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Wendi S Lambert, Silvia Pasini, Cathryn R Formichella, Purnima Ghose, Victoria Vest, Brian Carlson, Vincent Yao, David J Calkins; Treatment with p38 Inhibitor BIRB 796 is Neuroprotective in Models of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):618.
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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, thus preserving RGC axon structure and function would be beneficial and could abate subsequent disease progression. We assessed the neuroprotective effect of the p38 inhibitor, BIRB 796 (doramapimod) in an acute glaucoma model (microbead occlusion) in rats and squirrel monkeys (SMs), and in a chronic model, the DBA/2J mouse.
We induced ocular hypertension in rats by intracamerally injecting 5ul of 15um polystyrene microbeads in one eye and an equivalent volume of saline in the fellow eye. SMs received 40ul of 35um microbeads in one or both eyes. We applied BIRB 796 (3%) daily via topical corneal drops for 4 weeks (rats), 24 weeks (mice), or 29 weeks (SMs). We intravitreally injected 0.1% CTB 48hrs to 5 days prior to tissue collection to examine anterograde transport.
Microbead occlusion elevated IOP 33% in rats and 42% in SMs (p<0.02); IOP increased 43% in DBA/2J mice over the course of the study (p<0.00001, n=20). BIRB 796 treatment did not affect IOP in any cohort. In vehicle-treated rats, elevated IOP reduced anterograde axonal transport to the superior colliculus (SC) by 47% (p = 0.0001, n = 8); BIRB 796 treatment prevented this reduction (p = 0.06, n = 9). BIRB 796 treatment also rescued RGC axons in the optic nerve following elevated IOP (1.8% loss vs 12.6% loss in vehicle cohort, p = 0.013). In SMs, BIRB 796 treatment reduced levels of downstream p38 MAPK targets phosphorylated Hsp27 (p<0.04) and phosphorylated MK2 (p<0.04, n = 3+ eyes per group). Treatment also reduced levels of Alzheimer’s precursor protein (APP; p<0.02) in the optic nerve head. In DBA/2J mice, BIRB 796 treatment had no effect on anterograde transport, optic nerve degeneration, RGC soma number, but did reduce the expression of Bax and lipocalin-2 in the SC (p<0.02, n = 6).
Our data suggest that the p38 MAPK pathway plays a role in glaucomatous neurodegeneration. Short-term treatment with BIRB 796 attenuated axonal transport deficits and axon loss in rats. Long-term BIRB treatment reduced activation of p38 MAPK target proteins in SM retinas, and modified expression of proteins involved in glaucoma pathology in the SM and DBA/2J optic projection.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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