INT-777 is a novel specific semisynthetic TGR5 agonist used for alleviating cardiomyocyte injury and improving cognitive impairment and synaptic dysfunction in mice model of AD.[1][2]
In vitro, INT-777 induced a dose-dependent (10 μM to 60 μM) decrease in Isc, when INT-777 added on the serosal side of seromuscular stripped distal colon segments in Ussing chambers.[5] In vitro experiment it shown that treatment with 25 μm of INT-777 for 48 h in αTC1-6 cells as well as in mouse and human islets under high glucose conditions obviously increased PC1 mRNA. However, INT-777 (25 μm) had no effect on PC1 mRNA in cells exposed to low glucose conditions.[6] In vitro, combination 100 ng/ml LPS with treatment of 30 μM INT-777 dramatically decreased the transient increase in mRNA levels for Tnfα, monocyte chemoattractant protein-1 (Mcp-1), Il-6 and Il-1β in macrophages.[7]
In vivo efficacy test it indicated that treatment with 30μg/kg of INT-777 dramatically reduced NLRP3-ASC inflammasome activation in microglia, decreased brain edema and neuroinflammation, resulted in improved short-term neurobehavioral functions at 24 h after subarachnoid hemorrhage.[3] In vivo study it suggested that mice were treated with 1.5 or 3.0 μg/mouse INT-777, single intracerebroventricular (i.c.v.) injection of LPS obviously induced mouse behavioral impairments in Morris water maze, novel object recognition, and Y-maze avoidance tests were ameliorated.[7].
References:
[1]. Wu X, et al. Neuroprotective effects of INT-777 against Aβ1-42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice. Brain Behav Immun. 2018 Oct;73:533-545.
[2]. Deng L, et al. Activation of TGR5 Partially Alleviates High Glucose-Induced Cardiomyocyte Injury by Inhibition of Inflammatory Responses and Oxidative Stress. Oxid Med Cell Longev, 2019: 6372786.
[3]. Hu X, et al. INT-777 attenuates NLRP3-ASC inflammasome-mediated neuroinflammation via TGR5/cAMP/PKA signaling pathway after subarachnoid hemorrhage in rats. Brain Behav Immun. 2021 Jan;91:587-600.
[4]. Wu X, et al. Inhibitory effect of INT-777 on lipopolysaccharide-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jan 10;88:360-374.
[5]. Sorrentino G, et al. Bile Acids Signal via TGR5 to Activate Intestinal Stem Cells and Epithelial Regeneration. Gastroenterology. 2020 Sep;159(3):956-968.e8.
[6]. Kumar DP, et al. Activation of Transmembrane Bile Acid Receptor TGR5 Modulates Pancreatic Islet α Cells to Promote Glucose Homeostasis. J Biol Chem. 2016 Mar 25;291(13):6626-40.
[7]. Pols TW, et al. TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metab. 2011 Dec 7;14(6):747-57.
INT-777 是一种新型特异性半合成 TGR5 激动剂，用于减轻 AD 小鼠模型的心肌细胞损伤，改善认知障碍和突触功能障碍。[1][2]
在体外，当 INT-777 添加到 Ussing 室的浆膜剥离的远端结肠段的浆膜侧时，INT-777 诱导 Isc 剂量依赖性（10 μM 至 60 μM）减少。[5] 体外实验表明，25 μm INT-777 处理 αTC1-6 细胞以及高糖条件下小鼠和人胰岛细胞 48 小时后，PC1 mRNA 明显增加。然而，INT-777 (25 μm) 对暴露于低葡萄糖条件的细胞中的 PC1 mRNA 没有影响。[6] 在体外，100 ng/ml LPS 与 30 μM INT-777 的组合显着降低巨噬细胞中 Tnfα、单核细胞趋化蛋白-1 (Mcp-1)、IL-6 和 Il-1β mRNA 水平的瞬时升高。[7]
体内药效试验表明，用 30μg/kg 的 INT-777 治疗可显着降低小胶质细胞中 NLRP3-ASC 炎性体的激活，减少脑水肿和神经炎症，从而改善蛛网膜下腔出血后 24 小时的短期神经行为功能。 [3] 体内研究表明，小鼠经 1.5 或 3.0 μg/小鼠 INT-777 处理后，单次侧脑室 (i.c.v.) 注射 LPS 可明显诱导小鼠在 Morris 水迷宫中的行为障碍，新颖的对象识别和 Y 迷宫回避测试得到改善。[7]。