کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
6275231 | 1614839 | 2013 | 9 صفحه PDF | دانلود رایگان |
Because of their favorable action profiles in humans, both memantine and melatonin are particularly interesting candidates as neuroprotectants in acute ischemic stroke. Until now, the signaling mechanisms mediating memantine's neuroprotective actions remained essentially uninvestigated. In addition, we have combined memantine with melatonin, which is a well-known neuroprotective molecule. Herein, we examined the effects of memantine (20Â mg/kg, i.p.) administered alone or in combination with melatonin (4Â mg/kg, i.p.) on the activation of signaling transduction pathways, IgG extravasation and ischemic injury in mice submitted to 90Â min of intraluminal middle cerebral artery occlusion, followed by 24Â h of reperfusion. In these studies, both agents reduced ischemic injury and the density of DNA-fragmentation. Notably, melatonin/memantine combination reduced ischemic injury further as compared with memantine treatment, which was associated with reduced IgG extravasation, indicating vascular leakage in the brain. Animals receiving memantine exhibited elevated ERK-1/2 and decreased p21 and p38/MAPK activations, while it had no significant effect on phosphorylated Akt and SAPK/JNK1/2 in the ischemic brain. However, melatonin increased the activation of Akt and reduced the activations of ERK-1/2, p21, p38/MAPK and SAPK/JNK1/2 significantly. Synergistic effects of memantine and melatonin were observed in the inactivation of p21, p38/MAPK and SAPK/JNK1/2 pathways. Moreover, memantine reversed the effects of melatonin on the activation of ERK-1/2 pathway. Here, we provide evidence that free radical scavenger melatonin potentiates the effects of memantine on ischemic brain injury via inactivations of p21 and stress kinases p38/MAPK and SAPK/JNK1/2 pathways.
⺠Signaling mechanisms mediating memantine's neuroprotective actions remained essentially uninvestigated. ⺠Effects of memantine and melatonin on vascular leakage remained uninvestigated. ⺠Synergistic effects of memantine and melatonin were observed in the inactivation of p21, p38/MAPK and SAPK/JNK1/2 pathways. ⺠Anti-synergistic effects of memantine and melatonin were observed in the regulation of ERK-1/2 pathway. ⺠Effects of memantine on signaling pathways were compared with a well-known neuroprotective melatonin.
Journal: Neuroscience - Volume 237, 1 May 2013, Pages 268-276