pazopanib and Parkinson-Disease

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons and the accumulation of Lewy bodies (LB) in the substantia nigra (SN). Evidence shows that microglia-mediated neuroinflammation plays a key role in PD pathogenesis. Using TNF-α as an indicator for microglial activation, we established a cellular model to screen compounds that could inhibit neuroinflammation. From 2471 compounds in a small molecular compound library composed of FDA-approved drugs, we found 77 candidates with a significant anti-inflammatory effect. In this study, we further characterized pazopanib, a pan-VEGF receptor tyrosine kinase inhibitor (that was approved by the FDA for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma). We showed that pretreatment with pazopanib (1, 5, 10 μM) dose-dependently suppressed LPS-induced BV2 cell activation evidenced by inhibiting the transcription of proinflammatory factors iNOS, COX2, Il-1β, and Il-6 through the MEK4-JNK-AP-1 pathway. The conditioned medium from LPS-treated microglia caused mouse DA neuronal MES23.5 cell damage, which was greatly attenuated by pretreatment of the microglia with pazopanib. We established an LPS-stimulated mouse model by stereotactic injection of LPS into mouse substantia nigra. Administration of pazopanib (10 mg·kg

Topics: Animals; Anti-Inflammatory Agents; Dopaminergic Neurons; Lipopolysaccharides; Mice; Microglia; Neurodegenerative Diseases; Parkinson Disease; Transcription Factor AP-1

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.

Topics: Animals; Caspase 8; Dopamine; Ferroptosis; HSP90 Heat-Shock Proteins; Molecular Chaperones; Parkinson Disease; Parkinsonian Disorders; Rats; Rotenone