Oxymatrine-associated protection in an MPTP mouse model is accompanied by increased miR-141-3p and reduced HMGB1.

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IntroductionOxymatrine (OMT) alleviates damage to dopaminergic (DA) neurons and microglia-mediated neuroinflammation in an MPTP mouse model of parkinsonism by inhibiting the High-mobility group protein B1 (HMGB1) pathway. However, the precise mechanism by which OMT inhibits HMGB1 remains unclear. Although miR-141-3p is downregulated in the peripheral blood serum of Parkinson's disease (PD) patients, its potential relationship with HMGB1 remains unclear.MethodsTargetScan software and dual-luciferase reporter gene assays predicted that miR-141-3p binds to the 3'-UTR of HMGB1 mRNA. BV2 cells were transfected with miR-141-3p mimics and stimulated with MPP+ in vitro experiments. C57BL/6 J mice received stereotaxic injections of miR-141-3p agomir or miR-141-3p antagomir into the bilateral substantia nigra pars compacta (SNpc). Subsequently, the mice were intraperitoneally injected with MPTP four times within a single day. After miR-141-3p antagomir injection, OMT was administered continuously by injection for 7 days. Behavioral tests were assessed using the rotarod and open field tests. Real-time PCR, western blot, ELISA, and immunofluorescence staining were performed on BV2 cells and SNpc tissues.ResultsOur study showed an inverse correlation between HMGB1 and miR-141-3p expression in both BV2 microglia exposed to MPP+ and MPTP-treated mice. TargetScan analysis identified complementary binding sites between miR-141-3p and the 3'-UTR of HMGB1 mRNA, which was subsequently confirmed through dual-luciferase reporter assays. Through experiments in BV2 microglia exposed to MPP+ and in MPTP-treated mice, miR-141-3p downregulates HMGB1, reduces pro-inflammatory cytokine readouts, and in vivo is associated with improved rotarod and open-field performance and attenuated Tyrosine Hydroxylase (TH)-positive neuronal loss. OMT increases miR-141-3p in the MPTP model, alongside reduced HMGB1 and inflammatory readouts, and these effects are diminished by miR-141-3p inhibition.ConclusionmiR-141-3p targets HMGB1 to inhibit microglial reaction and mitigate neuroinflammation both in vivo and vitro experiments, reduce TH-positive neuronal loss in the MPTP model. OMT increases miR-141-3p in the MPTP model, alongside reduced HMGB1 and inflammatory readouts, and these effects are diminished by miR-141-3p inhibition.

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