Encompassing live cell imaging and morphometrics at the microscopical level, we showed here, for the first time, protection of neuronal-like cells by the novel drug candidate, SKIP, against the Parkinson’s disease-related neurotoxin, rotenone. Mechanistically, rotenone disrupted microtubule dynamics, which SKIP partially repaired through microtubule end-binding proteins, coupled with increasing neurite branch length. Given the previous association of rotenone toxicity with increased dopaminergic cell death hallmarking Parkinson’s disease, we chose an established rat model of 6-hydroxydopamine (6-OHDA) toxicity to initially evaluate SKIP in vivo. SKIP pretreatment showed protection against nigral dopaminergic cell degeneration and improved motor behavior in the forelimb asymmetry test. With Parkinson’s disease being a major neurodegenerative disorder, afflicting millions of people globally, and with disease modification challenges, SKIP may hold promise for future therapeutic development.

包括微观层面的活细胞成像和形态测量学，我们在这里首次展示了新型候选药物 SKIP 对神经元样细胞的保护作用，使其免受帕金森病相关的神经毒素鱼藤酮的侵害。从机制上讲，鱼藤酮破坏了微管动力学，SKIP 通过微管末端结合蛋白进行了部分修复，同时增加了神经突分支的长度。鉴于之前鱼藤酮毒性与帕金森病标志性多巴胺能细胞死亡增加的关联，我们选择了一种已建立的 6-羟基多巴胺 (6-OHDA) 毒性大鼠模型来初步评估 SKIP 体内 。SKIP 预处理在前肢不对称测试中显示出对黑质多巴胺能细胞变性的保护和改善的运动行为。