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Signal transduction pathways involved in melatonin‐induced neuroprotection after focal cerebral ischemia in mice
Author(s) -
Kilic Ülkan,
Kilic Ertugrul,
Reiter Russel J.,
Bassetti Claudio L.,
Hermann Dirk M.
Publication year - 2005
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/j.1600-079x.2004.00178.x
Subject(s) - melatonin , neuroprotection , mapk/erk pathway , signal transduction , endocrinology , protein kinase b , medicine , kinase , ischemia , pharmacology , biology , biochemistry
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 ∼30–35%, 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.