Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, 510632, China.
Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University, Guangzhou, China.
Neuropharmacology. 2018 Sep 1;139:137-149. doi: 10.1016/j.neuropharm.2018.06.027. Epub 2018 Jun 22.
Retinitis pigmentosa (RP) is a hereditary blinding disease characterized by neurodegeneration of photoreceptors. Retinal ganglion cells (RGCs) in animal models of RP exhibit an abnormally high spontaneous activity that interferes with signal processing. Blocking AMPA/Kainate receptors by bath application of CNQX decreases the spontaneous firing, suggesting that inhibiting these receptors in vivo may help maintain the function of inner retinal neurons in rd10 mice experiencing photoreceptor degeneration. To test this, rd10 mice were i.p. injected with CNQX or GYKI 52466 (an AMPA receptor antagonist) for 1-2 weeks, and examined for their retinal morphology (by immunocytochemistry), function (by MEA recordings) and visual behaviors (using a black/white box). Our data show that iGluRs were up-regulated in the inner plexiform layer (IPL) of rd10 retinas. Application of CNQX at low doses both in vitro and in vivo, attenuated the abnormal spontaneous spiking in RGCs, and increased the light-evoked response of ON RGCs, whereas GYKI 52466 had little effect. CNQX application also improved the behavioral performance. Interestingly, in vivo administration of CNQX delayed photoreceptor degeneration, evidenced by the increased cell number and restored structure. CNQX also improved the structure of bipolar cells. Together, we demonstrated that during photoreceptor degeneration, blockade of the non-NMDA iGluRs decelerates the progression of RGCs dysfunction, possibly by dual mechanisms including slowing photoreceptor degeneration and modulating signal processing within the IPL. Accordingly, this strategy may effectively extend the time window for treating RP.
色素性视网膜炎（RP）是一种遗传性致盲疾病，其特征是光感受器的神经退行性变。RP 动物模型中的视网膜神经节细胞（RGCs）表现出异常高的自发性活动，干扰信号处理。通过在浴中施加 CNQX 来阻断 AMPA/Kainate 受体可以降低自发性放电，这表明在体内抑制这些受体可能有助于维持经历光感受器变性的 rd10 小鼠的内视网膜神经元的功能。为了验证这一点，rd10 小鼠通过腹腔注射 CNQX 或 GYKI 52466（一种 AMPA 受体拮抗剂）1-2 周，并通过免疫细胞化学检查其视网膜形态（通过 MEA 记录检查其功能）和视觉行为（使用黑/白箱）。我们的数据表明，rd10 视网膜的内丛状层（IPL）中 iGluRs 上调。在体外和体内以低剂量应用 CNQX 可减弱 RGCs 异常自发性放电，并增加 ON RGCs 的光诱发反应，而 GYKI 52466 则几乎没有作用。CNQX 应用也改善了行为表现。有趣的是，CNQX 的体内给药延迟了光感受器的变性，这表现为细胞数量的增加和结构的恢复。CNQX 还改善了双极细胞的结构。总之，我们证明了在光感受器变性期间，非 NMDA iGluR 的阻断可减缓 RGC 功能障碍的进展，其可能通过两种机制，包括减缓光感受器变性和调节 IPL 内的信号处理。因此，该策略可能有效地延长治疗 RP 的时间窗口。
