Inhibitory effect of INT-777 on lipopolysaccharide-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice

Progress in Neuro-psychopharmacology & Biological Psychiatry
Xian WuSu-Su Tang

Abstract

Neuroinflammation plays an important role in the pathophysiology of Alzheimer's disease (AD) and memory impairment. Herein, we evaluated the neuroprotective effects of 6-ethyl-23(S)-methyl-cholic acid (INT-777), a specific G-protein coupled bile acid receptor 1 (TGR5) agonist, in the LPS-treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of LPS remarkably induced mouse behavioral impairments in Morris water maze, novel object recognition, and Y-maze avoidance tests, which were ameliorated by INT-777 (1.5 or 3.0 μg/mouse, i.c.v.) treatment. Importantly, INT-777 treatment reversed LPS-induced TGR5 down-regulation, suppressed the increase of nuclear NF-κB p65, and mitigated neuroinflammation, evidenced by lower proinflammatory cytokines, less activation of microglia, and increased the ratio of p-CREB/CREB or mBDNF/proBDNF in the hippocampus and frontal cortex. In addition, INT-777 treatment also suppressed neuronal apoptosis, as indicated by the reduction of TUNEL-positive cells, decreased activation of caspase-3, increased the ratio of Bcl-2/Bax, and ameliorated synaptic dysfunction as evidenced by the upregulation of PSD95 and synaptophysin in the hippocampus and frontal cortex. Taken t...Continue Reading

Citations

Jan 28, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·John Y L Chiang, Jessica M Ferrell
Apr 25, 2019·Annual Review of Nutrition·John Y L Chiang, Jessica M Ferrell
Dec 12, 2019·Frontiers in Endocrinology·Jenna BloemerVishnu Suppiramaniam
Aug 14, 2020·International Journal of Molecular Sciences·Chunyue WangDi Wang
Nov 25, 2018·International Journal of Molecular Sciences·Wen-Ying ChenChun-Jung Chen
Nov 11, 2020·Nutritional Neuroscience·Diulie Valente de SouzaAlencar Kolinski Machado
Jun 27, 2019·Neuroscience Letters·Q LeyrolleA Nadjar

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