TGR5 Agonist INT-777 Alleviates Inflammatory Neurodegeneration in Parkinson’s Disease Mouse Model by Modulating Mitochondrial Dynamics in Microglia

• Published in: Neuroscience 2022-05, Vol.490, p.100-119
• Main Authors: Huang, Rui, Gao, Yuyuan, Chen, Jianing, Duan, Qingrui, He, Peikun, Zhang, Jiahui, Huang, Heling, Zhang, Qingxi, Ma, Guixian, Zhang, Yuhu, Nie, Kun, Wang, Lijuan
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Animals; bile acid; Cholic Acids - pharmacology; cognitive impairment; Disease Models, Animal; Dopaminergic Neurons - metabolism; Mice; Mice, Inbred C57BL; Microglia - metabolism; Mitochondrial Dynamics; mitochondrial homeostasis; neuroinflammation; Parkinson Disease, Secondary - drug therapy; Parkinson’s disease; TGR5 signaling; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2022.02.028

[Display omitted] •INT-777 alleviated motor deficits and cognitive impairment in a MPTP-induced PD model.•INT-777 inhibited neuronal death and microglia activation in three brain regions.•INT-777 suppressed microglia activation in the hippocampus via TNF signaling.•INT-777 reversed microglial mitochondrial damage through TGR5 to inhibit TNF-α levels.•INT-777 prevented neurodegeneration by inhibiting the release of TNF-α from microglia. Parkinson’s disease (PD) is one of the most common chronic progressive neurodegenerative diseases that affects both motor and non-motor functions. Bile acids modulate the immune system by targeting brain receptors. INT-777, a 6α-ethyl-23(S)-methyl derivative of cholic acid (S-EMCA), acts as an agonist for Takeda G protein-coupled receptor-5 (TGR5) and has neuroprotective properties. However, the effects of INT-777 on PD have not yet been investigated. In a subchronic PD model, mice treated with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed motor deficits and cognitive impairment that were ameliorated after intranasal administration of INT-777. INT-777 prevented MPTP-induced neurodegeneration and microglia activation in the substantia nigra pars compacta, hippocampus, and cortical layer V. Based on bioinformatics and wet lab data, INT-777 inhibited microglia activation by suppressing the release of tumor necrosis factor alpha (TNF-α) in the hippocampus, along with secondary chemokines (C–C motif ligand 3 (CCL3) and CCL6) in these three brain regions. INT-777 inhibited TNF-α production by repairing mitochondrial damage, which was associated with nuclear factor-erythroid 2-related factor-2 (NRF2) activation and p62/LC3B-mediated autophagy. INT-777 reversed the downregulation of heme oxygenase-1 (HO1), NAD(P)H quinone oxidoreductase-1 (NQO1) and accumulation of p62 in microglia treated with 1-methyl-4-phenylpyridinium (MPP+). However, TGR5 knockdown in microglia abolished INT-777′s inhibition of TNF-α release, resulting in neuronal death. Therefore, PD cognitive impairment is associated with hippocampal TNF-α elevation as a result of mitochondrial damage in microglia. Our data reveal the potential role of TGR5 in modulating inflammation-mediated neurodegeneration in PD, and provides new insights for bile acid metabolites as promising disease-modifying drugs for PD.