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-3 beta (GSK-3 beta) 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-3 beta and selective MAPK isoforms including p38 alpha, p38 beta, and p38 delta but not p38 gamma. 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-3 beta 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-3 beta and p38 MAPK family.