Effect of MCI-9042, a 5-HT2 receptor antagonist, on retinal ganglion cell death and retinal ischemia
Effect of MCI-9042, a 5-HT2 receptor antagonist, on retinal ganglion cell death and retinal ischemia
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DOI：
10.1016/s0014-4835(02)00333-0
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发表时间：
2003-04-01
影响因子：
3.4
通讯作者：
Mano, T
中科院分区：
文献类型：
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作者：
Inoue-Matsuhisa, E;Sogo, S;Mano, T
研究了MCI-9042（三菱制药公司）在体外对谷氨酸诱导的视网膜神经节细胞（RGC）死亡和大鼠视网膜缺血的神经保护作用。从6日龄Wistar大鼠视网膜细胞中纯化RGCs，并在无血清培养基中培养。应用25mum谷氨酸后，RGCs的存活率分别用或不用几种5-羟色胺2 （5-HT2）受体拮抗剂：MCI-9042、M-1 （MCI-9042的主要代谢物）、酮色林和LY-53857；钙黄素-乙酰氧基甲酯染色评价。眼内压升高（130 mmHg, 50 min）诱导视网膜缺血。在缺血再灌注前30分钟和缺血再灌注后30分钟分别以3,30 mg/kg或基础剂量腹腔注射MCI-9042。缺血再灌注后第7天，采用组织学、形态计量学分析和视网膜电图（ERGs）记录评估视网膜损伤。25 muM谷氨酸使存活的RGCs数量减少到未治疗RGCs的60%到65%。MCI-9042、M-1、酮色林和LY-53857分别在浓度超过100 nM、1 nM、1 muM和100 nM时显著降低谷氨酸诱导的RGC死亡。缺血再灌注导致神经丛状内层与神经丛状外层厚度变薄，ERG记录a波和b波衰减。腹腔注射MCI-9042可明显减轻视网膜缺血的形态学和功能损伤。我们的数据表明，包括MCI-9042和M-1在内的5-HT2受体拮抗剂在培养的RGCs中具有神经保护作用，MCI-9042对缺血性视网膜疾病具有保护作用。2003爱思唯尔科学有限公司版权所有。
The neuroprotective effect of MCI-9042 (Mitsubishi Pharma Corporation) was investigated on glutamate-induced retinal ganglion cell (RGC) death in vitro and on rat retinal ischemia in vivo. RGCs were purified from retinal cells isolated from 6-day-old Wistar rats and cultured in serum-free media. After application of 25 muM glutamate, the viability of RGCs treated with or without several serotonin 2 (5-HT2) receptor antagonists: MCI-9042, M-1 (a major metabolite of MCI-9042), ketanserin, and LY-53857; was evaluated by calcein-acetoxymethyl ester staining. Retinal ischemia was induced by intraocular pressure (IOP) elevation (130 mmHg, 50 min). Rats were intraperitoneally injected with MCI-9042 at a dose of 3, 30 mg/kg or base at 30 min before and just after ischemia-reperfusion. Retinal damages were evaluated by histology, morphometric analysis and electroretinograms (ERGs) recordings at 7 days after ischemia-reperfusion. 25 muM glutamate decreased the number of viable RGCs to about 60 to 65% of untreated RGCs. MCI-9042, M-1, ketanserin, and LY-53857 significantly reduced glutamate-induced RGC death at concentrations of more than 100 nM, 1 nM, 1 muM and 100 nM, respectively. Ischemia-reperfusion caused thinning of the thickness between the inner plexiform layer and the outer plexiform layer and attenuation of a-and b-waves in ERG recordings. The intraperitoneal injection of MCI-9042 significantly reduced morphological and functional damages in retinal ischemia. Our data demonstrate that 5-HT2 receptor antagonists including MCI-9042 and M-1 have the neuroprotective effects in cultured RGCs and that MCI-9042 protects against ischemic retinal diseases. (C) 2003 Elsevier Science Ltd. All rights reserved.