Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain.
Int J Pharm. 2011 Oct 31;419(1-2):271-80. doi: 10.1016/j.ijpharm.2011.07.029. Epub 2011 Jul 22.
This is the first report on the efficacy of a new controlled release system developed for rasagiline mesylate (RM) in a rotenone-induced rat model of Parkinson's disease (PD). PLGA microspheres in vitro released RM at a constant rate of 62.3 μg/day for two weeks. Intraperitoneal injection of rotenone (2 mg/kg/day) to Wistar rats produced typical PD symptoms. Catalepsy, akinesia and swim tests outcomes in animals receiving RM either in solution or within microspheres showed a reversal in descent latency when compared to rotenone-treated animals, being this reversal specially pronounced in animals receiving RM microspheres (dose equivalent to 1 mg/kg/day RM injected i.p. every 15 days). Nissl-staining of brain sections showed selective degeneration of the substantia nigra (SNc) dopaminergic neurons in rotenone-treated animals which was markedly reverted by RM microspheres. PET/CT with (18)F-DG resulted in mean increases of accumulation of radiotracer in striatum and SNc of around 40% in animals treated with RM microspheres which also had significant beneficial effects on Bcl-2, Bax, TNF-α mRNA and SOD2 levels as detected by real-time RT-PCR. Our results confirm the robust effect achieved by the new controlled release system developed for RM which exhibited better in vivo efficacy than RM given in solution.
这是第一个关于甲磺酸雷沙吉兰（RM）新控释系统在鱼藤酮诱导的帕金森病（PD）大鼠模型中的疗效的报告。PLGA 微球在体外以每天 62.3μg 的恒定速率释放 RM，持续两周。腹腔注射鱼藤酮（2mg/kg/天）至 Wistar 大鼠产生典型的 PD 症状。接受 RM 溶液或微球治疗的动物的僵直、运动不能和游泳测试结果显示，与鱼藤酮处理的动物相比，潜伏期有逆转，而接受 RM 微球治疗的动物的逆转更为明显（相当于每天 15 天腹腔注射 1mg/kg/天 RM 的剂量）。大脑切片的尼氏染色显示，鱼藤酮处理的动物中黑质（SNc）多巴胺能神经元选择性退化，RM 微球明显逆转了这种退化。（18）F-DG 的 PET/CT 显示，接受 RM 微球治疗的动物纹状体和 SNc 中放射性示踪剂的累积平均增加了约 40%，实时 RT-PCR 检测到 RM 微球还对 Bcl-2、Bax、TNF-α mRNA 和 SOD2 水平有显著的有益影响。我们的结果证实了为 RM 开发的新控释系统所达到的强大效果，其体内疗效优于 RM 溶液。
