%0 Journal Article
%A Nacarkucuk, Efe
%A Bernis, Maria E.
%A Bremer, Anna-Sophie
%A Grzelak, Kora
%A Zweyer, Margit
%A Maes, Elke
%A Burkard, Hannah
%A Sabir, Hemmen
%T Neuroprotective Effect of Melatonin in a Neonatal Hypoxia–Ischemia Rat Model Is Regulated by the AMPK/mTOR Pathway
%J Journal of the American Heart Association
%V 13
%N 19
%@ 2047-9980
%C New York, NY
%I Association
%M DZNE-2024-01185
%P e036054
%D 2024
%X  Melatonin has been shown to be neuroprotective in different animal models of neonatal hypoxic-ischemic brain injury. However, its exact molecular mechanism of action remains unknown. Our aim was to prove melatonin's short- and long-term neuroprotection and investigate its role on the AMPK (AMP-activated protein kinase)/mTOR (mammalian target of rapamycin) pathway following neonatal hypoxic-ischemic brain injury.Seven-day-old Wistar rat pups were exposed to hypoxia-ischemia, followed by melatonin or vehicle treatment. Detailed analysis of the AMPK/mTOR/autophagy pathway, short- and long-term neuroprotection, myelination, and oligodendrogenesis was performed at different time points. At 7 days after hypoxia-ischemia, melatonin-treated animals showed a significant decrease in tissue loss, increased oligodendrogenesis, and myelination. Long-term neurobehavioral results showed significant motor improvement following melatonin treatment. Molecular pathway analysis showed a decrease in the AMPK expression, with a significant increase at mTOR's downstream substrates, and a significant decrease at the autophagy marker levels in the melatonin group compared with the vehicle group.Melatonin treatment reduced brain area loss and promoted oligodendrogenesis with a clear improvement of motor function. We found that melatonin associated neuroprotection is regulated via the AMPK/mTOR/autophagy pathway. Considering the beneficial effects of melatonin and the results of our study, melatonin seems to be an optimal candidate for the treatment of newborns with hypoxic-ischemic brain injury in high- as well as in low- and middle-income countries.
%K Animals
%K Melatonin: pharmacology
%K Hypoxia-Ischemia, Brain: metabolism
%K Hypoxia-Ischemia, Brain: drug therapy
%K Hypoxia-Ischemia, Brain: pathology
%K TOR Serine-Threonine Kinases: metabolism
%K Animals, Newborn
%K Rats, Wistar
%K Neuroprotective Agents: pharmacology
%K Disease Models, Animal
%K Signal Transduction: drug effects
%K AMP-Activated Protein Kinases: metabolism
%K AMP-Activated Protein Kinases: drug effects
%K Autophagy: drug effects
%K Oligodendroglia: drug effects
%K Oligodendroglia: metabolism
%K Oligodendroglia: pathology
%K Brain: drug effects
%K Brain: metabolism
%K Brain: pathology
%K Rats
%K Behavior, Animal: drug effects
%K AMPK/mTOR/autophagy (Other)
%K melatonin (Other)
%K neonatal hypoxia–ischemia (Other)
%K neuroprotection (Other)
%K rat (Other)
%K Melatonin (NLM Chemicals)
%K TOR Serine-Threonine Kinases (NLM Chemicals)
%K Neuroprotective Agents (NLM Chemicals)
%K mTOR protein, rat (NLM Chemicals)
%K AMP-Activated Protein Kinases (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%2 pmc:PMC11681444
%$ pmid:39319465
%R 10.1161/JAHA.124.036054
%U https://pub.dzne.de/record/272509