Central Administration of Biological, Innovative Products, and Clinical Studies, Egyptian Drug Authority, EDA, Giza, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Faculty of Pharmacy, King Salman International University (KSIU), South Sinai, 46612, Egypt.
Food Chem Toxicol. 2023 Nov;181:114069. doi: 10.1016/j.fct.2023.114069. Epub 2023 Oct 14.
Parkinson's disease (PD) is characterized by motor impairments and progressive dopaminergic neuronal death in the substantia nigra (SN). Recently, the involvement of other regulated cell death (RCD) machineries has been highlighted in PD. Necroptosis is controlled by p-RIPK1, p-RIPK3, and p-MLKL and negatively regulated by caspase-8. Ferroptosis is characterized by iron overload and accumulation of reactive oxygen species. Interestingly, the molecular chaperone complex HSP90/CDC37 has been reported to directly regulate necroptosis, ferroptosis, and some PD-associated proteins. We investigated the potential anti-necroptotic and anti-ferroptotic effects of the anti-cancer drug pazopanib, uncovering the HSP90/CDC37 complex as a master RCD modulator in rotenone-induced Parkinsonism in rats. Oral administration of 15 mg/kg pazopanib to rotenone-intoxicated rats for three weeks improved motor deficits, debilitated histopathological changes, and increased striatal dopaminergic levels. Pazopanib suppressed LRRK2 and c-Abl. Pazopanib displayed an anti-necroptotic effect through inhibition of the p-RIPK1/p-RIPK3/p-MLKL pathway and activation of caspase-8. Moreover, pazopanib inhibited the ferroptotic p-VEGFR2-PKCβII-PLC-γ-ACSL-4 pathway, iron, 4-HNE, and PTGS2 while increasing GPX-4 and GSH levels. Taken together, the current research sheds light on the repositioning of pazopanib targeting HSP90/CDC37 and its multiple RCD mechanisms, which would offer a new perspective for therapeutic strategies in PD.
帕金森病（PD）的特征是运动障碍和黑质（SN）中多巴胺能神经元的进行性死亡。最近，其他调控细胞死亡（RCD）机制在 PD 中的参与得到了强调。坏死性凋亡受 p-RIPK1、p-RIPK3 和 p-MLKL 控制，并受 caspase-8 负调控。铁死亡的特征是铁过载和活性氧的积累。有趣的是，分子伴侣复合物 HSP90/CDC37 已被报道可直接调节坏死性凋亡、铁死亡和一些与 PD 相关的蛋白质。我们研究了抗癌药物帕唑帕尼的潜在抗坏死性凋亡和抗铁死亡作用，揭示 HSP90/CDC37 复合物是鱼藤酮诱导的大鼠帕金森病中主要的 RCD 调节剂。在三周内，给鱼藤酮中毒的大鼠口服 15mg/kg 帕唑帕尼可改善运动缺陷、减弱的组织病理学变化和增加纹状体多巴胺水平。帕唑帕尼抑制了 LRRK2 和 c-Abl。帕唑帕尼通过抑制 p-RIPK1/p-RIPK3/p-MLKL 通路和激活 caspase-8 发挥抗坏死性凋亡作用。此外，帕唑帕尼抑制了铁死亡的 p-VEGFR2-PKCβII-PLC-γ-ACSL-4 途径，抑制了铁、4-HNE 和 PTGS2，同时增加了 GPX-4 和 GSH 水平。总之，目前的研究揭示了帕唑帕尼针对 HSP90/CDC37 的重新定位及其多种 RCD 机制，为 PD 的治疗策略提供了新的视角。
