We have previously shown that JM-20, a new chemical entity consisting of 1,5-benzodiazepine fused to a dihydropyridine moiety, protects against rotenone-induced neurotoxicity in an experimental model of Parkinson’s disease (PD). The aim of this study was to investigate the effect of a novel hybrid molecule, named JM-20, in in vitro and in vivo models of PD induced by 6-hydroxydopamine (6-OHDA). PC-12 cells were exposed to 6-OHDA and treated with JM-20. Protection against mitochondrial damage induced by 6-OHDA was also investigated using isolated rat brain mitochondria. We found that JM-20 protected PC-12 cells against cytotoxicity induced by 6-OHDA and inhibited hydrogen peroxide generation, mitochondrial swelling and membrane potential dissipation. For in vivo experiments, adult male Wistar rats were lesioned in the substantia nigra pars compacta (SNpc) by 6-OHDA administration. JM-20 was orally administered (10, 20 or 40 mg/kg), intragastric via gavage, 24 h after surgery and daily for seven days. Treatment with JM-20 significantly reduced the percentage of motor asymmetry and increased vertical exploration. It improved the redox state of the SNpc and the striatal tissue of these animals. Also, JM-20 reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in SNpc. Altogether, these results demonstrate that JM-20 is a potential neuroprotective agent against 6-OHDA-induced damage in both in vitro and in vivo models. The mechanism underlying JM-20 neuroprotection against 6-OHDA appears to be associated with the control of oxidative injury and mitochondrial impairment.

我们之前已经表明 JM-20 是一种新的化学实体，由与二氢吡啶部分融合的 1,5-苯二氮卓类组成，可在帕金森病 (PD) 的实验模型中防止鱼藤酮引起的神经毒性。本研究的目的是研究一种名为 JM-20 的新型杂交分子在6-羟基多巴胺 (6-OHDA) 诱导的 PD体外和体内模型中的作用。PC-12 细胞暴露于 6-OHDA 并用 JM-20 处理。还使用分离的大鼠脑线粒体研究了对 6-OHDA 诱导的线粒体损伤的保护作用。我们发现 JM-20 保护 PC-12 细胞免受 6-OHDA 诱导的细胞毒性，并抑制过氧化氢的产生、线粒体肿胀和膜电位耗散。对于体内在实验中，通过 6-OHDA 给药，成年雄性 Wistar 大鼠的黑质致密部 (SNpc) 受到损伤。JM-20 口服给药（10、20 或 40 mg/kg），通过管饲法灌胃，手术后 24 小时，每天给药，共 7 天。JM-20 治疗显着降低了运动不对称的百分比并增加了垂直探索。它改善了这些动物的 SNpc 和纹状体组织的氧化还原状态。此外，JM-20 减少了神经胶质纤维酸性蛋白的过度表达，并增加了 SN​​pc 中酪氨酸羟化酶阳性细胞的数量。总之，这些结果表明 JM-20 是一种潜在的神经保护剂，可在体外和体内对抗 6-OHDA 诱导的损伤楷模。JM-20 针对 6-OHDA 的神经保护机制似乎与控制氧化损伤和线粒体损伤有关。