Pazopanib ameliorates rotenone-induced Parkinsonism in rats by suppressing multiple regulated cell death mechanisms

• Published in: Food and chemical toxicology 2023-11, Vol.181, p.114069-114069, Article 114069
• Main Authors: Mansour, Heba M., Mohamed, Ahmed F., Khattab, Mahmoud M., El-Khatib, Aiman S.
• Format: Article
• Language: English
• Subjects: Ferroptosis; Heat shock protein-90; Necroptosis; Parkinson’s disease; Pazopanib; Regulated cell death
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2023.114069

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. [Display omitted] •Pazopanib inhibits necroptosis and its related kinases in a rat model of PD.•Pazopanib reduces ferroptosis biomarkers in a rat model of PD.•HSP90 regulates RCD by controlling the functionality and stability of its clients.•Pazopanib suppressed the activity of HSP90/CDC37, a key junction in various RCDs.•Pazopanib may be a potential disease-modifying treatment for PD.