Melatonin successfully rescues hippocampal bioenergetics and improves cognitive function following drug intoxication by promoting Nrf2‐ARE signaling activity |
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| Authors: | Li‐You Chen Ting‐Yi Renn Wen‐Chieh Liao Fu‐Der Mai Ying‐Jui Ho George Hsiao Ai‐Wei Lee Hung‐Ming Chang |
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| Affiliation: | 1. Department of Anatomy, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan;2. Department of Medical Education, Chung Shan Medical University Hospital, Taichung, Taiwan;3. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan;4. Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;5. School of Psychology, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan;6. Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan;7. Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan |
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| Abstract: | 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. |
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| Keywords: | bioenergetics cognitive function melatonin Nrf2‐ARE pathway oxidative stress |
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