Piperine regulates glycogen synthase kinase-3β-related signaling and attenuates cognitive decline in D-galactose-induced aging mouse model.
Piperine regulates glycogen synthase kinase-3β-related signaling and attenuates cognitive decline in D-galactose-induced aging mouse model.
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DOI：
10.1016/j.jnutbio.2019.108261
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发表时间：
2019-10
期刊：
影响因子：
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通讯作者：
Che Wang;Zhengxu Cai;Wei Wang;Min Wei;Xinhong Si;Yuting Shang;Zhaofei Yang;Tianbai Li
中科院分区：
文献类型：
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作者：
Che Wang;Zhengxu Cai;Wei Wang;Min Wei;Xinhong Si;Yuting Shang;Zhaofei Yang;Tianbai Li
老年性胆碱能功能障碍、广泛的神经炎症和脑内氧化应激是痴呆的主要致病因素。本研究旨在评价黑胡椒生物碱营养成分胡椒碱对D-半乳糖(D-Gal)致衰老小鼠认知功能障碍的保护作用，并探讨其可能的作用机制。反复皮下注射D-半乳糖(150 mg/kg，1次/d，共42d)建立小鼠衰老模型。第一次D-Gal染毒后14天，给予胡椒碱(2.5、5、10 mg/kg)或赋形剂，每日1次，连续28天。采用Morris水迷宫实验(MWM)评价小鼠的认知功能。行为测试后24小时，用分光光度法检测小鼠海马胆碱能功能和氧化应激水平。用双抗体夹心酶联免疫吸附测定法测定大鼠海马区促炎症细胞因子肿瘤坏死因子-α、白介素1β和白介素6的水平。用Western blotting、免疫组织化学或免疫荧光染色检测糖原合成酶3β(GSK-3β)及其上下游分子磷脂酰肌醇3-激酶(PI3K)、蛋白激酶B(AKT)、蛋白激酶C(PKC)、核因子E2相关因子2、核因子κB和微管相关蛋白tau在海马区的表达。我们的数据显示，慢性D-Gal暴露导致小鼠MWM的认知障碍，并伴有胆碱能障碍、广泛的氧化应激和神经炎症，以及海马区tau蛋白的过度磷酸化。所有这些神经化学、神经炎性和认知改变都可以通过重复服用胡椒碱4周而得到改善。此外，胡椒碱还通过调节蛋白激酶C和PI3K/Akt通路逆转D-半乳糖诱导的GSK-3β的激活，提示β相关信号可能参与胡椒碱对抗D-半乳糖诱导的小鼠认知功能减退的作用。
Aging-related cholinergic dysfunction, extensive neuroinflammation and oxidative stress in brain are predominant pathogenic factors for dementia. In the present study, we aimed to evaluate the protective effects of piperine, an alkaloid nutrient component ofPiper nigrum, against cognitive impairment in a senescent mouse model induced by D-galactose (D-Gal) and to explore the underlying mechanisms. Senescent mouse model was established by repeated subcutaneous injection of D-Gal (150 mg/kg, once daily for 42 days). Fourteen days after the first D-Gal exposure, piperine (2.5, 5, 10 mg/kg) or vehicle was intraperitoneally administered once daily for 28 days. The cognitive function of mice was evaluated by Morris water maze test (MWM). Twenty-four hours after behavioral test, the cholinergic function and oxidative stress level in mouse hippocampus were measured by spectrophotometric assays. In addition, the hippocampal levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β and interleukin-6, were quantified using enzyme-linked immunosorbent assay. Expressions of glycogen synthase kinase-3β (GSK-3β) and its upstream or downstream molecules including phosphatidylinositol 3-kinase (PI3K),protein kinase B (AKT), protein kinase C (PKC), NF-E2-related factor 2, nuclear factor-κB and microtubule-associated protein tau in hippocampus were determined by western blotting, immunohistochemical or immunofluorescent staining. Our data revealed that chronic D-Gal exposure in mice led to cognitive impairment in MWM, along with cholinergic malfunction, extensive oxidative stress and neuroinflammation, as well as hyperphosphorylation of tau protein in hippocampus. All these neurochemical, neuroinflammatory and cognitive alterations could be ameliorated by 4-week repeated piperine administration. Moreover, piperine also reversed D-Gal-induced GSK-3β activation through modulating PKC and PI3K/AKT pathways in senescent mouse hippocampus, suggesting GSK-3β-related signaling might be involved in the benefits of piperine against D-Gal-induced cognitive decline in mice.