Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT2 melatonin receptor in ischemic-stroke mice
Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT2 melatonin receptor in ischemic-stroke mice
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DOI：
10.1016/j.freeradbiomed.2012.01.030
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发表时间：
2012-05-01
影响因子：
7.4
通讯作者：
Shen, Yuh-Chiang
中科院分区：
文献类型：
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作者：
Chern, Chang-Ming;Liao, Jyh-Fei;Shen, Yuh-Chiang
褪黑激素对缺血性中风有许多保护作用，但其潜在的神经保护机制尚未完全了解。我们的目的是探讨褪黑激素的神经保护作用和MT2褪黑激素受体在小鼠缺血性中风模型中的激活之间的关系。雄性ICR小鼠进行短暂性中脑缺血/再灌注损伤，并给予褪黑激素（5和10 mg/kg，ip），每天一次，缺血后2小时开始。超过80%的小鼠在中风后5天内死亡，没有治疗。褪黑激素治疗通过减少大量中风诱导的自由基产生和显著的gp91（phox）细胞浸润来保持血脑屏障（BBB）的完整性，显著改善了中风小鼠的存活率和神经功能，并适度延长了中风小鼠的寿命。MT 2褪黑素受体拮抗剂（4-苯基-2-丙酰胺四氢萘（4P-PDOT）和luzindole）预处理可逆转褪黑素的这些保护作用。此外，中风后用褪黑激素治疗显著增强了脑梗塞前区域的内源性神经发生（双皮质素阳性）和细胞增殖（ki67阳性）。大多数ki67阳性细胞是nestin阳性和NG2阳性神经干/祖细胞，共表达两种神经发育蛋白（adam11和adamts20）和MT2褪黑激素受体。RT-PCR结果显示，脑卒中后doublecortin、ki67、adamts20和adam11的基因表达水平显著降低，但褪黑素治疗后可恢复其表达水平;此外，用4P-PDOT和luzindole预处理可拮抗褪黑素的恢复作用。我们的研究结果支持这一假设，即褪黑激素能够通过激活MT2褪黑激素受体，减少氧化/炎症应激，保护小鼠免受中风。这导致BBB完整性的保存，并通过上调神经发育基因/蛋白质表达来增强内源性神经发生。(c)2012 Elsevier Inc. All rights reserved.
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 10 mg/kg, ip) was administrated once daily starting 2 h after ischemia. More than 80% of the mice died within 5 days 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 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 pen-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. (c) 2012 Elsevier Inc. All rights reserved.