Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice
Version of Record online: 29 SEP 2004
Journal of Pineal Research
Volume 38, Issue 1, pages 67–71, January 2005
How to Cite
Kilic, Ü., Kilic, E., Reiter, R. J., Bassetti, C. L. and Hermann, D. M. (2005), Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice. Journal of Pineal Research, 38: 67–71. doi: 10.1111/j.1600-079X.2004.00178.x
- Issue online: 29 SEP 2004
- Version of Record online: 29 SEP 2004
- Received June 4, 2004; accepted August 20, 2004.
- ischemic tolerance;
- mitogen-activated protein kinase;
- phosphatidyl inositol-3 kinase/Akt
Abstract: 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.