Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT2 melatonin receptor in ischemic-stroke mice

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 mod...

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Bibliographic Details
Published in:Free radical biology & medicine 2012-05, Vol.52 (9), p.1634-1647
Main Authors: Chern, Chang-Ming, Liao, Jyh-Fei, Wang, Yea-Hwey, Shen, Yuh-Chiang
Format: Article
Language:English
Subjects:
Animal models
Animals
Antagonists
Base Sequence
Blood-brain barrier
Brain Ischemia - physiopathology
Cell proliferation
Cell survival
DNA Primers
Doublecortin
Doublecortin protein
Free radicals
Gene expression
genes
Immunohistochemistry
Injuries
Ischemia
Ischemic stroke
Ki67
longevity
Melatonin
Melatonin - physiology
Melatonin receptors
Mice
MT2 melatonin receptor
Neural stem cells
Neurodevelopmental genes
Neurogenesis
Neurogenesis - physiology
Neuroprotection
neuroprotective effect
Polymerase chain reaction
Preservation
protein synthesis
Real-Time Polymerase Chain Reaction
Receptor, Melatonin, MT2 - physiology
receptors
reverse transcriptase polymerase chain reaction
stem cells
Stress
Stroke
Stroke - physiopathology
Survival Rate
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Summary: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, ip) 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 life span 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 gp91phox 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 coexpressed two neurodevelopmental proteins (adam11 and adamts20) and the MT2 melatonin receptor. RT-PCR revealed that the gene expression levels 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 upregulating neurodevelopmental gene/protein expression. [Display omitted] ► Melatonin ameliorates neural functioning in ischemic-stroke mice. ► Melatonin reduces oxidative/inflammatory stress through the MT2 receptor. ► Melatonin preserves blood–brain barrier integrity through the MT2 receptor. ► Melatonin promotes endogenous neurogenesis through the MT2 receptor. ► Melatonin upregulates neurodevelopmental gene expression through the MT2 receptor.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2012.01.030