Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice
Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice
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DOI：
10.1111/j.1600-079x.2004.00178.x
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发表时间：
2005-01-01
影响因子：
10.3
通讯作者：
Hermann, DM
中科院分区：
文献类型：
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作者：
Kilic, Ü;Kilic, E;Hermann, DM
由于其对人类有利的作用，褪黑激素是作为急性缺血性中风的神经保护剂的特别有趣的候选者。到目前为止，介导褪黑激素神经保护作用的信号机制基本上尚未得到研究。在此，我们研究了口服褪黑素作为中风预防剂（4 mg/kg/天）或再灌注开始后立即腹腔注射（4 mg/kg）9周，对小鼠大脑中动脉管腔闭塞90分钟，然后再灌注24小时的信号转导途径激活的影响。在这些研究中，与接受稀释剂（假手术）治疗的动物相比，褪黑素显着减少了缺血性梗塞面积约 30-35%，无论吲哚是在缺血之前还是之后施用。根据蛋白质印迹法测定，在这两种情况下，接受褪黑激素的动物大脑中磷酸化 Akt 水平均升高。此外，预防性而非急性褪黑激素治疗后，有丝分裂原激活蛋白激酶/细胞外调节激酶 (ERK)-1/-2 和 Jun 激酶 (JNK)-1/-2 的磷酸化水平升高。我们的数据表明磷脂酰肌醇-3 激酶/Akt 信号在急性褪黑激素诱导的神经保护中发挥作用，而 ERK-1/-2 和/或 JNK-1/-2 似乎参与褪黑激素的长期作用。
Because of its favorable action profile in humans, melatonin is a particularly interesting candidate as a neuroprotectant in acute ischemic stroke. Until now, the signaling mechanisms mediating melatonin's neuroprotective actions remained essentially uninvestigated. Herein, we examined the effects of melatonin, administered either orally for 9 wk as a stroke prophylactic (4 mg/kg/day) or intraperitoneally immediately after reperfusion onset (4 mg/kg), on the activation of signal transduction pathways in mice submitted to 90 min of intraluminal middle cerebral artery occlusion, followed by 24 hr of reperfusion. In these studies, melatonin significantly reduced ischemic infarct size by similar to30-35%, as compared with animals receiving diluent (sham) treatment, independent of whether the indole was administered prior to or after ischemia. Under both conditions, animals receiving melatonin exhibited elevated phosphorylated Akt levels in their brains, as determined by Western blots. Additionally, phosphorylation levels of mitogen-activated protein kinase/extracellular-regulated kinase (ERK)-1/-2 and Jun kinase (JNK)-1/-2 were increased following prophylactic, but not acute, melatonin treatment. Our data suggest a role of phosphatidyl inositol-3 kinase/Akt signaling in acute melatonin-induced neuroprotection, while ERK-1/-2 and/or JNK-1/-2 rather appear to be involved in melatonin's long-term effects.