The Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, TN, 37232-2337, USA.
Sci Rep. 2020 May 22;10(1):8535. doi: 10.1038/s41598-020-65374-6.
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.
青光眼是一组与年龄和眼内压（IOP）敏感性相关的视神经病变。早期进展涉及视网膜神经节细胞（RGC）轴突功能障碍，这先于明显的变性。此前我们证明，p38MAPK 抑制剂可减轻诱导性微珠阻塞模型中大鼠青光眼的轴突功能障碍并减缓变性。在这里，我们评估了 p38MAPK 抑制剂 BIRB 796 通过三种不同持续时间的眼压升高模型（大鼠和松鼠猴的微珠阻塞和遗传 DBA/2J 小鼠模型）局部眼部给药的神经保护作用。虽然 BIRB 796 不影响 IOP，但在大鼠中治疗四周可防止顺行轴突运输到上丘的降解和视神经变性。在慢性 DBA/2J 模型和松鼠猴模型中治疗数月可降低视网膜和大脑中 p38 下游靶标的表达和激活，但不能挽救 RGC 轴突运输或变性，这表明 BIRB 796 在预防相关 RGC 投射变性中的疗效取决于实验模型的持续时间。这些结果强调了使用延长的治疗方案评估潜在的神经保护治疗化合物在多个模型中的疗效的重要性。
