Journal Article

DZNE-2024-01185

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Neuroprotective Effect of Melatonin in a Neonatal Hypoxia–Ischemia Rat Model Is Regulated by the AMPK/mTOR Pathway

Nacarkucuk, E. (First author)DZNE* ; Bernis, M. E.DZNE* ; Bremer, A.-S.DZNE* ; Grzelak, K.DZNE* ; Zweyer, M.DZNE* ; Maes, E.DZNE* ; Burkard, H.DZNE* ; Sabir, H. (Last author)DZNE*

2024
Association New York, NY

This record in other databases:    

Please use a persistent id in citations: doi:10.1161/JAHA.124.036054

Abstract: 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.

Keyword(s): Animals (MeSH) ; Melatonin: pharmacology (MeSH) ; Hypoxia-Ischemia, Brain: metabolism (MeSH) ; Hypoxia-Ischemia, Brain: drug therapy (MeSH) ; Hypoxia-Ischemia, Brain: pathology (MeSH) ; TOR Serine-Threonine Kinases: metabolism (MeSH) ; Animals, Newborn (MeSH) ; Rats, Wistar (MeSH) ; Neuroprotective Agents: pharmacology (MeSH) ; Disease Models, Animal (MeSH) ; Signal Transduction: drug effects (MeSH) ; AMP-Activated Protein Kinases: metabolism (MeSH) ; AMP-Activated Protein Kinases: drug effects (MeSH) ; Autophagy: drug effects (MeSH) ; Oligodendroglia: drug effects (MeSH) ; Oligodendroglia: metabolism (MeSH) ; Oligodendroglia: pathology (MeSH) ; Brain: drug effects (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Rats (MeSH) ; Behavior, Animal: drug effects (MeSH) ; AMPK/mTOR/autophagy ; melatonin ; neonatal hypoxia–ischemia ; neuroprotection ; rat ; Melatonin ; TOR Serine-Threonine Kinases ; Neuroprotective Agents ; mTOR protein, rat ; AMP-Activated Protein Kinases

---

Contributing Institute(s):

1. Neonatal Neuroscience (AG Sabir)
2. Nuclear Function in CNS Pathophysiology (AG Salomoni)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

---

Database coverage:
; ; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---