Melatonin rescues cerebral ischemic events through upregulated tunneling nanotube-mediated mitochondrial transfer and downregulated mitochondrial oxidative stress in rat brain - 02/06/21
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Abstract |
Background |
Cerebral ischemic events, comprising of excitotoxicity, reactive oxygen production, and inflammation, adversely impact the metabolic-redox circuit in highly active neuronal metabolic profile which maintains energy-dependent brain activities. Therefore, we investigated neuro-regenerative potential of melatonin (Mel), a natural biomaterial secreted by pineal gland.
Methods |
We specifically determined whether Mel could influence tunneling nanotubes (TNTs)-mediated transfer of functional mitochondria (Mito) which in turn may alter membrane potential, oxidative stress and apoptotic factors. In vitro studies assessed the effects of Mito on levels of cytochrome C, mitochondrial transfer, reactive oxygen species, membrane potential and mass, which were all further enhanced by Mel pre-treatment, whereas in vivo studies examined brain infarct area (BIA), neurological function, inflammation, brain edema and integrity of neurons and myelin sheath in control, ischemia stroke (IS), IS + Mito and IS + Mel-Mito group rats.
Results |
Results showed that Mel pre-treatment significantly increased mitochondrial transfer and antioxidants, and inhibited apoptosis. Mel-pretreated Mito also significantly reduced BIA with improved neurological function. Apoptotic, oxidative-stress, autophagic, mitochondrial/DNA-damaged biomarkers indices were also improved.
Conclusion |
Conclusively, Mel is a potent biomaterial which could potentially impart neurogenesis through repairing impaired metabolic-redox circuit via enhanced TNT-mediated mitochondrial transfer, anti-oxidation, and anti-apoptotic activities in ischemia.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
The proposed underlying mechanism of Mel-Mito therapy in rescuing cerebral ischemia. The in vitro results revealed therapeutic effect through Mel-mediated inhibition of (A) oxidative stress, autophagy, cell apoptosis, which was further supported by (B) refreshed mitochondria obtained through enhanced tunneling nanotube (TNT) transfer, implying a synergistic efficacy of Mel-Mito. This effect was also manifested in the in vivo results through inhibited vicious cycle of oxidative stress, apoptosis and mitochondrial exhaust.
Highlights |
• | Exogenous mitochondria were successfully transfused into the neuron cells for increasing/refreshing the number of mitochondria. |
• | Melatonin pretreatment facilitated the mitochondria on reducing the brain infract area. |
• | Melatonin upregulated neurogenesis by regulating TNT-transferred mitochondria in ischemia. |
List of abbreviations : Mito, Mel, TNTs, IS, BIA, IR, ETC, ARDS
Keywords : Acute ischemic stroke, Melatonin, Mitochondria, Oxidative stress, Apoptosis
Plan
Vol 139
Article 111593- juillet 2021 Retour au numéro
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