devouassoux, Damián Dorfman, and Monica Chianelli
Subjects: Male, Retinal Ganglion Cells, 0301 basic medicine, Tropomyosin receptor kinase B, chemistry.chemical_compound, 0302 clinical medicine, Animal Husbandry, RETINA, medicine.diagnostic_test, Azepines, Adaptation, Physiological, Sensory Systems, ISCHEMIA, Medicina Básica, medicine.anatomical_structure, Retinal ganglion cell, Reperfusion Injury, Benzamides, Cholera Toxin, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Blotting, Western, Neurociencias, Ischemia, Environment, complex mixtures, Retina, 03 medical and health sciences, Cellular and Molecular Neuroscience, Retinal Diseases, Internal medicine, Electroretinography, medicine, Animals, BRAIN DERIVED NEUROTROPHIC FACTOR, Rats, Wistar, Eye Proteins, Brain-derived neurotrophic factor, business.industry, Retinal Vessels, Retinal, equipment and supplies, medicine.disease, Rats, PRE-ISCHEMIC ENRICHED ENVIRONMENT, Ophthalmology, 030104 developmental biology, Endocrinology, chemistry, 030221 ophthalmology & optometry, bacteria, business, Reperfusion injury, Biomarkers
Abstract: Retinal ischemia is a condition associated with several degenerative diseases leading to visual impairment and blindness worldwide. Currently, there is no highly effective therapy for ischemic retinopathies. This study was designed to determine possible benefits of pre-exposure to enriched environment against retinal damage induced by acute ischemia. For this purpose, adult male Wistar rats were randomly assigned to a pre-ischemic standard environment or a pre-ischemic enriched environment for 3 weeks, followed by unilateral ischemia induced by increasing intraocular pressure above 120 mm Hg for 40 min and reperfusion for 1 or 2 weeks in standard environment. Animals were subjected to electroretinography and histological analysis. Pre-ischemic enriched environment afforded significant functional protection in eyes exposed to ischemia/reperfusion injury. A marked reduction in retinal layer thickness, reduced synaptophysin-immunoreactivity and retinal ganglion cell (RGC) number, and increased microglia/macrophage reactivity were observed in ischemic retinas from animals submitted to pre-ischemic standard environment, which were prevented by pre-ischemic enriched environment. A deficit in anterograde transport from the retina to the superior colliculus and the lateral geniculate nucleus was observed in animals exposed to pre-ischemic standard environment, which was lower in animals previously exposed to enriched environment. The exposure to enriched environment before ischemia increased retinal brain derived neurotrophic factor (BDNF) protein levels in ischemic retinas and the administration of ANA-12 (a TrkB antagonist) abolished the protective effect of enriched environment on retinal function and retinal ganglion cell number. These results indicate that pre-ischemic enriched environment increases retinal resilience to acute ischemic damage, possibly through a BDNF/TrkB mediated pathway. Fil: González Fleitas, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Aranda, Marcos Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dieguez, Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Devouassoux, Julián Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Chianelli, Mónica Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2019
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13. Involvement of microglia in early axoglial alterations of the optic nerve induced by experimental glaucoma

Author: Ruth E. Rosenstein, Pablo H. Sande, Damián Dorfman, María Florencia González Fleitas, Melina Paula Bordone, Laura A. Pasquini, and Alejandra Bosco
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, genetic structures, Neurociencias, Ocular hypertension, Minocycline, Lateral geniculate nucleus, Biochemistry, Retina, Luxol fast blue stain, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Animals, Rats, Wistar, Glial fibrillary acidic protein, biology, business.industry, Superior colliculus, Geniculate Bodies, Glaucoma, Optic Nerve, Axoglial Alterations, Anatomy, medicine.disease, eye diseases, Medicina Básica, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Retinal ganglion cell, Astrocytes, Axoplasmic transport, biology.protein, Optic nerve, Microglia, sense organs, business, Neuroglia, 030217 neurology & neurosurgery
Abstract: Glaucoma is a leading cause of blindness, characterized by retinal ganglion cell (RGC) loss and optic nerve (ON) damage. Cumulative evidence suggests glial cell involvement in the degeneration of the ON and RGCs. We analyzed the contribution of microglial reactivity to early axoglial alterations of the ON in an induced model of ocular hypertension. For this purpose, vehicle or chondroitin sulfate (CS) were weekly injected into the eye anterior chamber from Wistar rats for different intervals. The amount of Brn3a(+) RGC significantly decreased in CS-injected eyes for 10 and 15 (but not 6) weeks. A reduction in anterograde transport of β-subunit cholera toxin (CTB) was observed in the superior colliculus and the lateral geniculate nucleus contralateral to CS-injected eyes for 6 and 15 weeks. A disruption of CTB transport was observed at the proximal myelinated ON. A significant decrease in phosphorylated neurofilament heavy chain (pNFH)-immunoreactivity, an increase in Iba-1(+), ED1(+) (microglial markers), and glial fibrillary acidic protein (GFAP, astrocytes) (+) area, and decreased luxol fast blue (LFB) staining were observed in the ON at 6 and 15 weeks of ocular hypertension. Microglial reactivity involvement was examined through a daily treatment with minocycline (30 mg/kg, i.p.) for 2 weeks, after 4 weeks of ocular hypertension. Minocycline prevented the increase in Iba-1(+), ED-1(+), and GFAP(+) area, the decrease in pNFH-immunoreactivity and LFB staining, and the deficit in anterograde transport induced by 6 weeks of ocular hypertension. Thus, targeting microglial reactivity might prevent early axoglial alterations in the glaucomatous ON. Fil: Bordone, Melina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: González Fleitas, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Pasquini, Laura Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina Fil: Bosco, Alejandra. University of Utah; Estados Unidos Fil: Sande Casal, Pablo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2017
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14. Melatonin protects the retina from experimental nonexudative age-related macular degeneration in mice

Author: Damián Dorfman, Pablo H. Sande, Agustina Alaimo, Ruth E. Rosenstein, Horacio Eduardo Romeo, Monica Chianelli, María Florencia González Fleitas, Marcos L. Aranda, Hernán H. Dieguez, María I. Keller Sarmiento, and Juan Salvador Calanni
Subjects: 0301 basic medicine, medicine.medical_specialty, ESTRES OXIDATIVO, genetic structures, medicine.disease_cause, Antioxidants, Retina, Melanin, Melatonin, 03 medical and health sciences, Macular Degeneration, Mice, 0302 clinical medicine, Endocrinology, Internal medicine, ANCIANOS, medicine, MELATONINA, Animals, CEGUERA, Melanosome, Retinal pigment epithelium, ENFERMEDADES DE LA RETINA, business.industry, ANTIOXIDANTES, Macular degeneration, medicine.disease, eye diseases, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, medicine.anatomical_structure, RPE65, TRATAMIENTO MEDICO, sense organs, business, 030217 neurology & neurosurgery, Oxidative stress, medicine.drug
Abstract: Fil: Dieguez, Hernán H. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Centro de Estudios Farmacológicos y Botánicos. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Dieguez, Hernán H. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: González Fleitas, María F. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Centro de Estudios Farmacológicos y Botánicos. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: González Fleitas, María F. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Aranda, Marcos L. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Centro de Estudios Farmacológicos y Botánicos. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Aranda, Marcos L. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Calanni, Juan S. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Centro de Estudios Farmacológicos y Botánicos. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Calanni, Juan S. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Keller Sarmiento, María I. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Centro de Estudios Farmacológicos y Botánicos. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Keller Sarmiento, María I. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Chianelli, Mónica S. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Centro de Estudios Farmacológicos y Botánicos. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Chianelli, Mónica S. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Alaimo, Agustina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica. Laboratorio Interdisciplinario de. Dinámica Celular y Nano-Herramientas; Argentina Fil: Alaimo, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Pablo H. Sande. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Centro de Estudios Farmacológicos y Botánicos. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Pablo H. Sande. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Romeo, Horacio E. Pontificia Universidad Católica Argentina. Facultad de Ingeniería y Ciencias Agrarias; Argentina Fil: Romeo, Horacio E. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Romeo, Horacio E. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rosenstein, Ruth E. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Centro de Estudios Farmacológicos y Botánicos. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Rosenstein, Ruth E. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Dorfman, Damián. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Centro de Estudios Farmacológicos y Botánicos. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Abstract: Non-exudative age-related macular degeneration (NE-AMD) represents the leading cause of blindness in the elderly. Currently, there are no available treatments for NE-AMD. We have developed a NE-AMD model induced by superior cervical ganglionectomy (SCGx) in C57BL/6J mice, which reproduces the disease hallmarks. Several lines of evidence strongly support the involvement of oxidative stress in NEAMD- induced retinal pigment epithelium (RPE) and outer retina damage. Melatonin is a proven and safe antioxidant. Our aim was analyzing the effect of melatonin in the RPE/outer retina damage within experimental NE-AMD. The treatment with melatonin starting 48 h after SCGx, which had no effect on the ubiquitous choriocapillaris widening, protected visual functions, and avoided Bruch´s membrane thickening, RPE melanin content, melanosome number loss, retinoid isomerohydrolase (RPE65)- immunoreactivity decrease, and RPE and photoreceptor ultrastructural damage induced within experimental NE-AMD exclusively located at the central temporal (but not nasal) region. Melatonin also prevented the increase in outer retina/RPE oxidative stress markers, and a decrease in mitochondrial mass at 6 weeks post-SCGx. Moreover, when the treatment with melatonin started at 4 weeks post-SCGx, it restored visual functions and reversed the decrease in RPE melanin content and RPE65-immunoreactivity. These findings suggest that melatonin could become a promising safe therapeutic strategy for NE-AMD.
Published: 2019

15. Enriched environment provides neuroprotection against experimental glaucoma

Author: Marcos L. Aranda, Juan Salvador Calanni, Julián Daniel Devouassoux, Damián Dorfman, Ruth E. Rosenstein, María Florencia González Fleitas, and Monica Chianelli
Subjects: 0301 basic medicine, Male, Retinal Ganglion Cells, genetic structures, Ocular hypertension, Glaucoma, Biochemistry, Luxol fast blue stain, chemistry.chemical_compound, 0302 clinical medicine, GLAUCOMA, Axon, OPTIC NERVE, Chondroitin Sulfates, purl.org/becyt/ford/3.1 [https], Housing, Animal, Neuroprotection, ENRICHED ENVIRONMENT, Medicina Básica, medicine.anatomical_structure, Optic nerve, purl.org/becyt/ford/3 [https], medicine.medical_specialty, Cholera Toxin, CIENCIAS MÉDICAS Y DE LA SALUD, Neurociencias, Vision Disorders, Environment, Retinal ganglion, MICROGLIA, 03 medical and health sciences, Cellular and Molecular Neuroscience, Internal medicine, medicine, Animals, Rats, Wistar, Retina, RETINAL GANGLION CELLS, Retinal, Optic Nerve, medicine.disease, eye diseases, Rats, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Evoked Potentials, Visual, Ocular Hypertension, sense organs, 030217 neurology & neurosurgery
Abstract: Glaucoma is one of the most frequent causes of visual impairment worldwide, and involves selective damage to retinal ganglion cells (RGCs) and their axons. We analyzed the effect of enriched environment (EE) housing on the optic nerve, and retinal alterations in an induced model of ocular hypertension. For this purpose, male Wistar rats were weekly injected with vehicle or chondroitin sulfate (CS) into the eye anterior chamber for 10 weeks and housed in standard environment or EE. EE housing prevented the effect of experimental glaucoma on visual evoked potentials, retinal anterograde transport, phosphorylated neurofilament-immunoreactivity, axon number, microglial/macrophage reactivity (ionized calcium binding adaptor molecule 1-immunoreactivity), and astrocytosis (glial fibrillary acidic protein-immunostaining), as well as oligodendrocytes alterations (luxol fast blue staining, and myelin basic protein-immunoreactivity) in the proximal portion of the optic nerve. Moreover EE prevented the increase in ionized calcium binding adaptor molecule-1 levels, and RGC loss (Brn3a-immunoreactivity) in the retina from hypertensive eyes. EE increased retinal brain-derived neurotrophic factor levels. When EE housing started after 6 weeks of ocular hypertension, a preservation of visual evoked potentials amplitude, axon, and Brn3a(+) RGC number was observed. Taken together, these results suggest that EE preserved visual functions, reduced optic nerve axoglial alterations, and protected RGCs against glaucomatous damage. Fil: González Fleitas, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Devouassoux, Julián Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Aranda, Marcos Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Calanni, Juan Salvador. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Chianelli, Mónica Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2019
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16. The 'Use It or Lose It' Dogma in the Retina: Visual Stimulation Promotes Protection Against Retinal Ischemia

Author: Georgia A. Milne, Hernán H. Dieguez, Marcos L. Aranda, Leonel Langellotti, Damián Dorfman, Magdalena Miranda, María Florencia González Fleitas, Florencia Altschuler, and Ruth E. Rosenstein
Subjects: 0301 basic medicine, Male, Retinal Ganglion Cells, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Neurociencias, Neuroscience (miscellaneous), Ischemia, Stimulation, Tropomyosin receptor kinase B, Retina, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Electroretinography, Animals, Rats, Wistar, RETINA, Environmental enrichment, medicine.diagnostic_test, business.industry, Superior colliculus, Brain-Derived Neurotrophic Factor, Retinal, Azepines, medicine.disease, ISCHEMIA, Medicina Básica, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, BDNF, Neurology, chemistry, VISUAL STIMULATION, Benzamides, SUPERIOR COLLICULUS, business, 030217 neurology & neurosurgery, Locomotion, Photic Stimulation
Abstract: Enriched environment (EE) protects the retina from adult rats against ischemia/reperfusion (I/R) injury; however, how the components of EE contribute to the recovery after retinal ischemic damage remains unclear. We analyzed the contribution of social, cognitive, and visual stimulation on functional and histological alterations induced by I/R. Male Wistar rats were submitted to unilateral ischemia by increasing intraocular pressure to 120 mmHg for 40 min. After ischemia, animals were housed in the following conditions: standard environment (SE), enriched environment (EE), novelty environment (NE), standard social environment (SoE), standard visual environment (SVE), or visual environment (VE). In another set of experiments, rats were submitted to bilateral ischemia and housed in SE or EE. At 2 weeks post-ischemia, rats were subjected to electroretinography and histological analysis. EE (but not SoE or NE) afforded functional and histological protection against unilateral ischemia. EE did not induce protection in animals submitted to bilateral ischemia. VE protected retinal function and histology and increased retinal BDNF levels, while a TrkB receptor antagonist prevented the protective effect of VE against I/R damage. In animals submitted to unilateral ischemia, EE and VE induced an increase in c-fos immunoreactivity in the ipsi and contralateral superior colliculus, whereas in animals submitted to bilateral ischemia, no changes in c-fos-immunoreactivity were observed in either superior colliculus from EE-housed animals. These results support that visual stimulation could be a potent stimulus for driving retinal protection in adult rats through a BDNF/TrkB-dependent mechanism, likely involving the superior colliculus. Fil: González Fleitas, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Aranda, Marcos Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dieguez, Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Milne, Georgia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Langellotti, Leonel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Miranda, Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Altschuler, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2019

17. Oxidative stress damage circumscribed to the central temporal retinal pigment epithelium in early experimental non-exudative age-related macular degeneration

Author: Marcos L. Aranda, Ruth E. Rosenstein, Agustina Alaimo, María Florencia González Fleitas, Hernán H. Dieguez, Damián Dorfman, and Horacio Eduardo Romeo
Subjects: 0301 basic medicine, Male, Pathology, ESTRES OXIDATIVO, Time Factors, genetic structures, Gene Expression, Retinal Pigment Epithelium, Mitochondrion, medicine.disease_cause, NON-EXUDATIVE AGE-RELATED MACULAR DEGENERATION, Biochemistry, Melanin, Macular Degeneration, Mice, 0302 clinical medicine, MITOCHONDRIA, OXIDATIVE STRESS, chemistry.chemical_classification, ENVEJECIMIENTO, ANTIOXIDANT SYSTEM, ANTIOXIDANTES, Medicina Química, purl.org/becyt/ford/3.1 [https], Ganglionectomy, Mitochondria, Medicina Básica, medicine.anatomical_structure, RETINAL PIGMENT EPITHELIUM, purl.org/becyt/ford/3 [https], medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, GANGLIOS, NF-E2-Related Factor 2, Superior Cervical Ganglion, Biology, 03 medical and health sciences, Physiology (medical), medicine, Animals, Humans, CEGUERA, Reactive oxygen species, Retina, Retinal pigment epithelium, DEGENERACION MACULAR, SUPERIOR CERVICAL GANGLION, Membrane Proteins, Macular degeneration, medicine.disease, eye diseases, Mice, Inbred C57BL, Disease Models, Animal, Oxidative Stress, 030104 developmental biology, chemistry, MITOCONDRIA, Choroid, Lipid Peroxidation, sense organs, Reactive Oxygen Species, 030217 neurology & neurosurgery, Oxidative stress, Heme Oxygenase-1
Abstract: Fil: Dieguez, Hernán H. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Laboratorio de Neuroquímica Retinal y Oftamología Experimental; Argentina Fil: Dieguez, Hernán H. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Romeo, Horacio. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Romeo, Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Alaimo, Agustina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Laboratorio Interdisciplinario de Dinámica Celular y Nanoherramientas; Argentina Fil: Alaimo, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: González Fleitas, María F. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Laboratorio de Neuroquímica Retinal y Oftamología Experimental; Argentina Fil: González Fleitas, María F. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Aranda, Marcos L. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Laboratorio de Neuroquímica Retinal y Oftamología Experimental; Argentina Fil: Aranda, Marcos L. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth E. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Laboratorio de Neuroquímica Retinal y Oftamología Experimental; Argentina Fil: Rosenstein, Ruth E. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana. Laboratorio de Neuroquímica Retinal y Oftamología Experimental; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Estudios Farmacológicos y Botánicos; Argentina Abstract: Non-exudative age-related macular degeneration (NE-AMD) represents the leading cause of blindness in the elderly. The macular retinal pigment epithelium (RPE) lies in a high oxidative environment because its high metabolic demand, mitochondria concentration, reactive oxygen species levels, and macular blood flow. It has been suggested that oxidative stress-induced damage to the RPE plays a key role in NE-AMD pathogenesis. The fact that the disease limits to the macular region raises the question as to why this area is particularly susceptible. We have developed a NE-AMD model induced by superior cervical ganglionectomy (SCGx) in C57BL/6J mice, which reproduces the disease hallmarks exclusively circumscribed to the temporal region of the RPE/outer retina. The aim of this work was analyzing RPE regional differences that could explain AMD localized susceptibility. Lower melanin content, thicker basal infoldings, higher mitochondrial mass, and higher levels of antioxidant enzymes, were found in the temporal RPE compared with the nasal region. Moreover, SCGx induced a decrease in the antioxidant system, and in mitochondria mass, as well as an increase in mitochondria superoxide, lipid peroxidation products, nuclear Nrf2 and heme oxygenase-1 levels, and in the occurrence of damaged mitochondria exclusively at the temporal RPE. These findings suggest that despite the well-known differences between the human and mouse retina, it might not be NE-AMD pathophysiology which conditions the localization of the disease, but the macular RPE histologic and metabolic specific attributes that make it more susceptible to choroid alterations leading initially to a localized RPE dysfunction/damage, and secondarily to macular degeneration.
Published: 2019

18. Chronobiotic effect of melatonin in experimental optic neuritis

Author: Florencia Altschuler, Juan Salvador Calanni, Omar Narvaez, Damián Dorfman, María Florencia González Fleitas, Pablo H. Sande, Ruth E. Rosenstein, Luis Concha, and Marcos L. Aranda
Subjects: Male, 0301 basic medicine, Melanopsin, medicine.medical_specialty, Optic Neuritis, genetic structures, Chronobiotic, Antioxidants, Melatonin, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Internal medicine, medicine, Animals, Pupillary light reflex, Circadian rhythm, Rats, Wistar, Chronobiology Phenomena, Drug Implants, Pharmacology, Retina, Chemistry, Rod Opsins, eye diseases, Circadian Rhythm, Rats, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Retinal ganglion cell, Optic nerve, sense organs, Locomotion, 030217 neurology & neurosurgery, medicine.drug
Abstract: Optic neuritis (ON) is an inflammatory condition of the optic nerve, which leads to retinal ganglion cell (RGC) loss. A subset of RGCs expressing the photopigment melanopsin regulates non-image-forming visual system (NIFVS) functions such as pupillary light reflex (PLR) and circadian rhythms. Melatonin is a chronobiotic agent able to regulate the circadian system. We analyzed the effect of ON on the NIFVS, and the effect of melatonin on the NIFVS alterations induced by ON. For this purpose, optic nerves from male Wistar rats received vehicle or bacterial lipopolysaccharide (LPS), and one group of animals received a subcutaneous pellet of melatonin or a sham procedure. The NIFVS was analyzed in terms of: i) blue light-evoked PLR, ii) the communication between the retina and the suprachiasmatic nuclei (by anterograde transport, and ex vivo magnetic resonance images), iii) locomotor activity rhythm, and iv) Brn3a(+) and melanopsin(+) RGC number (by immunohistochemistry). Experimental ON significantly decreased the blue light-evoked PLR, induced a misconnection between the retina and the suprachiasmatic nuclei, decreased Brn3a(+) RGCs, but not melanopsin(+) RGC number. A bilateral injection of LPS significantly increased the light (but not dark) phase locomotor activity, rhythm periodicity, and time of offset activity. Melatonin prevented the decrease in blue light-evoked PLR, and locomotor activity rhythm alterations induced by ON. These results support that ON provoked alterations of the circadian physiology, and that melatonin could restore the circadian system misalignment.
Published: 2021
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19. Critical Role of Monocyte Recruitment in Optic Nerve Damage Induced by Experimental Optic Neuritis

Author: Marcos L. Aranda, Pablo H. Sande, María Florencia González Fleitas, Ruth E. Rosenstein, Monica Chianelli, Hernán H. Dieguez, Gonzalo Piñero, Damián Dorfman, María I. Keller Sarmiento, Florencia Altschuler, and Diego Guerrieri
Subjects: 0301 basic medicine, Lipopolysaccharides, Male, medicine.medical_specialty, Chemokine, BLOOD-BRAIN BARRIER, CIENCIAS MÉDICAS Y DE LA SALUD, Indazoles, Optic Neuritis, Neurociencias, Neuroscience (miscellaneous), Monocytes, Permeability, NEUROINFLAMMATION, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Animals, Optic neuritis, Rats, Wistar, Neuroinflammation, Chemokine CCL2, Evans Blue, OPTIC NERVE, Microglia, biology, Monocyte, Optic Nerve, medicine.disease, Recombinant Proteins, Medicina Básica, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Neurology, chemistry, Retinal ganglion cell, MONOCYTES, Blood-Brain Barrier, Tissue Plasminogen Activator, Optic nerve, biology.protein, Propionates, 030217 neurology & neurosurgery, CCL2
Abstract: Neuroinflammatory diseases are characterized by blood-brain barrier disruption (BBB) and leukocyte infiltration. We investigated the involvement of monocyte recruitment in visual pathway damage provoked by primary optic neuritis (ON) induced by a microinjection of bacterial lipopolysaccharide (LPS) into the optic nerve from male Wistar rats. Increased Evans blue extravasation and cellularity were observed at 6 h post-LPS injection. In WT-GFPþ/WT chimeric rat optic nerves, the presence of GFP(+) neutrophils and GFP(+) monocytes, and in wild-type rat optic nerves, an increase in CD11b+CD45low and CD11b+CD45high cell number, were observed at 24 h post-LPS. Gamma-irradiation did not affect the increase in BBB permeability, but significantly lessened the decrease in pupil light reflex (PLR), and retinal ganglion cell (RGC) number induced by LPS. At 6 h post-LPS, an increase in chemokine (C-C motif) ligand 2 (CCL2) immunoreactivity co-localized with neutrophils (but not microglia/macrophages or astrocytes) was observed, while at 24 h post-injection, an increase in Iba-1-immunoreactivity and its co-localization with CCL2 became evident. The co-injection of LPS with bindarit (a CCL2 synthesis inhibitor) lessened the effect of LPS on PLR, and RGC loss. The treatment with etoposide or gadolinium chloride that significantly decreased peripheral monocyte (but not neutrophil or lymphocyte) percentage decreased the effect of LPS on PLR, and RGC number. Moreover, a negative correlation between PRL and monocyte (but not lymphocyte or neutrophil) percentage was observed at 7 days post-LPS. Taken together, these results support that monocytes are key players in the initial events that take place during primary ON. Fil: Aranda, Marcos Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Guerrieri, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Piñero, Gonzalo Miguel. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: González Fleitas, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Altschuler, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dieguez, Hernán. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Keller Sarmiento, María Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Chianelli, Mónica Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Sande Casal, Pablo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2018

20. Superior cervical gangliectomy induces non-exudative age-related macular degeneration in mice

Author: María Florencia González Fleitas, Ruth E. Rosenstein, Horacio Eduardo Romeo, Hernán Dieguez, Marcos L. Aranda, Georgia A. Milne, and Damián Dorfman
Subjects: 0301 basic medicine, Photoreceptors, Male, Superior cervical ganglion, genetic structures, Medicine (miscellaneous), lcsh:Medicine, CHOROID, Retinal Pigment Epithelium, Macular Degeneration, 0302 clinical medicine, Immunology and Microbiology (miscellaneous), RETINA, PHOTORECEPTORS, AGE-RELATED MACULAR DEGENERATION, purl.org/becyt/ford/3.1 [https], Medicina Básica, medicine.anatomical_structure, RETINAL PIGMENT EPITHELIUM, purl.org/becyt/ford/3 [https], lcsh:RB1-214, Research Article, Photoreceptor Cells, Vertebrate, cis-trans-Isomerases, medicine.medical_specialty, GANGLIOS, CIENCIAS MÉDICAS Y DE LA SALUD, Neurociencias, Neuroscience (miscellaneous), General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Ophthalmology, medicine, lcsh:Pathology, Animals, Experimental model, Melanins, Retina, Retinal pigment epithelium, DEGENERACION MACULAR, business.industry, Choroid, Age-related macular degeneration, lcsh:R, EXPERIMENTAL MODEL, SUPERIOR CERVICAL GANGLION, Exudative age-related macular degeneration, eye diseases, Mice, Inbred C57BL, 030104 developmental biology, 030221 ophthalmology & optometry, Bruch Membrane, sense organs, business
Abstract: Non-exudative age-related macular degeneration, a prevalent cause of blindness, is a progressive and degenerative disease characterized by alterations in Bruch's membrane, retinal pigment epithelium, and photoreceptors exclusively localized in the macula. Although experimental murine models exist, the vast majority take a long time to develop retinal alterations and, in general, these alterations are ubiquitous, with many resulting from non-eye-specific genetic manipulations; additionally, most do not always reproduce the hallmarks of human age-related macular degeneration. Choroid vessels receive sympathetic innervation from the superior cervical ganglion, which, together with the parasympathetic system, regulates blood flow into the choroid. Choroid blood flow changes have been involved in age-related macular degeneration development and progression. At present, no experimental models take this factor into account. The aim of this work was to analyze the effect of superior cervical gangliectomy (also known as ganglionectomy) on the choroid, Bruch's membrane, retinal pigment epithelium and retina. Adult male C57BL/6J mice underwent unilateral superior cervical gangliectomy and a contralateral sham procedure. Although superior cervical gangliectomy induced ubiquitous choroid and choriocapillaris changes, it induced Bruch's membrane thickening, loss of retinal pigment epithelium melanin content and retinoid isomerohydrolase, the appearance of drusen-like deposits, and retinal pigment epithelium and photoreceptor atrophy, exclusively localized in the temporal side. Moreover, superior cervical gangliectomy provoked a localized increase in retinal pigment epithelium and photoreceptor apoptosis, and a decline in photoreceptor electroretinographic function. Therefore, superior cervical gangliectomy recapitulated the main features of human non-exudative age-related macular degeneration, and could become a new experimental model of dry age-related macular degeneration, and a useful platform for developing new therapies., Summary: Ubiquitous alteration of choroid circulation causes localized retinal alterations in mice that are similar to human non-exudative age-related macular degeneration, thus providing a new potential experimental model of the disease.
Published: 2018

21. Melatonin as a Therapeutic Resource for Inflammatory Visual Diseases

Author: Ruth E. Rosenstein, Hernán Dieguez, Damián Dorfman, Agustina Iaquinandi, Pablo H. Sande, María Florencia González Fleitas, and Marcos L. Aranda
Subjects: 0301 basic medicine, nitrosative damage, CIENCIAS MÉDICAS Y DE LA SALUD, genetic structures, Inmunología, oxidative damage, Article, Melatonin, Oxidative damage, Uveitis, 03 medical and health sciences, ocular inflammation, 0302 clinical medicine, Animals, Humans, Medicine, Pharmacology (medical), Optic neuritis, Ocular inflammation, Pharmacology, optic neuritis, business.industry, Anti-Inflammatory Agents, Non-Steroidal, General Medicine, medicine.disease, eye diseases, Psychiatry and Mental health, Medicina Básica, 030104 developmental biology, Neurology, Immunology, sense organs, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Background: Uveitis and optic neuritis are prevalent ocular inflammatory diseases, and highly damaging ocular conditions. Both diseases are currently treated with corticosteroids, but they do not have adequate efficacy and are often associated with severe side effects. Thus, uveitis and optic neuritis remain a challenging field to ophthalmologists and a significant public health concern. Objective: This review summarizes findings showing the benefits of a treatment with melatonin in experimental models of these inflammatory ocular diseases. Results: Oxidative and nitrosative damage, tumor necrosis factor, and prostaglandin production have been involved in the pathogeny of uveitis and optic neuritis. Melatonin is an efficient antioxidant and antinitridergic, and has the ability to reduce prostaglandin and tumor necrosis factor levels both in the retina and optic nerve. Moreover, melatonin not only prevents functional and structural consequences of experimental uveitis and optic neuritis, but it is also capable of suppressing the actively ongoing ocular inflammatory response. Conclusions: Since melatonin protects ocular tissues against inflammation, it could be a potentially useful anti-inflammatory therapy in ophthalmology. Fil: Aranda, Marcos Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: González Fleitas, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dieguez, Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Iaquinandi, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Sande Casal, Pablo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2017

22. Maternal administration of melatonin exerts short- and long-term neuroprotective effects on the offspring from lipopolysaccharide-treated mice

Author: Fernando Correa, Ruth E. Rosenstein, Ana Maria Franchi, Ana Paula Domínguez Rubio, María Aurelia Zorrilla Zubilete, Damián Dorfman, Julieta Aisemberg, and Maria Victoria Bariani
Subjects: 0301 basic medicine, Lipopolysaccharides, medicine.medical_specialty, MELATONIN, CIENCIAS MÉDICAS Y DE LA SALUD, Offspring, FETAL BRAIN, Brain damage, LIPOPOLYSACCHARIDE, Obstetricia y Ginecología, Medicina Clínica, Neuroprotection, NEUROINFLAMMATION, Melatonin, 03 medical and health sciences, Mice, 0302 clinical medicine, Endocrinology, Obstetric Labor, Premature, Pregnancy, Internal medicine, Birth Injuries, medicine, Histone acetyltransferase activity, Animals, Inflammation, Fetus, Mice, Inbred BALB C, biology, business.industry, medicine.disease, EPIGENETICS, Nitric oxide synthase, 030104 developmental biology, Neuroprotective Agents, Brain Injuries, biology.protein, Premature Birth, Female, medicine.symptom, OFFSPRING, business, 030217 neurology & neurosurgery, BEHAVIOR, medicine.drug
Abstract: Preterm birth is a major contributor to early and delayed physical and cognitive impairment. Epidemiological and experimental data indicate that maternal infections are a significant and preventable cause of preterm birth. Recently, melatonin has been suggested to exert neuroprotective effects in several models of brain injury. Here, we sought to investigate whether the administration of melatonin is able to prevent lipopolysaccharide (LPS)-induced fetal brain damage in a model of LPS-induced preterm labor. For this purpose, 15-day pregnant BALB/c mice received intraperitoneally 2 doses of LPS or vehicle: the first one at 10:00 hours (0.26 mg/kg) and the second at 13:00 hours (0.52 mg/kg). On day 14 of pregnancy, a group of mice was subcutaneously implanted with a pellet of 25 mg melatonin. This experimental protocol resulted in 100% of preterm birth and pup death in the LPS group and a 50% of term birth and pup survival in the melatonin + LPS group. In the absence of melatonin, fetuses from LPS-treated mothers showed histological signs of brain damage, microglial/macrophage activation, and higher levels of IL-1β, inducible nitric oxide synthase (NOS), and neuronal NOS mRNAs as well as increased histone acetyltransferase activity and histone H3 hyperacetylation. In contrast, antenatal administration of melatonin prevented LPS-induced fetal brain damage. Moreover, when behavioral traits were analyzed in the offspring from control, melatonin, and melatonin + LPS, no significant differences were found, suggesting that melatonin prevented LPS-induced long-term neurodevelopmental impairments. Collectively, our results suggest that melatonin could be a new therapeutic tool to prevent fetal brain damage and its long-term consequences induced by maternal inflammation. Fil: Domínguez Rubio, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Correa, Fernando Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Aisemberg, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Bariani, Maria Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Zorrilla Zubilete, María Aurelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Franchi, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2017

23. Treatment with melatonin after onset of experimental uveitis attenuates ocular inflammation

Author: A.P. Domínguez Rubio, Dafne Magalí Silberman, Daniel A. Sáenz, Pablo H. Sande, Ana Maria Franchi, Damián Dorfman, Monica Chianelli, Diego C. Fernandez, and Ruth E. Rosenstein
Subjects: Pharmacology, medicine.medical_specialty, medicine.diagnostic_test, biology, Aqueous humour, business.industry, Hamster, Retinal, medicine.disease, biology.organism_classification, eye diseases, Melatonin, chemistry.chemical_compound, Endocrinology, chemistry, Internal medicine, medicine, Tumor necrosis factor alpha, business, Uveitis, Mesocricetus, Electroretinography, medicine.drug
Abstract: Background and Purpose Uveitis is a prevalent intraocular inflammatory disease and one of the most damaging ocular conditions. Pretreatment with melatonin prevented ocular inflammation induced by an intravitreal injection of bacterial LPS in the Syrian hamster. Here, we have assessed the anti-inflammatory effects of melatonin administered after the onset of ocular inflammation. Experimental Approach The eyes of male Syrian hamsters were intravitreally injected with vehicle or LPS. Melatonin was injected i.p. every 24 h, starting 12 or 24 h after the LPS injection. A clinical evaluation (with a score index based on clinical symptoms), the number of infiltrating cells, protein concentration and PGE2 and PGF2α levels in the aqueous humour, as well as retinal NOS activity, lipid peroxidation and TNF-α levels were assessed. Retinal function was assessed by scotopic electroretinography, and light microscopy and immunohistochemistry were used to evaluate the state of the retinal structure. Key Results Both treatment regimens with melatonin decreased clinical symptoms, reduced the leakage of cells and proteins, and decreased PG levels in aqueous humour from eyes injected with LPS. In addition, melatonin treatment blocked the decrease in scotopic electroretinogram a- and b-wave amplitude, protected the retinal structure and reduced the increase in NOS activity, lipid peroxidation and TNF-α levels, induced by LPS. Conclusions and Implications These results indicate that treatment with melatonin, starting after the onset of uveitis, attenuated ocular inflammation induced by LPS in the Syrian hamster and support the use of melatonin as a therapeutic resource for uveitis treatment.
Published: 2014
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24. Post-ischemic environmental enrichment protects the retina from ischemic damage in adult rats

Author: Diego C. Fernandez, Monica Chianelli, Ruth E. Rosenstein, Marcos L. Aranda, Magdalena Miranda, and Damián Dorfman
Subjects: Male, retina, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Neurociencias, Ischemia, Environment, Retina, chemistry.chemical_compound, Retinal Diseases, Developmental Neuroscience, Internal medicine, Electroretinography, Animals, adult rat, Medicine, Rats, Wistar, Environmental enrichment, Glial fibrillary acidic protein, biology, medicine.diagnostic_test, business.industry, Glutamate receptor, Retinal, Anatomy, medicine.disease, Rats, Disease Models, Animal, Medicina Básica, Endocrinology, medicine.anatomical_structure, Neurology, chemistry, Reperfusion Injury, ischemic damage, biology.protein, business, Reperfusion injury, enviormental enrichment
Abstract: The aim of this study was to elucidate whether post-ischemic enriched environment (EE) housing protects the retina from ischemic damage in adult rats, and the involvement of glutamate in retinal protection induced by EE housing. For this purpose, ischemia was induced by increasing intraocular pressure to 120 mm Hg for 40 min. After ischemia, animals were housed in a standard environment (SE) or EE and subjected to electroretinography and histological analysis. EE housing afforded significant functional protection in eyes exposed to ischemia/reperfusion injury. A marked reduction in retinal thickness and ganglion cell number, and an increase in Müller cell glial fibrillary acidic protein (GFAP) levels were observed in ischemic retinas from SE-housed animals, which were reversed by EE housing. A deficit in anterograde transport from the retina to the superior colliculus was observed in SE- but not in EE-housed animals. In SE-housed animals, ischemia induced a significant decrease in retinal glutamate uptake and glutamine synthetase activity, whereas EE housing reversed the effect of ischemia on these parameters. The intravitreal injection of supraphysiological levels of glutamate partially reproduced retinal alterations induced by ischemia/reperfusion, which were abrogated by EE housing. These results indicate that EE housing significantly protected retinal function and histology from ischemia/reperfusion injury in adult rats, likely through a glutamate-dependent mechanism. Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Fernandez, Diego Carlos. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Chianelli, Monica Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Miranda, Magdalena. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Aranda, Marcos L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Rosenstein, Ruth Estela. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2013
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25. Neuroprotective effect of melatonin in experimental optic neuritis in rats

Author: Marcos L. Aranda, Monica Chianelli, Damián Dorfman, Andrea De Laurentiis, Ruth E. Rosenstein, María Florencia González Fleitas, María I. Keller Sarmiento, and Pablo H. Sande
Subjects: 0301 basic medicine, Lipopolysaccharides, Male, medicine.medical_specialty, Optic Neuritis, genetic structures, Nitric Oxide Synthase Type II, Neuroprotection, Luxol fast blue stain, Melatonin, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, Animals, Optic neuritis, Rats, Wistar, Retina, biology, business.industry, Tumor Necrosis Factor-alpha, Nitric oxide synthase 2, medicine.disease, Rats, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Neuroprotective Agents, Retinal ganglion cell, Cyclooxygenase 2, Optic nerve, biology.protein, Lipid Peroxidation, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Optic neuritis (ON) is an inflammatory, demyelinating, and neurodegenerative condition of the optic nerve, which might induce permanent vision loss. Currently, there are no effective therapies for this disorder. We have developed an experimental model of primary ON in rats through a single microinjection of 4.5 μg of bacterial lipopolysaccharide (LPS) into the optic nerve. Since melatonin acts as a pleiotropic therapeutic agent in various neurodegenerative diseases, we analyzed the effect of melatonin on LPS-induced ON. For this purpose, LPS or vehicle were injected into the optic nerve from adult male Wistar rats. One group of animals received a subcutaneous pellet of 20 mg melatonin at 24 hr before vehicle or LPS injection, and another group was submitted to a sham procedure. Melatonin completely prevented the decrease in visual evoked potentials (VEPs), and pupil light reflex (PLR), and preserved anterograde transport of cholera toxin β-subunit from the retina to the superior colliculus. Moreover, melatonin prevented microglial reactivity (ED1-immunoreactivity, P < 0.01), astrocytosis (glial fibrillary acid protein-immunostaining, P < 0.05), demyelination (luxol fast blue staining, P < 0.01), and axon (toluidine blue staining, P < 0.01) and retinal ganglion cell (Brn3a-immunoreactivity, P < 0.01) loss, induced by LPS. Melatonin completely prevented the increase in nitric oxide synthase 2, cyclooxygenase-2 levels (Western blot) and TNFα levels, and partly prevented lipid peroxidation induced by experimental ON. When the pellet of melatonin was implanted at 4 days postinjection of LPS, it completely reversed the decrease in VEPs and PLR. These data suggest that melatonin could be a promising candidate for ON treatment.
Published: 2016

26. Therapeutic efficacy of melatonin in reducing retinal damage in an experimental model of early type 2 diabetes in rats

Author: Ezequiel M. Salido, Monica Chianelli, Damián Dorfman, María I. Keller Sarmiento, Melina Paula Bordone, Andrea De Laurentiis, and Ruth E. Rosenstein
Subjects: Male, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, endocrine system diseases, Neurociencias, melatonin, Type 2 diabetes, Melatonin, chemistry.chemical_compound, Endocrinology, Diabetes mellitus, Internal medicine, Electroretinography, Animals, Medicine, Rats, Wistar, Diabetic Retinopathy, diabetes, Tumor Necrosis Factor-alpha, business.industry, Type 2 Diabetes Mellitus, Retinal, Diabetic retinopathy, Catalase, Thiobarbiturates, medicine.disease, Streptozotocin, Immunohistochemistry, Rats, rats, Medicina Básica, Glucose, Postprandial, Diabetes Mellitus, Type 2, chemistry, business, medicine.drug
Abstract: Diabetic retinopathy (DR) is a leading cause of acquired blindness in adults, mostly affected by type 2 diabetes mellitus (T2DM). We have developed an experimental model of early T2DM in adult rats which mimics some features of human T2DM at its initial stages and provokes significant retinal alterations. The aim of this work was to analyze the effect of melatonin on retinal changes induced by the moderate metabolic derangement. For this purpose, adult male Wistar rats received a control diet or 30% sucrose in the drinking water. Three weeks after this treatment, animals were injected with vehicle or streptozotocin (STZ, 25 mg/kg). One day or 3 wk after vehicle or STZ injection, animals were subcutaneously implanted with a pellet of melatonin. Fasting and postprandial glycemia, and glucose, and insulin tolerance tests were analyzed. At 12 wk of treatment, animals which received a sucrose-enriched diet and STZ showed significant differences in metabolic tests, as compared with control groups. Melatonin, which did not affect glucose metabolism in control or diabetic rats, prevented the decrease in the electroretinogram a-wave, b-wave, and oscillatory potential amplitude, and the increase in retinal lipid peroxidation, NOS activity, TNFα, Müller cells glial fibrillary acidic protein, and vascular endothelial growth factor levels. In addition, melatonin prevented the decrease in retinal catalase activity. These results indicate that melatonin protected the retina from the alterations observed in an experimental model of DR associated with type 2 diabetes. Fil: Salido, Ezequiel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Bordone, Melina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: de Laurentiis, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Chianelli, Monica Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Keller Sarmiento, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina
Published: 2012
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27. Early Distal Axonopathy of the Visual Pathway in Experimental Diabetes

Author: Ruth E. Rosenstein, Diego C. Fernandez, Damián Dorfman, Laura A. Pasquini, and Hernán J. Aldana Marcos
Subjects: Male, Retinal Ganglion Cells, Cholera Toxin, Pathology, medicine.medical_specialty, genetic structures, Cell Count, Diabetes Mellitus, Experimental, Pathology and Forensic Medicine, Myelin, Diabetic Neuropathies, medicine, Animals, Visual Pathways, Rats, Wistar, Coloring Agents, Retina, Diabetic Retinopathy, business.industry, Superior colliculus, Regular Article, Anatomy, Diabetic retinopathy, medicine.disease, Streptozotocin, Axons, Rats, Microscopy, Electron, medicine.anatomical_structure, Retinal ganglion cell, Optic nerve, business, Retinopathy, medicine.drug
Abstract: Diabetic retinopathy is a leading cause of acquired blindness. Visual function disorders have been observed in diabetic patients with very early retinopathy or even before the onset of retinopathy. The aim of the present work was to analyze the visual pathway in an early stage of experimental diabetes. Diabetes was induced in Wistar rats by an i.p. injection of streptozotocin. A deficit in anterograde transport from the retina to the superior colliculus was observed 6 weeks after streptozotocin injection. At this time point, morphologic studies did not reveal retinal ganglion cell loss or substantial alterations in the superior colliculus. The optic nerve was morphometrically evaluated at intraorbital (unmyelinated and myelinated) and intracranial sections. In animals that had been diabetic for 6 weeks, a large increase in astrocyte reactivity occurred in the distal (but not the intraorbital) portion, which coincided with significant axon loss. Moreover, profound myelin alterations and altered morphologic features of oligodendrocyte lineage were observed at the distal (but not the proximal) optic nerve portion. The present results suggest that axoglial alterations at the distal portion of the optic nerve could be the first structural change in the diabetic visual pathway.
Published: 2012
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28. EARLY HISTOLOGIC AND FUNCTIONAL STUDY OF RADIAL OPTIC NEUROTOMY OUTCOMES IN NORMAL RAT EYES

Author: Nicolás Belforte, J. Oscar Croxatto, Pablo H. Sande, Ruth E. Rosenstein, and Damián Dorfman
Subjects: Male, medicine.medical_specialty, Intraocular pressure, CIENCIAS MÉDICAS Y DE LA SALUD, Optic nerve, Photic Stimulation, Optic Disk, Ophthalmologic Surgical Procedures, Reflex, Pupillary, Retina, Ophthalmology, Visual evoked potentials, Radial optic neurotomy, Electroretinography, Animals, Medicine, Pupillary light reflex, Visual Pathways, Rats, Wistar, Intraocular Pressure, medicine.diagnostic_test, business.industry, Optic Nerve, General Medicine, Electroretinogram, Decompression, Surgical, Otras Ciencias Médicas, Rats, Reflex, Rat, Evoked Potentials, Visual, business, Ophthalmologic Surgical Procedure
Abstract: BACKGROUND: Radial optic neurotomy (RON) has been proposed as a treatment for central retinal vein occlusion. However, it is still under debate whether RON would be an adequate treatment or a dangerous procedure, and persuasive animal studies are lacking. The aim of this study was to analyze the early histologic and functional outcomes of RON in normal rat eyes. METHODS: Radial optic neurotomy was performed by cutting into the optic nerve edge at the nasal hemisphere, while the contralateral eye underwent a sham procedure. The retinal function was assessed by scotopic electroretinography, and the visual pathway was assessed by flash visual evoked potentials. Intraocular pressure was assessed with a tonometer, the pupillary light reflex was measured after exposing eyes to a 30-second light flash, whereas the optic nerve head structure was examined by histologic analysis. RESULTS: In normal rat eyes, RON provoked minor histologic alterations at the optic nerve head level and a transient decrease in the electroretinography. No changes in visual evoked potentials, intraocular pressure, and pupillary light reflex were observed in rat eyes submitted to RON. CONCLUSION: To our knowledge, this is the first study describing the early histopathologic and functional consequences of RON in normal rat eyes. Fil: Belforte, Nicolás Adalberto. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Sande Casal, Pablo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Dorfman, Damián. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Croxatto, Juan Oscar. Fundación Oftalmología Argentina "J. Malbrán"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina
Published: 2011
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29. Effect of retinal ischemia on the non-image forming visual system

Author: Ruth E. Rosenstein, Damián Dorfman, Melina Paula Bordone, and María Florencia González Fleitas
Subjects: Melanopsin, Male, Retinal Ganglion Cells, medicine.medical_specialty, Cholera Toxin, CIENCIAS MÉDICAS Y DE LA SALUD, Time Factors, genetic structures, Light, Physiology, Movement, Neurociencias, Biology, Lateral geniculate nucleus, Retinal ganglion, Retina, chemistry.chemical_compound, Ischemia, Physiology (medical), Ophthalmology, medicine, Electroretinography, Animals, Pupillary light reflex, Rats, Wistar, Non-image forming visual system, Vision, Ocular, medicine.diagnostic_test, Intrinsically photosensitive retinal ganglion cells, Rod Opsins, Geniculate Bodies, Retinal, Anatomy, eye diseases, Circadian Rhythm, Rats, Medicina Básica, medicine.anatomical_structure, chemistry, Suprachiasmatic Nucleus, sense organs
Abstract: Retinal ischemic injury is an important cause of visual impairment. The loss of retinal ganglion cells (RGCs) is a key sign of retinal ischemic damage. A subset of RGCs expressing the photopigment melanopsin (mRGCs) regulates non-image-forming visual functions such as the pupillary light reflex (PLR), and circadian rhythms. We studied the effect of retinal ischemia on mRGCs and the non-image-forming visual system function. For this purpose, transient ischemia was induced by raising intraocular pressure to 120 mm Hg for 40 min followed by retinal reperfusion by restoring normal pressure. At 4 weeks post-treatment, animals were subjected to electroretinography and histological analysis. Ischemia induced a significant retinal dysfunction and histological alterations. At this time point, a significant decrease in the number of Brn3a(+) RGCs and in the anterograde transport from the retina to the superior colliculus and lateral geniculate nucleus was observed, whereas no differences in the number of mRGCs, melanopsin levels, and retinal projections to the suprachiasmatic nuclei and the olivary pretectal nucleus were detected. At low light intensity, a decrease in pupil constriction was observed in intact eyes contralateral to ischemic eyes, whereas at high light intensity, retinal ischemia did not affect the consensual PLR. Animals with ischemia in both eyes showed a conserved locomotor activity rhythm and a photoentrainment rate which did not differ from control animals. These results suggest that the non-image forming visual system was protected against retinal ischemic damage. Fil: González Fleitas, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquimica Retiniana y Oftalmolog.exp.; Argentina Fil: Bordone, Melina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquimica Retiniana y Oftalmolog.exp.; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquimica Retiniana y Oftalmolog.exp.; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquimica Retiniana y Oftalmolog.exp.; Argentina
Published: 2014

30. Experimental optic neuritis induced by the microinjection of lipopolysaccharide into the optic nerve

Author: Pablo H. Sande, Ruth E. Rosenstein, Damián Dorfman, and Marcos L. Aranda
Subjects: Lipopolysaccharides, Male, Pathology, medicine.medical_specialty, Cholera Toxin, CIENCIAS MÉDICAS Y DE LA SALUD, Optic Neuritis, genetic structures, Microinjections, visual evoked potentials, Neurociencias, Reflex, Pupillary, optic nerve, Luxol fast blue stain, Retina, pupil light reflex, Leukocyte Count, Developmental Neuroscience, medicine, Electroretinography, Animals, Optic neuritis, Axon, Rats, Wistar, Microinjection, optic neuritis, Chemistry, lipopolysaccharide, neurodegeneration, Optic Nerve, medicine.disease, eye diseases, Rats, Medicina Básica, Disease Models, Animal, medicine.anatomical_structure, Neurology, Retinal ganglion cell, inflammation, Axoplasmic transport, Optic nerve, Evoked Potentials, Visual, demyelination, sense organs, Neuroscience
Abstract: Optic neuritis (ON) is a condition involving primary inflammation, demyelination, and axonal injury in the optic nerve which leads to retinal ganglion cell (RGC) loss, and visual dysfunction. We investigated the ability of a single microinjection of bacterial lipopolysaccharide (LPS) directly into the optic nerve to induce functional and structural alterations compatible with ON. For this purpose, optic nerves from male Wistar rats remained intact or were injected with vehicle or LPS. The effect of LPS was evaluated at several time points post-injection in terms of: i) visual pathway and retinal function (visual evoked potentials (VEPs) and electroretinograms, (ERGs), respectively), ii) anterograde transport from the retina to its projection areas, iii) consensual pupil light reflex (PLR), iv) optic nerve histology, v) microglia/macrophage reactivity (by Iba-1- and ED1-immunostaining), vi) astrocyte reactivity (by glial fibrillary acid protein-immunostaining), vii) axon number (by toluidine blue staining), vii) demyelination (by myelin basic protein immunoreactivity and luxol fast blue staining), viii) optic nerve ultrastructure, and ix) RGC number (by Brn3a immunoreactivity). LPS induced a significant and persistent decrease in VEP amplitude and PLR, without changes in the ERG. In addition, LPS induced a deficit in anterograde transport, and an early inflammatory response consisting in an increased cellularity, and Iba-1 and ED1-immunoreactivity in the optic nerve, which were followed by changes in axonal density, astrocytosis, demyelination, and axon and RGC loss. These results suggest that the microinjection of LPS into the optic nerve may serve as a new experimental model of primary ON. Fil: Aranda, Marcos Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Sande, Pablo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina
Published: 2014

31. Environmental enrichment protects the retina from early diabetic damage in adult rats

Author: Marcos L. Aranda, Pablo H. Sande, Ruth E. Rosenstein, María Florencia González Fleitas, Monica Chianelli, Damián Dorfman, and Diego C. Fernandez
Subjects: Male, Vascular Endothelial Growth Factor A, Eye Diseases, Visual System, lcsh:Medicine, chemistry.chemical_compound, Blood-Retinal Barrier, Medicine and Health Sciences, lcsh:Science, Multidisciplinary, Glial fibrillary acidic protein, diabetes, purl.org/becyt/ford/3.1 [https], Housing, Animal, Sensory Systems, Vascular endothelial growth factor, Vascular endothelial growth factor A, diabetic retinopathy, Medicina Básica, medicine.anatomical_structure, Retinal Disorders, purl.org/becyt/ford/3 [https], Research Article, medicine.drug, Astrocyte, enriched environment, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Neurociencias, Synaptophysin, Blood–retinal barrier, Environment, Biology, Thiobarbituric Acid Reactive Substances, Cataract, Retina, Diabetes Mellitus, Experimental, Internal medicine, medicine, Animals, Rats, Wistar, Retinopathy, Diabetic Retinopathy, Tumor Necrosis Factor-alpha, Brain-Derived Neurotrophic Factor, lcsh:R, Biology and Life Sciences, Retinal, Streptozotocin, Ophthalmology, Endocrinology, chemistry, biology.protein, lcsh:Q, retinal disease, Neuroscience
Abstract: Diabetic retinopathy is a leading cause of reduced visual acuity and acquired blindness. Available treatments are not completely effective. We analyzed the effect of environmental enrichment on retinal damage induced by experimental diabetes in adult Wistar rats. Diabetes was induced by an intraperitoneal injection of streptozotocin. Three days after vehicle or streptozotocin injection, animals were housed in enriched environment or remained in a standard environment. Retinal function (electroretinogram, and oscillatory potentials), retinal morphology, blood-retinal barrier integrity, synaptophysin, astrocyte and Müller cell glial fibrillary acidic protein, vascular endothelial growth factor, tumor necrosis factor-α, and brain-derived neurotrophic factor levels, as well as lipid peroxidation were assessed in retina from diabetic animals housed in standard or enriched environment. Environmental enrichment preserved scotopic electroretinogram a-wave, b-wave and oscillatory potential amplitude, avoided albumin-Evan's blue leakage, prevented the decrease in retinal synaptophysin and astrocyte glial fibrillary acidic protein levels, the increase in Müller cell glial fibrillary acidic protein, vascular endothelial growth factor and tumor necrosis factor-α levels, as well as oxidative stress induced by diabetes. In addition, enriched environment prevented the decrease in retinal brain-derived neurotrophic factor levels induced by experimental diabetes. When environmental enrichment started 7 weeks after diabetes onset, retinal function was significantly preserved. These results indicate that enriched environment could attenuate the early diabetic damage in the retina from adult rats. Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Aranda, Marcos L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: González Fleitas, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Chianelli, Monica Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Fernandez, Diego Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Moron; Argentina Fil: Sande, Pablo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2014

32. Global and Ocular Hypothermic Preconditioning Protect the Rat Retina from Ischemic Damage

Author: Ruth E. Rosenstein, Melina Paula Bordone, Damián Dorfman, Monica Chianelli, Ezequiel M. Salido, and María Florencia González Fleitas
Subjects: Male, Retinal Ganglion Cells, Anatomy and Physiology, genetic structures, Visual System, lcsh:Medicine, Cell Count, Biochemistry, chemistry.chemical_compound, Hypothermia, Induced, Neurobiology of Disease and Regeneration, lcsh:Science, Multidisciplinary, medicine.diagnostic_test, Glutamate receptor, Neurochemistry, Sensory Systems, Cold Temperature, medicine.anatomical_structure, Retinal ganglion cell, Anesthesia, Reperfusion Injury, Intravitreal Injections, Medicine, Retinal Disorders, medicine.symptom, Research Article, medicine.medical_specialty, Ischemia, Glutamic Acid, Biology, Retinal Diseases, Ocular System, Glutamate-Ammonia Ligase, Ophthalmology, medicine, Electroretinography, Animals, Rats, Wistar, Retina, lcsh:R, Retinal, Biological Transport, Recovery of Function, Hypothermia, medicine.disease, eye diseases, Rats, chemistry, Cellular Neuroscience, lcsh:Q, sense organs, Reperfusion injury, Neuroscience
Abstract: Retinal ischemia could provoke blindness. At present, there is no effective treatment against retinal ischemic damage. Strong evidence supports that glutamate is implicated in retinal ischemic damage. We investigated whether a brief period of global or ocular hypothermia applied 24 h before ischemia (i.e. hypothermic preconditioning, HPC) protects the retina from ischemia/reperfusion damage, and the involvement of glutamate in the retinal protection induced by HPC. For this purpose, ischemia was induced by increasing intraocular pressure to 120 mm Hg for 40 min. One day before ischemia, animals were submitted to global or ocular hypothermia (33°C and 32°C for 20 min, respectively) and fourteen days after ischemia, animals were subjected to electroretinography and histological analysis. Global or ocular HPC afforded significant functional (electroretinographic) protection in eyes exposed to ischemia/reperfusion injury. A marked alteration of the retinal structure and a decrease in retinal ganglion cell number were observed in ischemic retinas, whereas global or ocular HPC significantly preserved retinal structure and ganglion cell count. Three days after ischemia, a significant decrease in retinal glutamate uptake and glutamine synthetase activity was observed, whereas ocular HPC prevented the effect of ischemia on these parameters. The intravitreal injection of supraphysiological levels of glutamate induced alterations in retinal function and histology which were significantly prevented by ocular HPC. These results support that global or ocular HPC significantly protected retinal function and histology from ischemia/reperfusion injury, probably through a glutamate-dependent mechanism.
Published: 2013

33. Effect of experimental diabetic retinopathy on the non-image-forming visual system

Author: Nuria de Zavalía, Nicolás Belforte, Ruth E. Rosenstein, Damián Dorfman, Pablo H. Sande, Diego A. Golombek, Leandro P. Casiraghi, and Diego C. Fernandez
Subjects: Melanopsin, Male, Retinal Ganglion Cells, medicine.medical_specialty, Cholera Toxin, CIENCIAS MÉDICAS Y DE LA SALUD, Physiology, Neurociencias, Biology, EXPERIMENTAL DIABETIC RETINOPATHY, Retinal ganglion, Diabetes Mellitus, Experimental, chemistry.chemical_compound, MELANOPSIN, Physiology (medical), Internal medicine, medicine, Electroretinography, Animals, Pupillary light reflex, Circadian rhythm, Rats, Wistar, PUPIL LIGHT REFLEX, Ocular Physiological Phenomena, RETINAL GANGLION CELLS, Diabetic Retinopathy, medicine.diagnostic_test, Intrinsically photosensitive retinal ganglion cells, Rod Opsins, Genes, fos, Retinal, Anatomy, Circadian Rhythm, Rats, Medicina Básica, Light intensity, Endocrinology, chemistry, Gene Expression Regulation, Evoked Potentials, Visual, sense organs
Abstract: Diabetic retinopathy is a leading cause of blindness. Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin, are involved in non-image-forming visual responses such as photoentrainment of circadian rhythms and pupillary light reflex. Since several reports indicate that retinal ganglion cells are affected by diabetes, we investigated the non-image-forming visual system in an advanced stage of experimental diabetes in rats induced by streptozotocin. After 15 wks of diabetes induction, clear alterations in the visual function were observed and all animals developed mature cataracts. At this time point, concomitantly with a significant decrease in the number of Brn3a(+) retinal ganglion cells, no differences in the number of melanopsin-containing cells, melanopsin levels, and retinal projections to the suprachiasmatic nuclei and the olivary pretectal nucleus were observed. At high light intensity, afferent pupil light reflex appears to be conserved in diabetic animals. After 15 wks of diabetes induction, a significant decrease in light-induced c-Fos expression in the suprachiasmatic nuclei was found. In diabetic animals, the locomotor activity pattern was conserved, although a delay in the time needed for re-entrainment after a phase delay was observed. In diabetic animals, lensectomy reversed the alterations in c-Fos expression and in the locomotor activity rhythm. These results suggest that the neuronal substrate of the non-image-forming visual system remained largely unaffected at advanced stages of diabetes, and that lensectomy, a relatively easy and safe surgery, could partially restore circadian alterations induced by diabetes. Fil: Fernandez, Diego Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Sande, Pablo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: de Zavalia, Nuria Maria Asuncion. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Belforte, Nicolás Adalberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina Fil: Casiraghi, Leandro Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina Fil: Golombek, Diego Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Cronobiología; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina
Published: 2013

34. Ischemic conditioning protects the rat retina in an experimental model of early type 2 diabetes

Author: Damián Dorfman, Ezequiel M. Salido, María I. Keller Sarmiento, Melina Paula Bordone, Monica Chianelli, Marcos L. Aranda, and Ruth E. Rosenstein
Subjects: Male, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, endocrine system diseases, Neurociencias, Ischemia, Diabetes Mellitus, Experimental, chemistry.chemical_compound, Developmental Neuroscience, Diabetes mellitus, Internal medicine, medicine, Animals, Humans, Rats, Wistar, RETINA, Ischemic Preconditioning, ISCHEMIC CONDITIONING, Retina, Diabetic Retinopathy, business.industry, EXPERIMENTAL MODEL OF EARLY TYPE 2 DIABETES, DIABETIC RETINOPATHY, Retinal, Diabetic retinopathy, medicine.disease, Streptozotocin, Rats, Vascular endothelial growth factor, Medicina Básica, Disease Models, Animal, Endocrinology, medicine.anatomical_structure, Postprandial, Neurology, chemistry, Diabetes Mellitus, Type 2, business, medicine.drug
Abstract: Diabetic retinopathy is a leading cause of acquired blindness in adults, mostly affected by type 2 diabetes mellitus (T2DM). We have developed an experimental model of early T2DM in adult rats which mimics some features of human T2DM at its initial stages, and provokes significant retinal alterations. We investigated the effect of ischemic conditioning on retinal changes induced by the moderate metabolic derangement. For this purpose, adult male Wistar rats received a control diet or 30% sucrose in the drinking water, and 3 weeks after this treatment, animals were injected with vehicle or streptozotocin (STZ, 25 mg/kg). Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 min; this maneuver started 3 weeks after vehicle or STZ injection and was weekly repeated in one eye, while control eyes were submitted to a sham procedure. Fasting and postprandial glycemia, and glucose, and insulin tolerance tests were analyzed. At 12 weeks of treatment, animals which received a sucrose-enriched diet and STZ showed significant differences in metabolic tests, as compared with control groups. Brief ischemia pulses in one eye and a sham procedure in the contralateral eye did not affect glucose metabolism in control or diabetic rats. Ischemic pulses reduced the decrease in the electroretinogram a-wave, b-wave, and oscillatory potential amplitude, and the increase in retinal lipid peroxidation, NOS activity, TNFα, Müller cells glial fibrillary acidic protein, and vascular endothelial growth factor levels observed in diabetic animals. In addition, ischemic conditioning prevented the decrease in retinal catalase activity induced by T2DM. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies to treat diabetic retinopathy associated with T2DM. Fil: Salido, Ezequiel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Dorfman, Damián. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Bordone, Melina Paula. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Chianelli, Monica Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Keller Sarmiento, Maria Ines. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Aranda, Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; Argentina Fil: Rosenstein, Ruth Estela. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2012

35. Ischemic conditioning protects from axoglial alterations of the optic pathway induced by experimental diabetes in rats

Author: Damián Dorfman, Ruth E. Rosenstein, Hernán J. Aldana Marcos, Diego C. Fernandez, and Laura A. Pasquini
Subjects: Blood Glucose, Male, Retinal Ganglion Cells, Time Factors, genetic structures, Visual System, lcsh:Medicine, Endocrinology, Neurobiology of Disease and Regeneration, Ischemic Preconditioning, lcsh:Science, Transcription Factor Brn-3A, Multidisciplinary, Diabetic retinopathy, Animal Models, Neurotransmitters, Sensory Systems, Oligodendroglia, medicine.anatomical_structure, Optic nerve, Medicine, Retinal Disorders, Retinopathy, medicine.drug, Research Article, medicine.medical_specialty, Superior Colliculi, Ischemia, Retina, Diabetes Mellitus, Experimental, Model Organisms, Glutamate-Ammonia Ligase, Internal medicine, medicine, Animals, Visual Pathways, Biology, Diabetic Endocrinology, Diabetic Retinopathy, business.industry, Body Weight, lcsh:R, Biological Transport, Optic Nerve, Diabetes Mellitus Type 1, medicine.disease, Streptozotocin, Oligodendrocyte, Axons, eye diseases, Surgery, Rats, Enzyme Activation, Ophthalmology, Cellular Neuroscience, Astrocytes, Ischemic preconditioning, Rat, lcsh:Q, business, Neuroscience
Abstract: Diabetic retinopathy is a leading cause of blindness. Visual function disorders have been demonstrated in diabetics even before the onset of retinopathy. At early stages of experimental diabetes, axoglial alterations occur at the distal portion of the optic nerve. Although ischemic conditioning can protect neurons and synaptic terminals against ischemic damage, there is no information on its ability to protect axons. We analyzed the effect of ischemic conditioning on the early axoglial alterations in the distal portion of the optic nerve induced by experimental diabetes. Diabetes was induced in Wistar rats by an intraperitoneal injection of streptozotocin. Retinal ischemia was induced by increasing intraocular pressure to 120 mm Hg for 5 min; this maneuver started 3 days after streptozotocin injection and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. The application of ischemia pulses prevented a deficit in the anterograde transport from the retina to the superior colliculus, as well as an increase in astrocyte reactivity, ultraestructural myelin alterations, and altered morphology of oligodendrocyte lineage in the optic nerve distal portion at early stages of experimental diabetes. Ischemia tolerance prevented a significant decrease of retinal glutamine synthetase activity induced by diabetes. These results suggest that early vision loss in diabetes could be abated by ischemic conditioning which preserved axonal function and structure.
Published: 2012

36. Effect of Angeli's salt on the glutamate/glutamine cycle activity and on glutamate excitotoxicity in the hamster retina

Author: Daniel A. Sáenz, Damián Dorfman, Monica Chianelli, and María Elena Knott
Subjects: Male, CIENCIAS MÉDICAS Y DE LA SALUD, Glutamine, Excitotoxicity, Glutamate-glutamine cycle, Glutamic Acid, Biology, medicine.disease_cause, NITROXYL, Retina, Cellular and Molecular Neuroscience, Glutamatergic, GLUTAMATE-GLUTAMINE CYCLE, Cricetinae, medicine, Animals, RETINA, Nitrites, Mesocricetus, Glutaminase, Otras Medicina Básica, Glutamate receptor, Cell Biology, Cell biology, Medicina Básica, Biochemistry, Metabotropic glutamate receptor, NMDA receptor, EXCITOTOXICITY, NITRIC OXIDE
Abstract: Glutamate is the main excitatory neurotransmitter in the retina, but it is toxic when present in excessive amounts. It is well known that NO is involved in glutamate excitotoxicity, but information regarding the possibility that NO-related species could reciprocally affect glutamate synaptic levels was not previously provided. The dependence of glutamatergic neurons upon glia via the glutamate/glutamine cycle to provide the precursor for neurotransmitter glutamate is well established. The aim of the present work was to comparatively analyze the effect of nitroxyl and NO on the retinal glutamate/glutamine cycle in vitro activity. For this purpose, Angeli's salt (AS) and diethylamine NONOate (DEA/NO) were used as nitroxyl and NO donor, respectively. AS and DEA/NO significantly decreased retinal l-glutamate uptake and glutamine synthetase activity, but only AS decreased l-glutamine influx. Dithiothreitol prevented all the effects of AS and DEA/NO. The intravitreal injection of DEA/NO (but not AS) or a supraphysiological concentration of glutamate induced retinal histological alterations. Although AS could increase glutamate synaptic concentration in vitro, the histological alterations induced by glutamate were abrogated by AS. These results suggest that nitroxyl could regulate the hamster retinal glutamatergic pathway by acting through differential mechanisms at pre- and postsynaptic level. Fil: Knott, María Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Chianelli, Mónica Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina Fil: Saenz, Daniel Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Published: 2011

37. Enriched Environment Protects the Optic Nerve from Early Diabetes-Induced Damage in Adult Rats

Author: Ruth E. Rosenstein, Damián Dorfman, and Marcos L. Aranda
Subjects: Male, Retinal Ganglion Cells, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Neurociencias, lcsh:Medicine, Environment, optic nerve, Diabetes Mellitus, Experimental, Myelin, Internal medicine, Glial Fibrillary Acidic Protein, medicine, Animals, Rats, Wistar, Axon, lcsh:Science, Retina, adult rats, Diabetic Retinopathy, Multidisciplinary, Glial fibrillary acidic protein, biology, Brain-Derived Neurotrophic Factor, lcsh:R, Calcium-Binding Proteins, Microfilament Proteins, Myelin Basic Protein, Optic Nerve, purl.org/becyt/ford/3.1 [https], Anatomy, Streptozotocin, Axons, Rats, Myelin basic protein, diabetic retinopathy, Medicina Básica, medicine.anatomical_structure, Endocrinology, Retinal ganglion cell, Astrocytes, biology.protein, Optic nerve, purl.org/becyt/ford/3 [https], lcsh:Q, enriched environment, Research Article, medicine.drug
Abstract: Diabetic retinopathy is a leading cause of reduced visual acuity and acquired blindness. Axoglial alterations of the distal (close to the chiasm) optic nerve (ON) could be the first structural change of the visual pathway in streptozotocin (STZ)-induced diabetes in rats. We analyzed the effect of environmental enrichment on axoglial alterations of the ON provoked by experimental diabetes. For this purpose, three days after vehicle or STZ injection, animals were housed in enriched environment (EE) or remained in a standard environment (SE) for 6 weeks. Anterograde transport, retinal morphology, optic nerve axons (toluidine blue staining and phosphorylated neurofilament heavy immunoreactivity), microglia/macrophages (ionized calcium binding adaptor molecule 1 (Iba-1) immunoreactivity), astrocyte reactivity (glial fibrillary acid protein-immunostaining), myelin (myelin basic protein immunoreactivity), ultrastructure, and brain derived neurotrophic factor (BDNF) levels were assessed in non-diabetic and diabetic animals housed in SE or EE. No differences in retinal morphology or retinal ganglion cell number were observed among groups. EE housing which did not affect the STZ-induced weight loss and hyperglycemia, prevented a decrease in the anterograde transport from the retina to the superior colliculus, ON axon number, and phosphorylated neurofilament heavy immunoreactivity. Moreover, EE housing prevented an increase in Iba-1 immunoreactivity, and astrocyte reactivity, as well as ultrastructural myelin alterations in the ON distal portion at early stages of diabetes. In addition, EE housing avoided a decrease in BDNF levels induced by experimental diabetes. These results suggest that EE induced neuroprotection in the diabetic visual pathway. Fil: Dorfman, Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Aranda, Marcos L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina
Published: 2015
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