褪黑素通过MT2受体、ERK和Nrf2相关抗氧化潜能之间的相互作用信号通路减轻由Klotho基因缺陷引起的记忆损伤。
Melatonin attenuates memory impairment induced by Klotho gene deficiency via interactive signaling between MT2 receptor, ERK, and Nrf2-related antioxidant potential.
作者信息
Shin Eun-Joo, Chung Yoon Hee, Le Hoang-Lan Thi, Jeong Ji Hoon, Dang Duy-Khanh, Nam Yunsung, Wie Myung Bok, Nah Seung-Yeol, Nabeshima Yo-Ichi, Nabeshima Toshitaka, Kim Hyoung-Chun
机构信息
Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea (Drs Shin, Le, Dang, Nam, and Kim); Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Chung); Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea (Dr Jeong); School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea (Dr Wie); Ginseng Research Laboratory, Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea (Dr Nah); Laboratory of Molecular Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation, Kobe 650-0047, Japan (Dr Y-I Nabeshima); Department of Regional Pharmaceutical Care and Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan (Dr T Nabeshima).
出版信息
Int J Neuropsychopharmacol. 2014 Dec 30;18(6):pyu105. doi: 10.1093/ijnp/pyu105.
BACKGROUND
We demonstrated that oxidative stress plays a crucial role in cognitive impairment in klotho mutant mice, a genetic model of aging. Since down-regulation of melatonin due to aging is well documented, we used this genetic model to determine whether the antioxidant property of melatonin affects memory impairment.
METHODS
First, we examined the effects of melatonin on hippocampal oxidative parameters and the glutathione/oxidized glutathione (GSH/GSSG) ratio and memory dysfunction of klotho mutant mice. Second, we investigated whether a specific melatonin receptor is involved in the melatonin-mediated pharmacological response by application with melatonin receptor antagonists. Third, we examined phospho-extracellular-signal-regulated kinase (ERK) expression, nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, Nrf2 DNA binding activity, and glutamate-cysteine ligase (GCL) mRNA expression. Finally, we examined effects of the ERK inhibitor SL327 in response to antioxidant efficacy and memory enhancement mediated by melatonin.
RESULTS
Treatment with melatonin resulted in significant attenuations of oxidative damage, a decrease in the GSH/GSSG ratio, and a significant amelioration of memory impairment in this aging model. These effects of melatonin were significantly counteracted by the selective MT2 receptor antagonist 4-P-PDOT. Importantly, 4-P-PDOT or SL327 also counteracted melatonin-mediated attenuation in response to the decreases in phospho-ERK expression, Nrf2 nuclear translocation, Nrf2 DNA-binding activity, and GCL mRNA expression in the hippocampi of klotho mutant mice. SL327 also counteracted the up-regulation of the GSH/GSSG ratio and the memory enhancement mediated by melatonin in klotho mutant mice.
CONCLUSIONS
Melatonin attenuates oxidative stress and the associated memory impairment induced by klotho deficiency via signaling interaction between the MT2 receptor and ERK- and Nrf2-related antioxidant potential.
背景
我们已证明氧化应激在衰老的基因模型——klotho突变小鼠的认知障碍中起关键作用。鉴于衰老导致褪黑素下调已有充分记录，我们利用该基因模型来确定褪黑素的抗氧化特性是否会影响记忆障碍。
方法
首先，我们研究了褪黑素对klotho突变小鼠海马氧化参数、谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）比值及记忆功能障碍的影响。其次，我们通过应用褪黑素受体拮抗剂来研究是否有特定的褪黑素受体参与褪黑素介导的药理反应。第三，我们检测了磷酸化细胞外信号调节激酶（ERK）表达、核因子红细胞2相关因子2（Nrf2）核转位、Nrf2 DNA结合活性及谷氨酸-半胱氨酸连接酶（GCL）mRNA表达。最后，我们检测了ERK抑制剂SL327对褪黑素介导的抗氧化功效及记忆增强作用的影响。
结果
在这个衰老模型中，褪黑素治疗显著减轻了氧化损伤，降低了GSH/GSSG比值，并显著改善了记忆障碍。褪黑素的这些作用被选择性MT2受体拮抗剂4-P-PDOT显著抵消。重要的是，4-P-PDOT或SL327也抵消了褪黑素介导的对klotho突变小鼠海马中磷酸化ERK表达、Nrf2核转位、Nrf2 DNA结合活性及GCL mRNA表达降低所产生的影响。SL327还抵消了褪黑素介导的klotho突变小鼠GSH/GSSG比值上调及记忆增强作用。
结论
褪黑素通过MT2受体与ERK及Nrf2相关抗氧化潜能之间的信号相互作用，减轻了klotho缺乏诱导的氧化应激及相关记忆障碍。
Zotero 插件