Search

La enfermedad de Alzheimer (AD) es una enfermedad progresiva de etiología multifactorial y aparición espontánea e idiopática. Sus características neuropatológicas incluyen el depósito extracelular de placas β-amiloides (Aβ) e intracelular de la proteína Tau hiperfosforilada en hipocampo y corteza. Una de las teorías que predomina es la falla en el metabolismo de la proteína precursora amiloide (APP) produciendo aumentos del péptido β-amiloide 1-42 (Aβ1-42). Se ha demostrado que las enzimas β-y γ-secretasas están asociadas a rafts de Cho en las membranas, favoreciendo el aumento de la actividad de las mismas (Xiong et al., 2008). Existeuna asociación entre los niveles de Cho y el desarrollo de AD (Ricciarelli et al., 2012; Zhang y Liu, 2015). El Cho presente en el cerebro tiene un origen independiente respecto al Cho presente en otros tejidos, estando separados por la barrera hematoencefálica (BHE) (Zhang y Liu, 2015). En el cerebro adulto son los astrocitos los responsables de sintetizar y proveer de Cho a las neuronas (Niewig et al., 2009)., Universidad Nacional de La Plata

Oxidative stress (OS) is defined as the imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense system. Living organisms produce ROS from molecular oxygen as a consequence of normal cellular metabolism. In order to prevent damage, cells have an antioxidant defense system constituted by an enzymatic component (including catalases, superoxide dismutases, etc.) and nonenzymatic antioxidants component (glutathione, α-tocopherol, ascorbic acid, etc.). When the levels of ROS exceed cell capacity, it can cause damage in cellular components such as carbohydrates, nucleic acids, lipids, and proteins, thus altering their function. Whenever this imbalance occurs within the central nervous system, it can lead to the development of the neurodegenerative disorders. Neurodegenerative diseases are characterized by the loss of neuronal cells and, in most cases, by the aggregates of proteins that form intracytoplasmic and intranuclear inclusions in neurons and glial cells. Data on the literature show that there are two possible mechanisms involved in most of neurodegenerative diseases: (1) mutations and/or aggregation of characteristic proteins of each disease such as α-synuclein in Parkinson’s disease (PD) or beta-amyloid peptide in Alzheimer’s disease (AD) and (2) dysfunction of mitochondrial energy metabolism in neurons. In this section, we will focus on this last one. Instituto de Investigaciones Bioquímicas de La Plata

In the current study we implemented ICV IGF-1 gene therapy in very old rats (28 months) and assessed the motor performance pre and 17-days after surgery. Glial immunoreactivity in striatum was evaluated by Iba1 and GFAP markers., Facultad de Ciencias Médicas

There is growing evidence that documents profound effects of estrogens on learning, memory, and mood as well as neurodevelopment and neurodegenerative diseases. However, the ability of estradiol to influence synaptic plasticity, neurotransmission, neurodegeneration and cognition, could be different depending on sex dimorphisms. It emerges that estrogens have different, even opposite, effects as well as similar effects in male and female brains. The protective effects of estradiol on neural cells are mediated in part by modulation of neurotrophic factors such as insulin like growth factor (IGF-l), tyrosine kinase A (Trk A), nerve growth factors (NGF), and the like. Also, it modulates the action of neurotrophins, which in turn regulate the synaptogenesis, synaptic plasticity and synaptic functions. By these actions estrogen prevents or slows down the neurodegenerative process. Another described effect of estradiol is the capacity to modulate inflammatory response mediated by glial cells. Neuroinflammation is a feature not only of many neurological disorders but also of aging, and it is accompanied by activation of glial cells and the release of proinflammatory cytokines and chemokines. Such activation is a normal response oriented to protect neural tissue. However, excessive and chronic activation of glia may lead to neurotoxicity and may be harmful for neural tissue. Estrogenic compounds may be candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of proinflammatory molecules by glial cells. In this chapter we will review different mechanisms that may be implicated in the diverse actions of estradiol, the differences according to gender and we empathize in the anti-inflammatory action on glial cell. We will also explore the interaction of estradiol with others neurotrophic factors, such as IGF-I in the regulation of neurodegeneration and memory impairment. Finally, the possibility of using selective estrogen receptor modulators (SERMs) to exert estradiollike neuroprotective actions in the brain as an alternative to estrogen will be discussed. Instituto de Investigaciones Bioquímicas de La Plata

Aging is associated with a progressive increase in the incidence of neurodegenerative diseases in both laboratory animals and humans. In the central nervous system, cholinergic and dopaminergic (DA) neurons are among the cells most susceptible to the deleterious effects of age. Thus, the basal forebrain cholinergic system is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer’s disease (AD). Parkinson's disease (PD), a degeneration of nigro-striatal DA neurons is the most conspicuous reflection of the vulnerability of DA neurons to age. Overall, there is growing evidence that a progressive decline in cognitive function and central DA activity represents basic features of normal aging both in humans and laboratory rodents. Exacerbation of these processes contributes to the symptoms of AD and PD, respectively. In this context, neurotrophic factors that can prevent or delay the decline in cognitive function and central DA activity during normal aging may reveal new therapeutic avenues for treatment of AD and PD and are therefore of clinical interest. Among the peptide factors, Insulin-like Growth Factor I (IGF-I) and Glial cell line-Derived Neurotrophic Factor are emerging as powerful neuroprotective molecules for the treatment of neurodegenerative pathologies. Among the neurosteroids, estrogens are recognized as neuroprotective and seem to act synergistically with IGF-I and possibly other neurotrophic peptides. This chapter will discuss the evidence supporting the neuroprotective relevance of the above factors., Instituto de Investigaciones Bioquímicas de La Plata

Neuroinflammation comprises a feature of many neurological disorders that is accompanied by the activation of glial cells and the release of pro-inflammatory cytokines and chemokines. Such activation is a normal response oriented to protect neural tissue and it is mainly regulated by microglia and astroglia. However, excessive and chronic activation of glia may lead to neurotoxicity and may be harmful for neural tissue. The ovarian hormone oestradiol exerts protective actions in the central nervous system that, at least in part, are mediated by a reduction of reactive gliosis. Several selective oestrogen receptor modulators may also exert neuroprotective effects by controlling glial inflammatory responses. Thus, tamoxifen and raloxifene decrease the inflammatory response caused by lipopolysaccharide, a bacterial endotoxin, in mouse and rat microglia cells in vitro. Tamoxifen and raloxifene are also able to reduce microglia activation in the brain of male and female rats in vivo after the peripheral administration of lipopolysaccharide. In addition, tamoxifen decreases the microglia inflammatory response induced by irradiation. Furthermore, treatment with tamoxifen and raloxifene resulted in a significant reduction of the number of reactive astrocytes in the hippocampus of young, middle-aged and older female rats after a stab wound injury. Tamoxifen, raloxifene and the new selective oestrogen receptor modulators ospemifene and bazedoxifene decrease the expression and release of interleukine-6 and interferon-γ inducible protein-10 in cultured astrocytes exposed to lipopolysaccharide. Ospemifene and bazedoxifene exert anti-inflammatory effects in astrocytes by a mechanism involving classical oestrogen receptors and the inhibition of nuclear factor-kappa B p65 transactivation. These data suggest that oestrogenic compounds are candidates to counteract brain inflammation under neurodegenerative conditions by targeting the production and release of pro-inflammatory molecules by glial cells. © 2011 Blackwell Publishing Ltd.

Muy poco se conoce sobre la concentración sérica de prolactina (PRL) bajo condiciones patológicas en perros. Para describir la relación entre las concentraciones séricas de PRL y las hormonas tiroideas se usaron cuarenta y cinco perros machos y hembras de raza pura y mestizos con sospecha clínica de hipotiroidismo, de los cuales se tomaron muestras de sangre para determinaciones séricas de PRL y tirotrofina (TSH), tiroxina (T4) y/o T4 libre (T4L). Las concentraciones de PRL en perros hipotiroideos y eutiroideos se compararon con el test de Mann-Whitney. Para la descripción adicional de los datos se correlacionó la PRL y la TSH, T4L o T4. El porcentaje cambio de la PRL se calculó en los pacientes en los que se realizó la prueba de estimulación con TRH. La concentracion sérica de PRL de la totalidad de los perros hipotiroideos (n= 34) y eutiroideos (n= 11) fue de 25.9±4.8 y 14.6±6.5 ng/ml, respectivamente (p >0.05). No se encontraron diferencias significativas entre la PRL y las diferentes hormonas tiroideas en ninguno de los grupos. El perro estimulado se clasificó como hipotiroideo subclínico (grado I). En ese animal la prolactina aumentó 5 veces (de 0.4 a 2.1 ng/ml) después de la inyección de TRH. Deben realizarse trabajos adicionales para describir la prolactinemia en caninos con hipotiroidismo., There is very scarce information concerning prolactin (PRL) serum concentrations under pathologic conditions in dogs. To describe the relationship between PRL and thyroid hormones serum concentrations forty-five cross- and pure-bred male and female dogs with clinical suspicious of hypothyroidism were blood sampled for PRL and thyrotropin (TSH), thyroxin (T4) and/or free T4 (FT4) serum determinations. Prolactin concentrations in hypothyroid and euthyroid dogs were compared by the Mann-Whitney test. For further description of data correlation analyses between PRL and TSH, FT4 or T4 were also tested. Percentage PRL change was calculated in the patient in which the TRH stimulation test was carried out. Overall serum PRL concentrations in hypothyroid (n= 34) and euthyroid (n= 11) dogs were 25.9±4.8 and 14.6±6.5 ng/ml, respectively (p >0.05). No significant correlation could be found between PRL and the different thyroid hormones in any group. The stimulated dog was classified as subclinical a hypothyroid (grade I). Prolactin increased 5 times (from 0.4 to 2.1 ng/ ml) after TRH injection in this animal. Further work should be done to describe prolactinemia in canine hypothyroidism., Facultad de Ciencias Veterinarias

Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. It consists of a nonapeptide component coupled to the ion zinc, which confers biological activity to the molecule. After its discovery in the early 1970s, thymulin was characterized as a thymic hormone involved in several aspects of intrathymic and extrathymic T cell differentiation. Subsequently, it was demonstrated that thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, a growing core of information, to be reviewed here, points to thymulin as a hypophysotropic peptide. In recent years, interest has arisen in the potential use of thymulin as a therapeutic agent. Thymulin was shown to possess anti-inflammatory and analgesic properties in the brain. Furthermore, an adenoviral vector harboring a synthetic gene for thymulin, stereotaxically injected in the rat brain, achieved a much longer expression than the adenovirally mediated expression in the brain of other genes, thus suggesting that an anti-inflammatory activity of thymulin prevents the immune system from destroying virus-transduced brain cells. Other studies suggest that thymulin gene therapy may also be a suitable therapeutic strategy to prevent some of the endocrine and metabolic alterations that typically appear in thymus-deficient animal models. The present article briefly reviews the literature on the physiology, molecular biology, and therapeutic potential of thymulin., Instituto de Investigaciones Bioquímicas de La Plata, Facultad de Ciencias Veterinarias, Comisión de Investigaciones Científicas de la provincia de Buenos Aires

The implementation of experimental gene therapy in animal models of neuroendocrine diseases is an area of growing interest. In the hypothalamus, restorative gene therapy has been successfully implemented in Brattleboro rats, an arginine vasopressin (AVP) mutant which suffers from diabetes insipidus, and in Koletsky (fak/fak) and in Zucker (fa/fa) rats which have leptin receptor mutations that render them obese, hyperphagic and hyperinsulinemic. In the above models, viral vectors expressing AVP, leptin receptor b and proopiomelanocortin, respectively, were stereotaxically injected in the relevant hypothalamic regions. In rats, aging brings about a progressive degeneration and loss of hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons, which are involved in the tonic inhibitory control of prolactin secretion and lactotropic cell proliferation. Stereotaxic injection of an adenoviral vector expressing insulin-like growth factor I corrected their chronic hyperprolactinemia and restored TIDA neuron numbers. Spontaneous intermediate lobe pituitary tumors in a retinoblastoma (Rb) gene mutant mouse were corrected by injection of an adenoviral vector expressing the human Rb cDNA and experimental prolactinomas in rats were partially reduced by intrapituitary injection of an adenoviral vector expressing the HSV1-thymidine kinase suicide gene. These results suggest that further implementation of gene therapy strategies in neuroendocrine models may be highly rewarding. Instituto de Investigaciones Bioquímicas de La Plata

En las últimas décadas, el promedio en la esperanza de vida de la población mundial ha aumentado debido a la mejora en la atención médica y las condiciones sociales y culturales. Este hecho viene de la mano con el consecuente deterioro motor y cognitivo, así como a un aumento en la incidencia de patologías relacionadas al envejecimiento, como es la Enfermedad de Parkinson. Durante el envejecimiento se observa una pérdida de la homeostasis cerebral y una neuroinflamación crónica, causada principalmente por microglia senescente. Estas células se encuentran polarizadas hacia un fenotipo proinflamatorio y generan una respuesta inmune exacerbada. De hecho, ha sido reportado que la progresión de muchas enfermedades neurodegenerativas depende de la activación de la microglia. Por tanto, es de gran interés diseñar estrategias que permitan modular el fenotipo de estas células gliales. Muchos factores neurotróficos producidos por las células gliales, como el IGF1, pueden polarizarlas hacia un fenotipo neuroprotector M2, promoviendo la supervivencia neuronal. Nuestro grupo de investigación ha fijado como objetivo de estudio combatir los efectos deletéreos del envejecimiento en ratas seniles mediante la implementación de la terapia génica con IGF1. En el presente trabajo de Tesis Doctoral hemos evaluado el efecto de esta terapia sobre la microglia en regiones del cerebro relacionadas con el desempeño motor, y su relación con la mejora en la performance motora debida a la terapia, anteriormente observada. Demostramos que la terapia génica con IGF1 aumenta el número de células microgliales con especificidad en el Núcleo Estriado de ratas seniles. Además, estas células presentan una mayor reactividad y se encuentran polarizadas hacia un fenotipo anti-inflamatorio M2. Observamos también que la microglia del Núcleo Estriado en ratas seniles tratadas con RAd-IGF1 presentan una mayor actividad fagocítica y mayor remodelación sináptica. A su vez, la terapia génica provocó una disminución en la expresión de genes pro-inflamatorios. Postulamos que estos cambios debidos a la sobreexpresión de IGF1, establecen un microambiente propicio para el correcto funcionamiento de las neuronas implicadas en el control motor generando una mejora de la conducta motora., In the last decades, the average life expectancy of the world population has increased due to the improvement in medical care and social and cultural conditions. This fact comes hand in hand with the consequent motor and cognitive loss, as well as an increase in the incidence of pathologies related to aging, such as Parkinson's disease. Aging presents a loss of cerebral homeostasis and chronic neuroinflammation, mainly caused by senescent microglia. These cells are polarized towards a proinflammatory phenotype and establish an exacerbated immune response. In fact, it has been reported that the progression of many neurodegenerative diseases depends on the activation of the microglia. Therefore, it is of great interest to design strategies that allow modulating the phenotype of these glial cells. Many neurotrophic factors produced by glial cells, such as IGF1, can polarize them towards an M2 neuroprotective phenotype, promoting neuronal survival. Our research group has set the goal to fight the deleterious effects of aging in senile rats by implementing gene therapy with IGF1. In the present Doctoral Thesis work we have evaluated the effect of this therapy on microglia in regions of the brain related to motor performance, and its relationship with the improvement in motor performance due to therapy, previously observed. We showed that gene therapy with IGF1 increased the number of microglial cells specifically in the Striatum of senile rats. In addition, these cells presented higher reactivity and were polarized towards an M2 anti-inflammatory phenotype. We also observed that the microglia of the Striatum of senile rats treated with RAd-IGF1 presented higher phagocytic activity and greater synaptic remodeling. Moreover, gene therapy caused a decrease in the expression of pro-inflammatory genes. We postulate the observed changes are due to the overexpression of IGF1 and that they establish a propitious microenvironment the proper functioning of the neurons involved in motor control, generating an improvement in motor behavior., Facultad de Ciencias Exactas

Parkinson’s Disease (PD) is a progressive neurodegenerative disorder which manifests as a motor disorder, characterized by slowness of movements, rigidity and tremor. Motor dysfunction of PD is due to dopamine loss in the neostriatum and due to the neurodegeneration of dopaminergic neuron’s cell bodies of the Substantia Nigra Pars Compacta (SNPC). Evidence suggests that chronic neuroinflammation, mediated by activated microglial and astroglial cells in the SNPC, could be essential for the degenerative process. It is well known that IGF1 plays a key role in neuroprotection in physiological conditions, both in health and disease. Previous studies of our group have shown that Rad-IGF ICV gene therapy had a restorative effect on motor skills of aged rats., Facultad de Ciencias Exactas