Of Mice and Monkeys: Neuroprotective Efficacy of the p38 Inhibitor BIRB 796 Depends on Model Duration in Experimental Glaucoma.

Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). Early progression involves retinal ganglion cell (RGC) axon dysfunction that precedes frank degeneration. Previously we demonstrated that p38 MAPK inhibition abates axonal dysfunction and slows degeneration in the inducible microbead occlusion model of glaucoma in rat. Here, we assessed the neuroprotective effect of topical eye delivery of the p38 MAPK inhibitor BIRB 796 in three models of glaucoma (microbead occlusion in rat and squirrel monkey and the genetic DBA/2 J mouse model) with distinct durations of IOP elevation. While BIRB 796 did not influence IOP, treatment over four weeks in rats prevented degradation of anterograde axonal transport to the superior colliculus and degeneration in the optic nerve. Treatment over months in the chronic DBA/2 J model and in the squirrel monkey model reduced expression and activation of p38 downstream targets in the retina and brain but did not rescue RGC axon transport or degeneration, suggesting the efficacy of BIRB 796 in preventing associated degeneration of the RGC projection depends on the duration of the experimental model. These results emphasize the importance of evaluating potential therapeutic compounds for neuroprotection in multiple models using elongated treatment paradigms for an accurate assessment of efficacy.

Astrocyte remodeling without gliosis precedes optic nerve Axonopathy.

Astroyctes serve myriad functions but are especially critical in white matter tracts, where energy-demanding axons propagate action potentials great distances between neurons. Axonal dependence on astrocytes for even normal function accentuates the critical role astrocytes serve during disease. In glaucoma, the most common optic neuropathy, sensitivity to intraocular pressure (IOP) challenges RGC axons early, including degradation of anterograde transport to the superior colliculus (SC). Astrocyte remodeling presages overt axon degeneration in glaucoma and thus may present a therapeutic opportunity. Here we developed a novel metric to quantify organization of astrocyte processes in the optic nerve relative to axon degeneration in the DBA/2 J hereditary mouse model of glaucoma. In early progression, as axons expand prior to loss, astrocyte processes become more parallel with migration to the nerve's edge without a change in overall coverage of the nerve. As axons degenerate, astrocyte parallelism diminishes with increased glial coverage and reinvasion of the nerve. In longitudinal sections through aged DBA/2 J nerve, increased astrocyte parallelism reflected elevated levels of the astrocyte gap-junction protein connexin 43 (Cx43). In the distal nerve, increased Cx43 also indicated with a higher level of intact anterograde transport from retina to SC. Our results suggest that progression of axonopathy in the optic nerve involves astrocyte remodeling in two phases. In an early phase, astrocyte processes organize in parallel, likely through gap-junction coupling, while a later phase involves deterioration of organization as glial coverage increases and axons are lost.