Neuroprotective Effect of Melatonin in a Neonatal Hypoxia–Ischemia Rat Model Is Regulated by the AMPK/mTOR Pathway

Abstract

Background 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. Methods and Results 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. Conclusions 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.

Keywords

• AMPK/mTOR/autophagy
• melatonin
• neonatal hypoxia–ischemia
• neuroprotection
• rat