Melatonin successfully rescues hippocampal bioenergetics and improves cognitive function following drug intoxication by promoting Nrf2‐ARE signaling activity

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, [ 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.

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

“…It is generally accepted that the dose and dosing time are highly related to the efficacy of the pharmacological action of melatonin. The dose of 10 mg/kg ip (which produces far higher melatonin levels than normal physiological concentrations in the body) and the dosing time (9:00 am-9:30 am) used for melatonin treatment in the present study are comparable with those used in previous studies [64][65][66] and have been proven to be effective. It has been reported that melatonin can be tolerated at large doses by healthy humans and subjects with Parkinson's disease without any severe adverse effects.…”

Melatonin ameliorates cuprizone‐induced reduction of hippocampal neurogenesis, brain‐derived neurotrophic factor, and phosphorylation of cyclic AMP response element‐binding protein in the mouse dentate gyrus

“…Melatonin has an antioxidative property and scavenges free radicals more effectively than do vitamins C and E (Korkmaz et al, ; Pieri, Marra, Moroni, Recchioni, & Marcheselli, ). Melatonin has positive effects about the hippocampus‐dependent cognitive function (Chen et al, ) as well as the hippocampal neurogenesis (Iggena, Winter, & Steiner, ; Yoo, Kim, Lee, et al, ; ). Additionally, it increases the number of proliferating cells and neuroblasts in the dentate gyrus of aged mice induced by D‐galactose treatment (Yoo, Kim, Lee, et al, ; ).…”

“…Melatonin has positive effects about the hippocampus-dependent cognitive function (Chen et al, 2017) as well as the hippocampal neurogenesis (Iggena, Winter, & Steiner, 2017;Yoo, Kim, Lee, et al, 2012;). Additionally, it increases the number of proliferating cells and neuroblasts in the dentate gyrus of aged mice induced by Dgalactose treatment (Yoo, Kim, Lee, et al, 2012;).…”

Curcumin ameliorates cisplatin‐induced cystopathy via activating NRF2 pathway

“…For instance, by activating the NRF2 signaling pathway, hydralazine induces stress resistance and extends the lifespan of Caenorhabditis elegans . Melatonin effectively rescues hippocampal bioenergetics through depressing the oxidative stress by promoting NRF2 molecular machinery . Additionally, to improve bladder function and to decrease the apoptosis of the bladder in STZ‐induced diabetic rats, Grape seed proanthocyanidin extract (GSPE) activated the NRF2 defense pathway and upregulated downstream hemeoxygenase‐1 (HO‐1) .…”

“…Previous studies have reported that cisplatin‐induced cystopathy was also associated with the neurogenic lesions, so we examined NGF whose mRNA expression was regulated by NRF2 in glioblastoma cells and normal human astrocytes and found NGF was significantly upregulated in the Cis‐Cur group compared with the Cis group. Also, the increased expression of NGF induced by activation of the NRF2 pathway was reported to promote neurite outgrowth .…”