Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2012 Nov;385(11):1077-81. doi: 10.1007/s00210-012-0796-1. Epub 2012 Sep 11.
We have previously reported that β(3)-adrenoceptor agonists dilate retinal blood vessels, but their effects on retinal neurons have been unclear. In this study, we examined the action of the β(3)-adrenoceptor agonist CL316243 against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA) in rats. CL316243 was injected into the vitreous cavity before, with, or after intravitreal NMDA injection. Seven days after NMDA injection, cell loss in the ganglion cell layer (GCL) and thinning of the inner plexiform layer were observed. The reduction in the number of cells in the GCL was diminished by injection of CL316243 at 15, 30, 60, or 120 min after NMDA injection, whereas no significant protective effect was observed when CL316243 was administered 240 min after NMDA injection. Neither preinjection of CL316243 30 min before NMDA nor simultaneous injection of CL316243 with NMDA exerted any protective effect. The β(3)-adrenoceptor antagonist L748337 almost completely abolished the protection conferred by CL316243 injection 120 min after NMDA injection. The number of parvalbumin-positive amacrine cells was decreased in eyes examined 1 day after NMDA treatment, but this was prevented by CL316243 injection at 120 min after NMDA injection. These results suggest that CL316243 exerts protective effects against NMDA-induced damage by stimulation of β(3)-adrenoceptors. β(3)-adrenoceptor agonists may be effective candidates for the treatment of retinal diseases associated with glutamate-induced excitotoxicity, including glaucoma and diabetic retinopathy.
我们之前曾报道过β（3）-肾上腺素受体激动剂可扩张视网膜血管，但它们对视网膜神经元的作用尚不清楚。在这项研究中，我们研究了β（3）-肾上腺素受体激动剂 CL316243 对大鼠玻璃体内注射 N-甲基-D-天冬氨酸（NMDA）引起的视网膜损伤的作用。CL316243 在玻璃体内注射 NMDA 之前、同时或之后注入玻璃体内。NMDA 注射后 7 天，观察到节细胞层（GCL）细胞丢失和内丛状层变薄。NMDA 注射后 15、30、60 或 120 分钟注射 CL316243 可减少 GCL 中细胞数量的减少，但 NMDA 注射后 240 分钟注射 CL316243 时未见明显保护作用。NMDA 前 30 分钟预先注射 CL316243 或同时注射 CL316243 和 NMDA 均无保护作用。β（3）-肾上腺素受体拮抗剂 L748337 几乎完全消除了 NMDA 注射后 120 分钟注射 CL316243 所带来的保护作用。NMDA 处理后 1 天，观察到副甲状腺素阳性无长突细胞的数量减少，但 NMDA 注射后 120 分钟注射 CL316243 可防止这种情况发生。这些结果表明，CL316243 通过刺激β（3）-肾上腺素受体对 NMDA 诱导的损伤发挥保护作用。β（3）-肾上腺素受体激动剂可能是治疗与谷氨酸诱导的兴奋性毒性相关的视网膜疾病（包括青光眼和糖尿病性视网膜病变）的有效候选药物。
