(−)‐Epicatechin Mitigates Oxidative Stress, Neuroinflammation and Hyperphosphorylation of TAU in Hippocampus of Senile Mice
(−)‐Epicatechin Mitigates Oxidative Stress, Neuroinflammation and Hyperphosphorylation of TAU in Hippocampus of Senile Mice
复制标题
(−)-表儿茶素减轻氧化应激、神经炎症和老年小鼠海马 TAU 的过度磷酸化
DOI：
10.1096/fasebj.31.1_supplement.814.7
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
F. Villarreal
中科院分区：
文献类型：
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作者：
I. Ramírez‐Sánchez;Alonso Rodríguez;T. Neri;P. Mendoza;G. Ceballos;F. Villarreal
有证据表明氧化应激（OS）和炎症是阿尔茨海默病等神经退行性病理的驱动因素。我们之前报道了可可黄烷醇(−)-表儿茶素（Epi）治疗对衰老诱导的OS和恢复26个月大小鼠前额皮质线粒体生物发生调节剂的有益作用。在本研究中，我们使用类似的小鼠衰老模型，研究了Epi减轻海马OS、炎症、tau蛋白过度磷酸化和可溶性β -淀粉样蛋白水平的能力，从而改善了记忆和焦虑水平。雄性小鼠（26月龄）给予2周Epi治疗（1 mg/kg/天BID，灌胃），并收集海马样本进行相关终点评估。OS标志物、蛋白羰基和丙二醛水平随着年龄的增长而显著升高（约3倍），Epi抑制了这一变化（p<0.05）。通过Western blots检测，促炎分子COX2、NFkB、TNF α、白细胞介素（1β、5和6）和干扰素γ的蛋白水平随着年龄的增长而增加（约2-2.5倍），并且在治疗过程中也显著抑制。衰老还会导致tau蛋白的高磷酸化，可溶性β -淀粉样蛋白水平增加（约2倍），神经生长因子减少（约75%），而Epi可以逆转这些变化。焦虑（开放场地测试）和物体识别（记忆）结果也通过治疗得到改善。综上所述，结果表明Epi具有显著减轻海马OS和神经炎症的独特能力，从而改善脑功能。这些结果可能解释了黑巧克力对人类记忆力的有益影响。
Evidence has implicated oxidative stress (OS) and inflammation as a driver of neurodegenerative pathologies such as Alzheimer's disease. We previously reported on the beneficial effects of treatment with the cacao flavanol (−)‐epicatechin (Epi) on aging‐induced OS and capacity to restore modulators of mitochondrial biogenesis in the prefrontal cortex of 26‐month‐old mice. In the present study, using a similar mouse model of aging, we examined the capacity of Epi to mitigate hippocampus OS, inflammation, hyperphosphorylation of tau protein, and soluble β‐amyloid protein levels leading to improved memory and anxiety levels. Male mice (26 month old) underwent 2 weeks of Epi treatment (1 mg/kg/day BID by oral gavage) and samples of hippocampus collected for the assessment of relevant endpoints. The assessment of the OS markers protein carbonyls and malondialdehyde levels evidence significant increases (~3 fold) with aging that are suppressed (p<0.05) by Epi. Using Western blots the protein levels of the proinflammatory molecules COX2, NFkB, TNF alpha, interleukins (1β, 5 and 6) and interferon gamma increase with aging (~2–2.5 fold) and are also significantly suppressed with treatment. Aging also leads to the hyperphosporylation of tau, increased soluble β‐amyloid levels (~ 2 fold) and reductions in nerve growth factor (~75%) which are reversed by Epi. Measures of anxiety (open field tests) and object recognition (memory) results were also improved by treatment. Altogether, results evidence a unique capacity of Epi to significantly mitigate hippocampus OS and neuroinflammation leading to improved brain function. These results may account for the beneficial effects that dark chocolate exerts on measures of memory in humans.