TY - JOUR
T1 - Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice
AU - Kilic, Ülkan
AU - Kilic, Ertugrul
AU - Reiter, Russel J.
AU - Bassetti, Claudio L.
AU - Hermann, Dirk M.
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
KW - Ischemic tolerance
KW - Mitogen-activated protein kinase
KW - Neuroprotection
KW - Phosphatidyl inositol-3 kinase/Akt
UR - http://www.scopus.com/inward/record.url?scp=12344307153&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=12344307153&partnerID=8YFLogxK
U2 - 10.1111/j.1600-079X.2004.00178.x
DO - 10.1111/j.1600-079X.2004.00178.x
M3 - Article
C2 - 15617539
AN - SCOPUS:12344307153
VL - 38
SP - 67
EP - 71
JO - Journal of Pineal Research
JF - Journal of Pineal Research
SN - 0742-3098
IS - 1
ER -