Melatonin arrests peroxynitrite-induced tau hyperphosphorylation and the overactivation of protein kinases in rat brain.
The purpose of this study was to examine the in vivo effect of melatonin (MEL) on peroxynitrite-induced tau hyperphosphorylation and the involvement of glycogen synthase kinase-3beta (GSK-3beta) and mitogen-activated protein kinase (MAPK) families. Melatonin was injected into the right cerebroventricle of the rats 1 hr before the bilateral hippocampal injection of 3-morpholino-sydnonimine chloride (SIN-1), the recognized donor of peroxynitrite. Thereafter, the phosphorylation level of tau and the activity of the kinases were analyzed. The injection of SIN-1 induced hyperphosphorylation of tau at pS396 epitope with a concomitant activation of GSK-3beta and selective MAPK isoforms including p38alpha, p38beta, and p38delta but not p38gamma. The effect of peroxynitrite was confirmed using uric acid, a recognized scavenger of peroxynitrite. Preinjection of MEL significantly arrested the peroxynitrite-induced hyperphosphorylation of tau and the activation of GSK-3beta and MAPKs. Melatonin also ameliorated peroxynitrite-induced oxidative stress. We conclude that MEL can efficiently arrest peroxynitrite-induced tau hyperphosphorylation, and the underlying mechanism may involve scavenging the reactive species and suppressing the activated GSK-3beta and p38 MAPK family.
Yin
Jun
J
Department of Pathophysiology, Hua-Zhong University of Science and Technology, Wuhan, China.
Liu
Ying-Hua
YH
Xu
Ya-Fei
YF
Zhang
Yong-Jie
YJ
Chen
Jian-Guo
JG
Shu
Bai-Hua
BH
Wang
Jian-Zhi
JZ
D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism*
D016875:tau Proteins; D030421:Peroxynitrous Acid; D014527:Uric Acid; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D008550:Melatonin