Publication: EFFECTS OF MEMANTINE AND MELATONIN ON SIGNAL TRANSDUCTION PATHWAYS VASCULAR LEAKAGE AND BRAIN INJURY AFTER FOCAL CEREBRAL ISCHEMIA IN MICE
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2013-05-01T00:00:00Z
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Kilic, U.
Yilmaz, B.
Reiter, R. J.
Yuksel, A.
Kilic, E.
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Abstract
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 (20 mg/kg, i.p.) administered alone or in combination with melatonin (4 mg/kg, i.p.) on the activation of signaling transduction pathways, IgG extravasation and ischemic injury in mice submitted to 90 min of intraluminal middle cerebral artery occlusion, followed by 24 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. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
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Kilic U., Yilmaz B., Reiter R. J. , Yuksel A., Kilic E., -EFFECTS OF MEMANTINE AND MELATONIN ON SIGNAL TRANSDUCTION PATHWAYS VASCULAR LEAKAGE AND BRAIN INJURY AFTER FOCAL CEREBRAL ISCHEMIA IN MICE-, NEUROSCIENCE, cilt.237, ss.268-276, 2013