Ethopropazine Hydrochloride

Parkinson's disease (PD) is a neurodegenerative disease characterized by degeneration and necrosis of dopaminergic neurons in the substantia nigra and decreased dopamine secretion in the striatum. Bile acids are important components of animal bile. In recent years, a variety of hydrophilic bile acids have been reported to have ameliorative effects in neurodegenerative diseases. Taurochenodeoxycholic acid (TCDCA) is one of the components of bile acids. However, whether TCDCA can treat PD and its specific mechanism is unclear. In this study, 1-methyl-4-phenylpyridine (MPTP)-induced PD model mice were established to investigate the effects of TCDCA on PD model mice and the impact of microglia-mediated neuroinflammation. Concurrently, in vitro cell experiments utilized the lipopolysaccharide (LPS)-induced BV-2 microglial inflammation model to further investigate the effect and mechanism of TCDCA in inhibiting neuroinflammation. TCDCA effectively improved dyskinesia, attenuated dopaminergic neuronal damage in the substantia nigra and striatum, and inhibited α-Synuclein (α-Syn) expression in the substantia nigra of PD mice. TCDCA significantly inhibited microglia and astrocyte activation in the substantia nigra of PD mice, and decreased the messenger ribonucleic acid (mRNA) and protein expressions of inflammatory factors. In addition, TCDCA was found to inhibit nitric oxide release and reactive oxygen species production in LPS-stimulated BV2 microglia. Furthermore, TCDCA suppressed the production of inflammatory factors, including interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α), both in vivo and in vitro. Meanwhile, TCDCA significantly promoted Takeda G protein-coupled receptor 5 (TGR5) protein expression and inhibited the phosphorylation of serine/threonine kinase B (AKT), nuclear factor κB (NFκB) and inhibitor of NFκB (IκBα). TCDCA promoted autophagy in vivo and in vitro by increasing adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation, inhibiting mammalian target of rapamycin (mTOR) phosphorylation, increasing LC3II/LC3I and Beclin1 expression, and decreasing P62 expression. Furthermore, TCDCA demonstrated mitochondrial protection by enhancing the expression of PTEN induced putative kinase 1 (Pink1) and Parkin. However, knockdown of TGR5 expression partially counteracted the inhibitory effect of TCDCA on LPS-treated BV-2 cells. Our results manifested that TCDCA activated autophagy and inhibited microglia-mediated neuroinflammation in experimental PD models probably through regulation of AKT/NFκB, AMPK/mTOR and Pink1/Parkin signaling pathways via activation of TGR5.

The selective removal of mitochondria by mitophagy proceeds via multiple mechanisms and is essential for human well-being. The PINK1/Parkin and NIX/BNIP3 pathways are strongly linked to mitochondrial dysfunction and hypoxia, respectively. Both are regulated by ubiquitylation and mitochondrial import. Recent studies have elucidated how the ubiquitin kinase PINK1 acts as a sensor of mitochondrial import stress through stable interaction with a mitochondrial import supercomplex. The stability of BNIP3 and NIX is regulated by the SCF^FBXL4 ubiquitin ligase complex. Substrate recognition requires an adaptor molecule, PPTC7, whose availability is limited by mitochondrial import. Unravelling the functional implications of each mode of mitophagy remains a critical challenge. We propose that mitochondrial import stress prompts a switch between these two pathways.