Department of Anatomy, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan.
J Pineal Res. 2017 Sep;63(2). doi: 10.1111/jpi.12417. Epub 2017 May 25.
Prolonged exposure to gamma-hydroxybutyric acid (GHB) would cause drug intoxication in which impaired cognitive function results from enhanced hippocampal oxidative stress may serve as a major symptom in this deficiency. Considering melatonin possesses significant anti-oxidative efficacy, this study aimed to determine whether melatonin would successfully promote the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) signaling, depress oxidative stress, and rescue hippocampal bioenergetics and cognitive function following drug intoxication injury. Adolescent rats subjected to 10 days of GHB were received melatonin at doses of either 10 or 100 mg/kg. Time-of-flight secondary ion mass spectrometry, biochemical assay, quantitative histochemistry, [ C]-2-deoxyglucose analysis, together with Morris water maze were employed to detect the molecular signaling, oxidative status, bioenergetic level, as well as the cognitive performances, respectively. Results indicated that in GHB-intoxicated rats, enhanced oxidative stress, increased cholesterol level, and decreased anti-oxidative enzymes activities were detected in hippocampal regions. Intense oxidative stress paralleled well with reduced bioenergetics and poor performance in behavioral testing. However, in rats treated with melatonin following GHB intoxication, all above parameters and cognitive function were gradually returned to nearly normal levels. Melatonin also remarkably promoted the translocation of Nrf2 from cytoplasm to nucleus in a dose-dependent manner, thereby increased the Nrf2-ARE signaling-related downstream anti-oxidative enzymes activities. As melatonin effectively rescues hippocampal bioenergetics through depressing the oxidative stress by promoting Nrf2-ARE molecular machinery, this study thus highlights for the first time that clinical use of melatonin may serve as a therapeutic strategy to improve the cognitive function in unsuspecting victims suffered from GHB intoxication injury.
长时间暴露于γ-羟基丁酸（GHB）会导致药物中毒，其中增强的海马氧化应激导致认知功能受损可能是这种缺乏症的主要症状。考虑到褪黑素具有显著的抗氧化功效，本研究旨在确定褪黑素是否能成功促进核因子红细胞 2 相关因子 2 和抗氧化反应元件（Nrf2-ARE）信号转导，抑制氧化应激，并在药物中毒损伤后挽救海马生物能量和认知功能。接受 10 天 GHB 处理的青春期大鼠接受了 10 或 100mg/kg 的褪黑素。飞行时间二次离子质谱、生化测定、定量组织化学、[C]-2-脱氧葡萄糖分析以及 Morris 水迷宫分别用于检测分子信号、氧化状态、生物能量水平以及认知表现。结果表明，在 GHB 中毒大鼠中，海马区域检测到氧化应激增强、胆固醇水平升高和抗氧化酶活性降低。强烈的氧化应激与生物能量降低和行为测试表现不佳密切相关。然而，在 GHB 中毒后用褪黑素治疗的大鼠中，所有上述参数和认知功能逐渐恢复到接近正常水平。褪黑素还以剂量依赖的方式显著促进 Nrf2 从细胞质向细胞核易位，从而增加了 Nrf2-ARE 信号相关下游抗氧化酶的活性。由于褪黑素通过促进 Nrf2-ARE 分子机制抑制氧化应激有效地挽救了海马生物能量，因此本研究首次强调，褪黑素的临床应用可能是改善不明原因 GHB 中毒损伤患者认知功能的一种治疗策略。
