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

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. Glaucoma is the primary source of permanent sightlessness around the world 1 , and is second only to cataract in producing vision loss. Estimates suggest that by 2020 over 75 million individuals will have glaucoma and that more than 10 million of those will already suffer from irreversible blindness 1-3. In glaucoma, stress associated with sensitivity to intraocular pressure (IOP) is transmitted at the optic nerve head, selectively targeting retinal ganglion cells (RGCs) and their axons 4,5. While age is a key risk factor, IOP is the only modifiable risk factor and the singular focus for clinical intervention 6. The use of topical IOP-lowering drugs is the first line treatment for glaucoma 7. Glaucoma progression can be slowed by reducing IOP, however RGC degeneration (and vision loss) continues for many. For nearly half the patients with glaucoma taking medications to reduce IOP, the disease will continue to worsen 6,8,9. Neurodegeneration in glaucoma is similar to other age-related neurodegenerative disorders like amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease in that axonal function is compromised prior to death of neurons 10-16. Deterioration of anterograde transport from RGCs to central targets in the brain arises early in animal models of glaucoma; degradation is followed by somatic drop-out in the retina subsequent to axonal loss in the optic nerve 17-19. Experimental interventions that preserve axonal transport can suspend or stop subsequent degeneration of axons and cell bodies 20-22. Given this progression, it is appropriate that the identification of neuroprotective therapies tha...

Restoring the Extracellular Matrix: A Neuroprotective Role for Collagen Mimetic Peptides in Experimental Glaucoma

“…We showed that intraocular delivery of CMP during a period of elevated IOP ameliorated deficits in the retinotopic representation of active transport in the superior colliculus ( Figures 5 , 6 ), the primary target for RGC axons in rodents. Elevated IOP is an important risk factor for RGC degeneration and vision loss in glaucoma ( Susanna et al, 2015 ), and slowing or stopping transport deficits in experimental models of glaucoma slows subsequent degenerative stages that occur in longer periods of microbead glaucoma, including axon degeneration followed by RGC body elimination ( Lambert et al, 2011 , 2017 , 2020 ; Dapper et al, 2013 ). Interestingly, this same CMP (CMP 03A) promoted repair of the corneal epithelial layer following acute injury ( Baratta RO.…”

“…This is an important observation since the colliculus represents the primary target for RGCs in the rodent visual system. Furthermore, experimental interventions that slow or abate transport degradation also prevent subsequent stages of degeneration (Lambert et al, 2011(Lambert et al, , 2017(Lambert et al, , 2020Dapper et al, 2013;Bernardo-Colón et al, 2018). With this in mind, we measured whether treatment with CMP could reduce the progression of anterograde transport degradation with IOP elevation.…”

Neuroprotection by WldS depends on retinal ganglion cell type and age in glaucoma

“…This is so as well in experimental models of glaucoma, which generally rely upon inducible or transgenic-related elevations in IOP [13,14]. In rodents, experimental interventions that slow or prevent loss of anterograde transport to RGC projection sites in the brain also impede axon degeneration in the optic nerve and cell body loss in the retina [5,[15][16][17]. Without intact transport, axons undergo Wallerian or Wallerian-like degeneration [1].…”

GLP-1 Receptor Agonist NLY01 Reduces Retinal Inflammation and Neuron Death Secondary to Ocular Hypertension

“…Elevated IOP induces deficits in axon transport along the optic nerve ( Lambert et al, 2017 , 2020 ) and reduction in NaV1.2 protein levels in RGCs ( Risner et al, 2020 ) after 4 weeks of ocular hypertension. In contrast, changes in RGC electrical signaling occur earlier after eIOP.…”

“…Elevated IOP induces deficits in axon transport along the optic nerve (Lambert et al, 2017(Lambert et al, , 2020 (Risner et al, 2018). In both the brain and the retina, dendritic pruning is linked to the production of C1q and the subsequent initiation of the classical complement cascade by CD11b + cells (Stevens et al, 2007).…”