Date of Award
Doctor of Philosophy (PhD)
Professor Alexander K. Ball
Transection of the optic nerve (axotomy) is a model of central nervous system (CNS) injury. Eighty to ninety percent of retinal ganglion cells (RGCs) die within two weeks after transection of the optic nerve. We demonstrated that the recently discovered neurotrophic factors glial cell-line derived neurotrophic factor (GDNF) and neurturin (NTN) enhance the survival of axotimized RGCs. We also showed that these factors produce additive neurotrophic effects with brain derived neurotrophic factor, suggesting that they act by independent mechamisms. We also demonstrated that the high affinity receptor for GDNF (GFRα-1) is localized to RGCs, Muller glia, and the astrocytes in the retina. GDNF was localized to RGCs, photoreceptors, and pigment epithelial cells, suggesting possible autocrine or paracrine roles for GDNF in the retina. Our results also demonstrate that an indirect neurprotective mechanism of GDNF is the upregulation of the glutamate transporter, GLAST-1, in the retinal glia. This mechanism may protect RGCs from glutamate mediated excitotoxicity. Our findings suggest that multiple neurotrophic factors may be required for the rescue of injured CNS neurons, as suggested by the findings that these factors act independently. We demonstrated that there are increases inducible nitric oxide synthase (iNOS) expression in retinal glial cells, and increases in constitutive (cNOS) expression in RGCs after axotomy, and that increases in NOS expression parallel the timecourse of RGC degeneration. Our results indicate that NO plays a toxic role in promoting RGC death after axotomy, as demonstrated by the findings that NOS inhibition enhances the survival of axotomized RGCs. Furthermore, we examined the neuroprotective effects of the anti-inflammatory cytokines-10 (IL-10), IL-4, and transforming growth factor-β (TGF-β on RGC survival. These cytokines have been shown to inhibit iNOS expression and NO synthesis by glial cells in vitro. Our in vivo studies showed that IL-10 and IL-4 enhanced the survival of axotomized RGCs, and suggest that one of the neuroprotective mechanisms of these cytokines is inhibiting peroxynitrite formation in the retina. These findings suggest that IL-10 and IL-4 inhibit NO synthesis in the retina may inhibit reactivity after optic nerve transection. Our findings point to the possible benefit of IL-10 or IL-4 treating CNS trauma and diseases of the CNS that demonstrate the presence of activated NO synthesizing glial cells.
Koeberle, Paulo D., "EFFECTS OF NEUROTROPHIC AND ANTI-INFLAMMATORY CYTOKINES ONF THE SURVIVAL OF AXOTOMIZED RETINAL GANGLION CELLS" (2001). Open Access Dissertations and Theses. Paper 1390.