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Nogo-A, a major myelin inhibitory protein, inhibits axon growth and synaptic function in the central nervous system. Glaucoma is a progressive neuropathy as a result of retinal ganglion cell (RGC) death. Synaptic degeneration is thought to be an early pathology of neurodegeneration in glaucoma and precedes RGC loss. Here experimental ocular hypertension model was induced in adult rats with laser coagulation of the episcleral and limbal veins. The expression of Nogo-A, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) in the retina was investigated using immunohistochemistry and Western blotting. We found that Nogo-A was expressed in the RGCs and upregulated after the induction of ocular hypertension. OMgp was only expressed in the inner plexiform layer. There was no MAG expression in the retina. Our data provided, for the first time, the expression patterns of three myelin proteins in the adult retina and suggested an important role of Nogo-A in the RGC death and synaptic degeneration in glaucoma.

Purpose: Myelin inhibitory proteins inhibit axon growth and synaptic function by binding to the Nogo-66 receptor (NgR)1 in the central nervous system. Glaucoma is a progressive neuropathy characterized by loss of vision as a result of retinal ganglion cell (RGC) death. Synaptic degeneration is thought to be an early pathology of neurodegeneration in glaucoma and precedes RGC loss. The authors aimed to examine whether the NgR1 antagonist promotes synaptic recovery and RGC survival in glaucoma., Methods: Experimental ocular hypertension model was induced in adult rats with laser coagulation of the episcleral and limbal veins. NgR1 antagonist, soluble NgR1 (sNgR-Fc) was administrated to examine their effect on synaptic recovery and RGC survival. Expression of c-Fos, a neuronal connectivity marker, in the retinas was investigated using immunohistochemistry., Results: NgR1 was expressed in RGCs and upregulated after intraocular pressure elevation. Treatment with sNgR-Fc significantly reduced RGC loss at 2 and 4 weeks after the induction of ocular hypertension and also promoted RGC survival after optic nerve transection. There was no RGC loss at 5 days but there was significant synaptic degeneration as measured by c-Fos. Administration of sNgR-Fc attenuated synaptic degeneration at 5 days, and at 2 and 4 weeks., Conclusions: These data suggest that synaptic degeneration may be an initial molecular mechanism for neurodegeneration in glaucoma and appropriate NgR1 antagonism may delay the progression of the disease.

Aims: Glaucoma is a common neurodegenerative disease that affects retinal ganglion cells (RGCs) and their axons. Little is known of the synaptic degeneration involved in the pathophysiology of glaucoma. Here we used an experimental ocular hypertension model in rats to investigate this issue., Methods: Elevated intraocular pressure (IOP) was induced by laser coagulation of the episcleral and limbal veins. RGCs were retrogradely labeled with Fluoro-Gold (FG). The c-fos protein was used as a neuronal connectivity marker. Expression of c-fos in the retinas was investigated by immunohistochemistry at 5 days and 2 weeks after the induction of ocular hypertension. Both surviving RGCs as revealed by retrograde FG-labeled and c-fos-labeled RGCs were counted., Results: The c-fos protein was mainly expressed in the nuclei and nucleoli of cells in the ganglion cell layer and inner nuclear layer in the normal retina. We also confirmed that c-fos was also expressed in the nuclei and nucleoli of RGCs retrogradely labeled with FG. There was no significant RGC loss at 5 days but about 13% RGC loss at 2 weeks after the induction of ocular hypertension. The number of RGCs expressing c-fos was significantly lower in the experimental animals at both 5 days and 2 weeks than normal., Conclusion: Our study suggests that there is synaptic disconnection for RGCs after ocular hypertension and it may precede the cell death in the early stage. It may provide insight into novel therapeutic strategies to slow the progress of glaucoma.

Glaucoma is a neurodegenerative disease of the visual system characterized by the elevation of intraocular pressure. While this elevated pressure is related to an increased resistance to the outflow of aqueous humor from the eye, their impacts to the etiology and pathogenesis of the disease are not fully understood. This study aims to employ in vivo Gd-DTPA enhanced magnetic resonance imaging to evaluate the ocular transport following an induction of ocular hypertension in a rat model of chronic glaucoma. An experimental ocular hypertension model was induced in adult rats using an argon laser to photocoagulate the episcleral and limbal veins on the surface of the eyeball. The enhancements of the MRI signal intensity in the anterior chamber and vitreous body were measured as a function of time following systemic administration of Gd-DTPA solution at 3 mmol/kg. Results showed a progressive T1-weighted signal increase in the vitreous body of the glaucomatous eye but not the control eye. This increase occurred earlier in the anterior vitreous body than the preretinal vitreous. Further, there was an earlier Gd-DTPA transport into the anterior chamber in the majority of glaucomatous eyes. Our findings revealed the leakage of Gd-DTPA at the aqueous-vitreous interface, which was likely resulted from increased permeability of blood-aqueous or aqueous-vitreous barrier. These may explain the sources of changing biochemical compositions in the glaucomatous chamber components, which may implicate the cascades of neurodegenerative processes in the retina and the optic nerve.

Glaucoma is a neurodegenerative disease of the visual system. While elevated intraocular pressure is considered to be a major risk factor, the primary cause and pathogenesis of the disease are still unclear. This study aims to employ in vivo manganese-enhanced magnetic resonance imaging (MEMRI) to evaluate dynamically the Mn(2+) enhancements in the visual components following an induction of ocular hypertension in a rat model of chronic glaucoma. The episcleral and limbal veins were photocoagulated unilaterally in the right eye using an argon laser to maintain a consistent elevation of intraocular pressure by about 1.6 times above the normal level. Two and six weeks after glaucoma induction, MnCl(2) solution (50 mM, 3 microL) was injected intravitreally into both eyes, and MEMRI was performed 2 to 5 h after injection. Results showed a delayed increase in T1-weighted signal intensity in the glaucomatous optic nerve at 6 weeks but not 2 weeks after glaucoma induction. In addition, there was an accumulation of Mn(2+) ions in the vitreous humour of the glaucomatous eye, with a high concentration of Mn(2+) ions at the optic nerve head and the retina. These MEMRI findings may help understand the disease mechanisms, monitor the effect of drug interventions in glaucoma models and complement the conventional techniques in examining the glaucomatous visual components.

This study aims to employ in vivo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to evaluate the ocular transport following an induction of ocular hypertension in a rat model of chronic glaucoma. Upon systemic administration of Gd-DTPA solution, T1-weighted signal increase was observed in the vitreous body of the glaucomatous eye but not the control eye. This increase occurred earlier in the anterior vitreous body than the preretinal vitreous. Further, there was an earlier Gd-DTPA transport into the anterior chamber in the majority of glaucomatous eyes. Our DCE-MRI findings revealed the leakage of Gd-DTPA at the aqueous-vitreous interface, which was likely resulted from increased permeability of blood-aqueous or aqueous-vitreous barrier. These may explain the sources of changing biochemical compositions in the chamber components, which may implicate the neurodegenerative processes in the glaucomatous visual components.

Axonal degeneration has been known to occur in the optic nerve (ON) of rat glaucoma model. Recently, quantitative diffusion tensor imaging (DTI) has been developed to investigate various white matter diseases in vivo. In this study, longitudinal DTI was thus employed to study such animal model in the present study. The results showed that radial diffusivity (lambda) and fractional anisotropy (FA) of the glaucomatous ON (gON) was increasing and decreasing respectively with time after glaucoma induction, whereas there was no significant change in the axial diffusivity (lambda//). Supported by the histological staining of the ON, such changes in the two DTI-derived parameters were attributed to the 10% decrease in the axonal density of the gON as compared to nON. It was shown for the first time that DTI can be sensitive enough to detect axonal degeneration in rat glaucoma model. DTI therefore holds promise for reliable diagnoses and assessment of the glaucoma disease in human upon careful interpretation of the DTI-derived directional diffusivities.

This study aims to employ in vivo manganese-enchanced MRI (MEMRI) to evaluate dynamically the Mn(2+) enhancements along the visual pathway following an induction of ocular hypertension in a rat model of chronic glaucoma. Results showed an accumulation of Mn(2+) ions in the vitreous humor of the glaucomatous eye, with no statistical changes in the total retinal thickness but a possible occlusion of the ions at the optic nerve head. Meanwhile, there was a reduction in Mn(2+) transport in the glaucomatous optic nerve in the later stage of our model. Fewer enhancements in the visual cortex projected from the glaucomatous eye were also detectable. These may help understand the disease mechanisms, monitor the effect of drug interventions to glaucoma models, and complement the conventional techniques in examining the visual components.

The antagonism of LINGO-1, a CNS-specific negative regulator of neuronal survival, was shown to promote short-term survival of retinal ganglion cell (RGC) in an ocular hypertension model. LINGO-1 antagonists, combined with brain-derived neurotrophic factor (BDNF), can increase the length of neuron survival through an unclear molecular mechanism. To determine the relationship between LINGO-1 and BDNF/TrkB receptor in neuronal protection, we show here that LINGO-1 forms a receptor complex with TrkB and negatively regulates its activation in the retina after ocular hypertension injury. LINGO-1 antagonist antibody 1A7 or soluble LINGO-1 (LINGO-1-Fc) treatment upregulates phospho-TrkB phosphorylation and leads to RGC survival after high intraocular pressure injury. This neuronal protective effect was blocked by anti-BDNF antibody. LINGO-1 antagonism therefore promotes RGC survival by regulating the BDNF and TrkB signaling pathway after ocular hypertension. [ABSTRACT FROM AUTHOR]