Acta Neuropharmacologica ›› 2018, Vol. 8 ›› Issue (4): 11-12.
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LIU Cai-hong,WU Xian,TANG Su-su,HONG Hao*
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Abstract: TGR5 (Takeda G-protein-coupled receptor 5) is a bile acid G protein-coupled receptor primarily expressed in liver,gallbladder,intestine,spleen,and brain and activated by bile acids. (AD). Herein,we evaluated the neuroprotective effects of TGR5 agonist,6α-ethyl-23(S)-methylcholic acid (S-EMCA,INT-777),in the Aβ1-42-treated mouse model of acute neurotoxicity. Single intracerebroventricular( i.c.v.) injection of aggregated Aβ1-42( 410 pmol/mouse;5 μL) into the mouse brain induced cognitive impairment,neuroinflammation,apoptosis,and synaptic dysfunction. In contrast,INT-777 (1.5 or 3.0 μg/mouse,i.c.v.) significantly improved Aβ1-42-induced cognitive impairment,as reflected by better performance in memory tests. Importantly, INT-777 treatment reversed Aβ1-42-induced TGR5 down-regulation,suppressed the increase of nuclear NF-κB p65,and mitigated neuroinflammation,as evidenced by lower proinflammatory cytokines and less Iba1-positive cells in the hippocampus and frontal cortex. INT-777 treatment also pronouncedly suppressed apoptosis through the reduction of TUNEL-positive cells, decreased activation of caspase-3,increased the ratio of Bcl-2/Bax,and ameliorated synaptic dysfunction by promoting dendritic spine generation with the upregulation of postsynaptic (PSD95) and presynaptic proteins in Aβ1-42-treated mice. Our results indicate that INT-777 has potent neuroprotective effects against Aβ1-42-induced neurotoxicity. Taken together,these findings suggest that TGR5 might participate in the pathogenesis of Alzheimer’s disease.
Key words: TGR5, INT-777, A&beta, 1-42, neurotoxicity, memory, neuroinflammation, apoptosis, Synaptic dysfunction
LIU Cai-hong,WU Xian,TANG Su-su,HONG Hao*. Involvement of TGR5 in Aβ-Induced Neurotoxicity in Vivo[J]. Acta Neuropharmacologica, 2018, 8(4): 11-12.
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