title: Thymol improves high-fat diet-induced cognitive deficits in mice via ameliorating brain insulin resistance and upregulating NRF2/HO-1 pathway.
abstract: The impaired insulin signaling has been recognized as a common pathogenetic mechanism between diabetes and Alzheimer's disease (AD). In the progression of AD, brain is characterized by defective insulin receptor substrate-1 (IRS-1) and increased oxidative stress. Thymol, a monoterpene phenol isolated from medicinal herbs, has exhibited robust neuroprotective effects. The present study was designed to investigate the protective effect of thymol on HFD-induced cognitive deficits, and explore the possible mechanisms. C57BL/6 J mice were fed for 12 weeks with either HFD or normal diet. The mice fed with HFD were dosed with metformin (200 mg/kg) or thymol (20, 40 mg/kg) daily. It was observed that thymol treatment significantly reversed the gain of body weight and peripheral insulin resistance induced by HFD. Meanwhile, thymol improved the cognitive impairments in the Morris Water Maze (MWM) test and decreased HFD-induced Aβ deposition and tau hyperphosphorylation in the hippocampus, which may be correlated with the inhibition of hippocampal oxidative stress and inflammation. In addition, thymol down-regulated the level of P-Ser307 IRS-1, and hence enhancing the expression of P-Ser473 AKT and P-Ser9 GSK3β. We further found that the protective effects of thymol on cognitive impairments were associated with the up-regulation of nuclear respiratory factor (Nrf2)/heme oxygenase-1(HO-1) pathway. In conclusion, thymol exhibited beneficial effects on HFD-induced cognitive deficits through improving hippocampal insulin resistance, and activating Nrf2/HO-1 signaling.
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China PharmaceuticalUniversity, Nanjing, 210009, People's Republic of China.
authors.lastname: FangFang
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China PharmaceuticalUniversity, Nanjing, 210009, People's Republic of China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China PharmaceuticalUniversity, Nanjing, 210009, People's Republic of China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Qin
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China PharmaceuticalUniversity, Nanjing, 210009, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China PharmaceuticalUniversity, Nanjing, 210009, People's Republic of China. spma@cpu.edu.cn.
authors.forename: Shiping
authors.initials: S
authors.lastname: Ma
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007333:Insulin Resistance; D007859:Learning Disabilities / Q000209:etiology / Q000523:psychology; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000523:psychology; D008687:Metformin / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D013943:Thymol / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D016207:Cytokines; D007004:Hypoglycemic Agents; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D013943:Thymol; D008687:Metformin; D051547:Heme Oxygenase-1
keywords: Cognitive deficits; High-fat diet; Insulin signaling; Nrf2; Oxidative stress; Thymol