Izumi Yukitoshi, Ishikawa Makoto, Benz Ann M, Izumi Masayo, Zorumski Charles F, Thio Liu Lin
Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Epilepsia. 2004 Sep;45(9):1043-8. doi: 10.1111/j.0013-9580.2004.01004.x.
Vigabatrin (VGB) is an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase. Its use as an antiepileptic drug (AED) has been limited because it causes retinal dysfunction, leading to visual field defects (VFDs). We performed this study to identify factors contributing to acute VGB retinotoxicity.
In ex vivo experiments, Sprague-Dawley rat retinas were isolated and incubated with VGB or GABA in the presence or absence of light. In in vivo experiments, Sprague-Dawley rats were given intraperitoneal injections of VGB and then exposed to light or kept in the dark. The retinas were analyzed histologically by using both light and electron microscopy.
Incubating retinas with 50-500 microM VGB under 20,000 Lux white light for < or = 20 h caused a characteristic time- and dose-dependent degeneration limited to the outer retina. Incubating retinas with 500 microM VGB in darkness for 20 h caused no damage. Five hundred micromolar GABA and 50 microM tiagabine were not toxic in the presence or absence of light. Sprague-Dawley rats exposed to an intense white light for 20 h after a 1,000-mg/kg intraperitoneal injection of VGB showed damage in the outer retina, whereas those kept in the dark did not.
Direct exposure of the retina to VGB causes acute retinotoxicity that depends on light exposure rather than GABA accumulation.
氨己烯酸（VGB）是γ-氨基丁酸（GABA）转氨酶的不可逆抑制剂。其作为抗癫痫药物（AED）的应用受到限制，因为它会导致视网膜功能障碍，进而引起视野缺损（VFDs）。我们开展这项研究以确定导致急性VGB视网膜毒性的因素。
在体外实验中，分离Sprague-Dawley大鼠的视网膜，并在有或无光照的情况下与VGB或GABA一起孵育。在体内实验中，给Sprague-Dawley大鼠腹腔注射VGB，然后使其暴露于光照下或置于黑暗中。使用光学显微镜和电子显微镜对视网膜进行组织学分析。
在20000勒克斯白光下，用50 - 500微摩尔VGB孵育视网膜≤20小时会导致特征性的、时间和剂量依赖性的变性，且仅限于视网膜外层。在黑暗中用500微摩尔VGB孵育视网膜20小时未造成损伤。500微摩尔GABA和50微摩尔噻加宾在有或无光照的情况下均无毒性。腹腔注射1000毫克/千克VGB后暴露于强光下20小时的Sprague-Dawley大鼠视网膜外层出现损伤，而置于黑暗中的大鼠则未出现损伤。
视网膜直接暴露于VGB会导致急性视网膜毒性，这种毒性取决于光照而非GABA的蓄积。
