Abstract
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.
Highlights
Glaucoma is the primary source of permanent sightlessness around the world[1], and is second only to cataract in producing vision loss
As seen in the experimental timelines for the three models we used (Fig. 1a), the inducible microbead occlusion model in rats was of short duration (4 weeks) compared to the genetic DBA/2 J model (24 weeks) and the inducible microbead occlusion model in squirrel monkeys (29 weeks)
Topical treatment with BIRB 796 had no effect on intraocular pressure (IOP) in any model but did protect anterograde transport to the rat superior colliculus (SC) and retinal ganglion cell (RGC) axon degeneration in the rat optic nerve after 4 weeks of IOP elevation (Figs. 2 and 3)
Summary
Glaucoma is the primary source of permanent sightlessness around the world[1], and is second only to cataract in producing vision loss. In a previous study we showed that inhibition of p38 mitogen-activated protein kinase (MAPK) with Ro3206145 protected against RGC axonal transport deficits and axon loss in rats with induced elevations in IOP www.nature.com/scientificreports via microbead occlusion of the anterior chamber[24]. BIRB 796 (doramapimod) binds to p38 MAPK and causes a conformational change so that ATP cannot bind[27,35,36] It has a dissociation rate much slower than that of other p38 inhibitors, and shows a high selectivity to and a picomolar affinity for p38, suggesting BIRB 796 would be a long-lasting drug with fewer off-target effects[27,35,36]. Microbead injection into the anterior chamber of rats elevated IOP for four weeks and reduced RGC axonal transport of cholera toxin subunit B from retina to the superior colliculus in vehicle-treated rats; BIRB 796 treatment prevented this reduction and protected RGC axons from degeneration in the optic nerve. Treatment did reduce expression of p38 downstream targets that increased with elevated IOP, suggesting BIRB 796 did reach the retinal projection in DBA/2 J mice and SMs
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