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

Neuroscience. 2022 May 10:490:100-119. doi: 10.1016/j.neuroscience.2022.02.028. Epub 2022 Mar 4.

Abstract

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.

Keywords: Parkinson’s disease; TGR5 signaling; bile acid; cognitive impairment; mitochondrial homeostasis; neuroinflammation.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 1-Methyl-4-phenylpyridinium
  • Animals
  • Cholic Acids / pharmacology
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microglia* / metabolism
  • Mitochondrial Dynamics*
  • Parkinson Disease, Secondary* / drug therapy
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 6alpha-ethyl-23(S)-methylcholic acid
  • Cholic Acids
  • Tumor Necrosis Factor-alpha
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 1-Methyl-4-phenylpyridinium