Benfotiamine protects MPTP-induced Parkinson’s disease mouse model via activating Nrf2 signaling pathway

by Kai Wang, Chao Han, Jinwei Yang, Wenhao Xu, Lei Wang, Huaiyu Li, Yu Wang

The pursuit of drugs and methods to safeguard dopaminergic neurons holds paramount importance in Parkinson’s disease (PD) research. Benfotiamine (BFT) has demonstrated neuroprotective properties, yet its precise mechanisms in PD remain elusive. This study investigated BFT’s potential protective effects against dopamine neuron damage in a PD animal model and the underlying mechanisms. The PD mouse model was induced by 5 consecutive MPTP injections, followed by BFT intervention for 28 days. Motor deficits were assessed via pole test, hang test, gait analysis, and open field test, while dopaminergic neuron damage was evaluated through Immunofluorescence, Nissl staining, and Western blot analysis of Tyrosine Hydroxylase (TH) in the substantia nigra and striatum. High Performance Liquid Chromatography quantified dopamine (DA) levels and its metabolites. Genetic pathways were explored using RNA-seq and bioinformatics analysis on substantia nigra tissues, confirmed by qPCR. Activation of the Nrf2 pathway was examined through nuclear translocation and expression of downstream antioxidant enzymes HO-1, GCLM, and NQO1 at mRNA and protein levels. Additionally, measurements of MDA content, GSH activity, and SOD activity were taken in the substantia nigra and striatum. BFT administration improved motor function and protected against dopaminergic neuron degeneration in MPTP mice, with partial recovery in TH expression and DA levels. RNA-seq analysis revealed distinct effects of BFT and the NLRP3 inhibitor MCC950 on Parkinson-related pathways and genes. Control of Nrf2 proved crucial for BFT, as it facilitated Nrf2 movement to the nucleus, upregulating antioxidant genes and enzymes while mitigating oxidative damage. This study elucidates BFT’s neuroprotective effects in a PD mouse model via Nrf2-mediated antioxidant mechanisms and gene expression modulation, underscoring its potential as a therapeutic agent for PD.