Neuroprotective effects of INT-777 against Aβ1–42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice

Wu, Xian; Lv, Yangge; Du, Yifeng; Chen, Fang; Reed, Miranda N.; Mei, Hu; Suppiramaniam, Vishnu; Tang, Shuming; Hong, Hao

doi:10.1016/j.bbi.2018.06.018

Cited by 64 publications

(33 citation statements)

References 58 publications

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“…In addition to FXR, systemic in ammation is also accompanied by reduced TGR5 signaling. In consistency, the neuroprotective effect of TGR5 has also been shown in Aβ1-42-induced cognitive impairment mouse models [12]. Additionally, TGR5 activation prohibits hepatic encephalopathy [11,60].…”

Section: Discussionmentioning

confidence: 77%

Dysregulated Bile Acid Receptor-mediated Signaling and IL-17A Induction are Implicated in Diet-associated Hepatic Health and Cognitive Function

Jena

Sheng

Nguyen

et al. 2020

Preprint

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Background: Chronic consumption of high sugar and high fat diet associated with liver inflammation and cognitive decline. This paper tests a hypothesis that the development and resolution of diet-induced nonalcoholic fatty liver disease (NAFLD) has an impact on neuroplasticity and cognition. Methods: C57BL/6 wild-type mice were fed with either a healthy control diet (CD) or a fructose, palmitate, and cholesterol (FPC)-enriched diet since weaning. When mice were 3-months old, FPC diet-fed mice were randomly assigned to receive either FPC-enriched diet with or without 6% inulin supplementation. At 8 months of age, all three groups of mice were euthanized followed by analysis of inflammatory signaling in the liver and brain, gut microbiota, and cecal metabolites. Results: Our data shows that FPC diet intake induced hepatic steatosis and inflammation in the liver and brain along with elevated RORγ and IL-17A signaling. Accompanied by microglia activation and reduced hippocampal long-term potentiation, FPC diet intake also reduced postsynaptic density-95 and brain derived neurotrophic factor, whereas inulin supplementation prevented diet-reduced neuroplasticity and the development of NAFLD. In the gut, FPC diet increased Coriobacteriaceae and Erysipelotrichaceae, which are implicated in cholesterol metabolism, and the genus Allobaculum, and inulin supplementation reduced them. Furthermore, FPC diet reduced FXR and TGR5 signalling, and inulin supplementation reversed these changes. Untargeted cecal metabolomics profiling uncovered 273 metabolites, and 104 had significant changes due to FPC diet intake or inulin supplementation. Among the top 10 most affected metabolites, FPC-fed mice had marked increase of zymosterol, a cholesterol biosynthesis metabolite, and reduced 2,8-dihydroxyquinoline, which has known benefits in reducing glucose intolerance; these changes were reversible by inulin supplementation. Additionally, the abundance of Barnesiella, Coprobacter, Clostridium XIVa, and Butyrivibrio were negatively correlated with FPC diet intake and the concentration of cecal zymosterol but positively associated with inulin supplementation. suggesting their benefits. Conclusion: Taken together, the presented data suggest that diet alters the gut microbiota and their metabolites, including bile acids. This will subsequently affect IL-17A signaling, resulting in systemic impacts on both hepatic metabolism and cognitive function.

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Section: Discussionmentioning

confidence: 77%

Dysregulated Bile Acid Receptor-mediated Signaling and IL-17A Induction are Implicated in Diet-associated Hepatic Health and Cognitive Function

Jena

Sheng

Nguyen

et al. 2020

Preprint

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“…In pre-clinical studies, targeting bile acid signaling has also been identified as a potential experimental therapy to alleviate various aspects of AD. Using a surgical model of AD, Aβ toxicity induced via single intracerebral ventricular injection of Aβ 1-42, treatment with INT-777 (6α-ethyl-23(S)-methylcholic acid, a TGR5 agonist) significantly attenuated the cognitive impairment and decreased neuroinflammation, as measured by decreased proinflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) cytokine production and microglia activation [ 77 ]. In contrast, an in vitro study using an SH-SY5Y treated Aβ 1-42 AD cell model noted FXR overexpression triggered neuronal apoptosis via activation of the cAMP-response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway [ 78 ].…”

Section: Bile Acids In Neurodegenerative Diseasesmentioning

confidence: 99%

Bile Acid Signaling in Neurodegenerative and Neurological Disorders

Grant

DeMorrow

2020

IJMS

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Bile acids are commonly known as digestive agents for lipids. The mechanisms of bile acids in the gastrointestinal track during normal physiological conditions as well as hepatic and cholestatic diseases have been well studied. Bile acids additionally serve as ligands for signaling molecules such as nuclear receptor Farnesoid X receptor and membrane-bound receptors, Takeda G-protein-coupled bile acid receptor and sphingosine-1-phosphate receptor 2. Recent studies have shown that bile acid signaling may also have a prevalent role in the central nervous system. Some bile acids, such as tauroursodeoxycholic acid and ursodeoxycholic acid, have shown neuroprotective potential in experimental animal models and clinical studies of many neurological conditions. Alterations in bile acid metabolism have been discovered as potential biomarkers for prognosis tools as well as the expression of various bile acid receptors in multiple neurological ailments. This review explores the findings of recent studies highlighting bile acid-mediated therapies and bile acid-mediated signaling and the roles they play in neurodegenerative and neurological diseases.

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“…Spatial learning and memory function were assessed by MWM test according to our previous studies [30]. It was conducted for 6 days including a 5-days training sessions, and a probe trial on the sixth day.…”

Section: Morris Water Maze (Mwm) Testmentioning

confidence: 99%

“…The recognition memory of mice was evaluated by NOR test as described previously [30,31]. Mice were placed in the center of the open eld chamber(72 cm × 72 cm × 36 cm).…”

Section: Novel Object Recognition (Nor) Testmentioning

confidence: 99%

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Pharmacological activation of GPR55 improved cognitive impairment, neuroinflammation, oxidative stress and apoptosis induced by lipopolysaccharide in mice

Wang

Xiang

et al. 2020

Preprint

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BackgroundNeuroinflammation, oxidative stress and apoptosis are implicated in the pathogenesis of Alzheimer’s disease (AD). The purpose of the present study was to investigate the neuroprotective effects and possible mechanism of G-protein coupled receptor 55 (GPR55) agonist, O-1602, on lipopolysaccharide (LPS)-induced cognitive deficits in mice. MethodsICR mice were treated with intracerebroventricular (i.c.v.) injection of LPS. Cognitive tests were performed, including the open field, Morris water maze, novel object recognition, and passive avoidance tests. The expression of GPR55, NF-κB p65, caspase-3, Bax and Bcl-2 were examined in the hippocampus by western blotting. Pro-inflammatory cytokines and microglia were detected by ELISA kit and immunohistochemical analyses, respectively. The malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity were examined by assay kits. Furthermore, TUNEL-staining was used to detect neuronal apoptosis.ResultsI.c.v. injection of LPS exhibited impaired performance in the behavior tests, which were ameliorated by O-1602 treatment(2.0 or 4.0 μg/mouse, i.c.v.). Importantly, O-1602 reversed GPR55 down-regulation, decreased the expression of NF-κB p65, and suppressed the accumulation of pro-inflammatory cytokines and microglia activation, decreased malondialdehyde (MDA) level, and increased superoxide dismutase (SOD) activity. In addition, O-1602 also significantly decreased Bax and increased Bcl-2 expression as well as decreased caspase-3 activity and TUNEL-positive cells, suppressed neuronal apoptosis in the hippocampus of LPS-treated mice.Conclusionswe conclude that O-1602 may ameliorate LPS-induced cognition deficits via inhibiting neuroinflammation, oxidative stress and apoptosis mediated by NF-κB signaling in mice.

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Neuroprotective effects of INT-777 against Aβ1–42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice

Cited by 64 publications

References 58 publications

Dysregulated Bile Acid Receptor-mediated Signaling and IL-17A Induction are Implicated in Diet-associated Hepatic Health and Cognitive Function

Dysregulated Bile Acid Receptor-mediated Signaling and IL-17A Induction are Implicated in Diet-associated Hepatic Health and Cognitive Function

Bile Acid Signaling in Neurodegenerative and Neurological Disorders

Pharmacological activation of GPR55 improved cognitive impairment, neuroinflammation, oxidative stress and apoptosis induced by lipopolysaccharide in mice

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