Melatonin ameliorates neural function by promoting endogenous neurogenesis through MT2 melatonin receptor in ischemic stroke mice.
Free Radic Biol Med. 2012 Feb 10. Epub 2012 Feb 10. PMID: 22330064
Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Melatonin has many protective effects against ischemic stroke, but the underlying neuroprotective mechanisms are not fully understood. Our aim was to explore the relationship between melatonin's neuroprotective effects and activation of the MT2 melatonin receptor in a murine ischemic stroke model. Male ICR mice were subjected to a transient middle cerebral ischemic/reperfusional injury and melatonin (5 and 10mg/kg, i.p.) was administrated once daily starting 2h after ischemia. More than 80% of the mice died within 5days after stroke without treatment. Melatonin treatment significantly improved the survival rates and neural functioning with modestly prolonged lifespan of the stroke mice by preserving blood-brain barrier (BBB) integrity via a reduction in the enormous amount of stroke-induced free radical production and significant gp91(phox) cell infiltration. These protective effects of melatonin were reversed by pretreatment with MT2 melatonin receptor antagonists (4-phenyl-2-propionamidotetralin (4P-PDOT) and luzindole). Moreover, treatment with melatonin after stroke dramatically enhanced endogenous neurogenesis (doublecortin-positive) and cell proliferation (ki67-positive) in the peri-infarct regions. Most ki67-positive cells were nestin-positive and NG2-positive neural stem/progenitor cells that co-expressed two neurodevelopmental proteins (adam11 and adamts20) and MT2 melatonin receptor. RT-PCR revealed that the gene expression level of doublecortin, ki67, adamts20 and adam11 are markedly reduced by stroke, but are restored by melatonin treatment; furthermore, pretreatment with 4P-PDOT and luzindole antagonized melatonin's restorative effect. Our results support the hypothesis that melatonin is able to protect mice against stroke by activating MT2 melatonin receptors, which reduces oxidative/inflammatory stress. This results in the preservation of BBB integrity and enhances endogenous neurogenesis by up-regulating neurodevelopmental gene/protein expression.