TY  - JOUR
AU  - Nacarkucuk, Efe
AU  - Bernis, Maria E.
AU  - Bremer, Anna-Sophie
AU  - Grzelak, Kora
AU  - Zweyer, Margit
AU  - Maes, Elke
AU  - Burkard, Hannah
AU  - Sabir, Hemmen
TI  - Neuroprotective Effect of Melatonin in a Neonatal Hypoxia–Ischemia Rat Model Is Regulated by the AMPK/mTOR Pathway
JO  - Journal of the American Heart Association
VL  - 13
IS  - 19
SN  - 2047-9980
CY  - New York, NY
PB  - Association
M1  - DZNE-2024-01185
SP  - e036054
PY  - 2024
AB  -  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.
KW  - Animals
KW  - Melatonin: pharmacology
KW  - Hypoxia-Ischemia, Brain: metabolism
KW  - Hypoxia-Ischemia, Brain: drug therapy
KW  - Hypoxia-Ischemia, Brain: pathology
KW  - TOR Serine-Threonine Kinases: metabolism
KW  - Animals, Newborn
KW  - Rats, Wistar
KW  - Neuroprotective Agents: pharmacology
KW  - Disease Models, Animal
KW  - Signal Transduction: drug effects
KW  - AMP-Activated Protein Kinases: metabolism
KW  - AMP-Activated Protein Kinases: drug effects
KW  - Autophagy: drug effects
KW  - Oligodendroglia: drug effects
KW  - Oligodendroglia: metabolism
KW  - Oligodendroglia: pathology
KW  - Brain: drug effects
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Rats
KW  - Behavior, Animal: drug effects
KW  - AMPK/mTOR/autophagy (Other)
KW  - melatonin (Other)
KW  - neonatal hypoxia–ischemia (Other)
KW  - neuroprotection (Other)
KW  - rat (Other)
KW  - Melatonin (NLM Chemicals)
KW  - TOR Serine-Threonine Kinases (NLM Chemicals)
KW  - Neuroprotective Agents (NLM Chemicals)
KW  - mTOR protein, rat (NLM Chemicals)
KW  - AMP-Activated Protein Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11681444
C6  - pmid:39319465
DO  - DOI:10.1161/JAHA.124.036054
UR  - https://pub.dzne.de/record/272509
ER  -