Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon 200-701, Korea.
Korean J Physiol Pharmacol. 2008 Apr;12(2):37-41. doi: 10.4196/kjpp.2008.12.2.37. Epub 2008 Apr 30.
Melatonin has been reported to protect neurons from a variety of neurotoxicity. However, the underlying mechanism by which melatonin exerts its neuroprotective property has not yet been clearly understood. We previously demonstrated that melatonin protected kainic acid-induced neuronal cell death in mouse hippocampus, accompanied by sustained activation of Akt, a critical mediator of neuronal survival. To further elucidate the neuroprotective action of melatonin, we examined in the present study the causal mechanism how Akt signaling pathway is regulated by melatonin in a rat primary astrocyte culture model. Melatonin resulted in increased astrocytic Akt phosphorylation, which was significantly decreased with wortmannin, a specific inhibitor of PI3K, suggesting that activation of Akt by melatonin is mediated through the PI3K-Akt signaling pathway. Furthermore, increased Akt activation was also significantly decreased with luzindole, a non-selective melatonin receptor antagonist. As downstream signaling pathway of Akt activation, increased levels of CREB phoshorylation and GDNF expression were observed, which were also attenuated with wortmannin and luzindole. These results strongly suggest that melatonin exerts its neuroprotective property in astrocytes through the activation of plasma membrane receptors and then PI3K-Akt signaling pathway.
褪黑素已被报道可保护神经元免受多种神经毒性的侵害。然而,褪黑素发挥其神经保护特性的潜在机制尚未被清楚地理解。我们之前的研究表明,褪黑素可保护小鼠海马中海马酸诱导的神经元细胞死亡,同时持续激活 Akt,Akt 是神经元存活的关键介质。为了进一步阐明褪黑素的神经保护作用,本研究在大鼠原代星形胶质细胞培养模型中检查了 Akt 信号通路如何被褪黑素调节的因果机制。褪黑素导致星形胶质细胞 Akt 磷酸化增加,而 wortmannin(PI3K 的特异性抑制剂)可显著降低 Akt 磷酸化,表明褪黑素对 Akt 的激活是通过 PI3K-Akt 信号通路介导的。此外,用 luzindole(一种非选择性褪黑素受体拮抗剂)也可显著降低 Akt 激活的增加。作为 Akt 激活的下游信号通路,观察到 CREB 磷酸化和 GDNF 表达水平增加,而 wortmannin 和 luzindole 也可减弱这些增加。这些结果强烈表明,褪黑素通过激活质膜受体,然后通过 PI3K-Akt 信号通路,在星形胶质细胞中发挥其神经保护作用。