State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
Institutes of Neuroscience and Third Affiliated Hospital, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450003, China.
Cell Signal. 2023 Sep;109:110781. doi: 10.1016/j.cellsig.2023.110781. Epub 2023 Jun 23.
Extraordinary excitability (hyperexcitability) is closely related to retinal ganglion cell (RGC) injury in glaucoma. Dopamine (DA) and its receptors are involved in modulating RGC excitability. We investigated how DA system affects RGC injury in chronic ocular hypertension (COH) experimental glaucoma model. Western blotting and immunohistochemistry results revealed that expression of DA D2-like receptor (D2R) in RGCs was increased in COH retinas. Patch-clamp recordings showed that outward K currents were downregulated, while Na currents and Na1.6 expression were upregulated in RGCs of COH retinas, which could be reversed by intravitreal pre-injection of the D2R antagonist sulpiride, but not by the D1-like receptor (D1R) antagonist SCH23390. However, pre-injection of the D1R agonist SKF81297 could partially reverse the increased expression of Na1.6 proteins. Consistently, the numbers of evoked action potentials induced by current injections were increased in RGCs of COH retinas, indicating that RGCs may be in a condition of hyperexcitability. The increased frequency of evoked action potentials could be partially block by pre-injection of sulpiride, SKF81297 or DA, respectively. Furthermore, the increased number of TUNEL-positive RGCs in COH retinas could be partially reduced by intravitreal pre-injection of sulpiride, but not by pre-injection of SCH23390. Moreover, pre-injection of SKF81297 or DA could reduce the number of TUNEL-positive RGCs in COH retinas. All these results indicate that in COH retina, activation of D2R enhances RGC hyperexcitability and injury, while activation of D1R results in the opposite effects. Selective inhibition of D2R or activation of D1R may be an effective strategy for treatment of glaucoma.
异常兴奋性（超兴奋性）与青光眼的视网膜神经节细胞（RGC）损伤密切相关。多巴胺（DA）及其受体参与调节 RGC 兴奋性。我们研究了 DA 系统如何影响慢性眼压升高（COH）实验性青光眼模型中的 RGC 损伤。Western 印迹和免疫组织化学结果显示，COH 视网膜中 RGC 中 DA D2 样受体（D2R）的表达增加。膜片钳记录显示，外向 K 电流下调，而 COH 视网膜中的 Na 电流和 Na1.6 表达上调，这可以通过玻璃体内预先注射 D2R 拮抗剂舒必利逆转，但不能通过 D1 样受体（D1R）拮抗剂 SCH23390 逆转。然而，D1R 激动剂 SKF81297 的预先注射可以部分逆转 Na1.6 蛋白的表达增加。一致地，COH 视网膜中 RGC 中由电流注射诱导的诱发动作电位的数量增加，表明 RGC 可能处于超兴奋性状态。诱发动作电位的频率增加可分别被舒必利、SKF81297 或 DA 的预先注射部分阻断。此外，COH 视网膜中 TUNEL 阳性 RGC 的数量增加可通过玻璃体内预先注射舒必利部分减少，但不能通过预先注射 SCH23390 减少。此外，SKF81297 或 DA 的预先注射可以减少 COH 视网膜中 TUNEL 阳性 RGC 的数量。所有这些结果表明，在 COH 视网膜中，D2R 的激活增强了 RGC 的超兴奋性和损伤，而 D1R 的激活则产生相反的效果。选择性抑制 D2R 或激活 D1R 可能是治疗青光眼的有效策略。
