Melatonin rescues cerebral ischemic events through upregulated tunneling nanotube-mediated mitochondrial transfer and downregulated mitochondrial oxidative stress in rat brain

Hon Kan Yip, Navneet Kumar Dubey, Kun Chen Lin, Pei Hsun Sung, John Y. Chiang, Yi Ching Chu, Chi Ruei Huang, Yi Ling Chen, Yue Hua Deng, Hsin Chung Cheng, Win Ping Deng

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number111593
JournalBiomedicine and Pharmacotherapy
Volume139
DOIs
Publication statusPublished - Jul 2021

Keywords

  • Acute ischemic stroke
  • Apoptosis
  • Melatonin
  • Mitochondria
  • Oxidative stress

ASJC Scopus subject areas

  • Pharmacology

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