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, [¹⁴C]‐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.

中文翻译：

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褪黑素通过促进Nrf2-ARE信号传导活性成功地拯救了海马生物能并改善了药物中毒后的认知功能

长时间接触γ-羟基丁酸（GHB）会引起药物中毒，其中海马氧化应激增强导致认知功能受损可能是该缺陷的主要症状。考虑到褪黑激素具有显着的抗氧化功效，本研究旨在确定褪黑激素是否能成功促进核因子红系2相关因子2和抗氧化反应元件（Nrf2‐ARE）信号传导，抑制氧化应激并拯救海马生物能和认知功能药物中毒后受伤。接受GHB 10天的青春期大鼠接受褪黑激素，剂量为10或100 mg / kg。飞行时间二次离子质谱，生化测定，定量组织化学，[ ¹⁴使用C] -2-脱氧葡萄糖分析法和Morris水迷宫法分别检测分子信号传导，氧化状态，生物能水平以及认知表现。结果表明，在GHB中毒的大鼠中，在海马区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。强烈的氧化应激与减少的生物能以及行为测试中的不良表现相吻合。然而，在GHB中毒后用褪黑激素治疗的大鼠中，所有上述参数和认知功能逐渐恢复至接近正常水平。褪黑素还以剂量依赖的方式显着促进了Nrf2从细胞质到细胞核的转运，从而增加了与Nrf2‐ARE信号相关的下游抗氧化酶的活性。由于褪黑素通过促进Nrf2-ARE分子机制通过抑制氧化应激而有效地挽救海马生物能，因此本研究首次强调了褪黑激素的临床应用可作为一种治疗策略，以提高不受怀疑的GHB中毒患者的认知功能受伤。