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The roles of MT1 and MT2 in the neuroprotective effects of melatonin and cell signaling after cerebral ischemia remain unknown. With the use of MT1 and MT2 knockout (<jats:italic>mt1\/2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>) mice treated with melatonin, we evaluated brain injury, edema formation, inducible nitric oxide synthase (iNOS) activity, and signaling pathways, including CREB, ATF\u20101, p21, Jun kinase (JNK)1\/2, p38 phosphorylation, resulting from ischemia\/reperfusion injury. We show that the infarct volume and brain edema do not differ between <jats:italic>mt1\/2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> and wild\u2010type (WT) animals, but melatonin treatment decreases infarct volume in both groups and brain edema in WT animals after middle cerebral artery occlusion. Notably, melatonin\u2019s neuroprotective effect was even more pronounced in <jats:italic>mt1\/2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> animals compared to that in WT animals. We also demonstrate that melatonin treatment decreased CREB, ATF\u20101, and p38 phosphorylation in both <jats:italic>mt1\/2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> and WT mice, while p21 and JNK1\/2 were reduced only in melatonin\u2010treated WT animals in the ischemic hemisphere. Furthermore, melatonin treatment lowered iNOS activity only in WT animals. We provide evidence that the absence of MT1 and MT2 has no unfavorable effect on ischemic brain injury. In addition, the neuroprotective effects of melatonin appear to be mediated through a mechanism independent of its membrane receptors. The underlying mechanism(s) should be further studied using selective melatonin receptor agonists and antagonists.<\/jats:p>","DOI":"10.1111\/j.1600-079x.2011.00932.x","type":"journal-article","created":{"date-parts":[[2011,8,12]],"date-time":"2011-08-12T01:09:57Z","timestamp":1313111397000},"page":"228-235","source":"Crossref","is-referenced-by-count":100,"title":["Evidence that membrane\u2010bound G protein\u2010coupled melatonin receptors MT1 and MT2 are not involved in the neuroprotective effects of melatonin in focal cerebral 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