Abstract
Abstract: :
The immune system is the major mechanism to fight off threats imposed on an organism. When dealing with the eye, imbalanced (hyper or hypo) immune response can lead to devastating outcome of either immune–mediated neuropathologies such as uvietis or to insufficient ability to cope with neurodegenerative conditions such as glaucoma. In both cases, loss of retinal ganglion cell (RGC) takes place and the regulation of the immune response rather than its suppression is essential for neuronal survival. Purpose:Chondroitin sulfate proteoglycan (CSPG) is induced in various pathological conditions such as the glial scar, Alzheimer’s disease and glaucoma and has been associated with neurodegeneration. We hypothesized that both CSPG and its degradation products play a role in controlling the local immune response and therefore contribute to the overall process of repair. This hypothesis is challenged in the present study. Methods: We examined the effects of CSPG–derived disaccharide (CSPG–DS) in two models of neurodegenerative conditions induced by either elevated intraocular pressure (IOP) or by experimental autoimmune uveitis (EAU), representing neuropathological conditions induced by non–inflammatory and inflammatory conditions, respectively. Immunohistochemical analysis was used to inspect the tissue following CSPG–DS treatment and for analysis of the in vitro effects of CSPG–DS on microglia and on neurons. Results:CSPG–DS treatment was highly neuroprotective in the rat model of elevated IOP: we found 72±3% surviving RGCs in the CSPG–DS treated animals, compared to 46± 5% in the control. In the EAU model, 52 ± 2% of the RGCs were lost in the control. CSPG–DS treatment resulted in a significant reduction in the RGCs loss to 24 ± 9%; steroid treatment caused further increase in RGC loss (59 ± 1.6%). Immunohistochemical analysis of the tissue following EAU showed that CSPG–DS treatment, on the one hand significantly reduced the number of T cells and on the other hand increased microglia activation. Our in vitro results indicate that CSPG–DS can reduce T cell motility and activation and activate microglia to express a neuroprotective phenotype. Moreover, CSPG–DS can directly protect neurons from glutamate toxicity in vitro. Discussion: Our results suggest that CSPG–DS can promote recovery in the visual system by its dual action – modulation of the immune response and neuroprotection. Therefore, CSPG–DS might prove to be highly efficient compound in coping with various neurodegenerative conditions regardless of the primary cause of insult.
Keywords: immunomodulation/immunoregulation • neuroprotection • proteoglycans/glycosaminoglycans