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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Melatonin arrests peroxynitrite-induced tau hyperphosphorylation and the overactivation of protein kinases in rat
Jun Yin1, Ying-Hua Liu, Ya-Fei Xu
1Department of Pathophysiology, Hua-Zhong University of Science and Technology, Wuhan, China.
Abstract:
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.
Insights
Melatonin (MEL) effectively prevents peroxynitrite-induced tau hyperphosphorylation in rats by scavenging reactive species and inhibiting key kinases like GSK-3beta and p38 MAPK.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Tau hyperphosphorylation is implicated in neurodegenerative diseases.
- Peroxynitrite is a reactive nitrogen species contributing to oxidative stress and neuronal damage.
- Glycogen synthase kinase-3beta (GSK-3beta) and mitogen-activated protein kinase (MAPK) families are key regulators of tau phosphorylation.
Purpose of the Study:
- To investigate the in vivo effect of melatonin on peroxynitrite-induced tau hyperphosphorylation.
- To determine the role of GSK-3beta and MAPK pathways in this process.
Main Methods:
- Melatonin was administered intracerebroventricularly in rats prior to hippocampal injection of SIN-1 (peroxynitrite donor).
- Tau phosphorylation levels and kinase activities (GSK-3beta, MAPKs) were analyzed.
- Uric acid was used to confirm peroxynitrite's effect.
Main Results:
- SIN-1 induced tau hyperphosphorylation at pS396 and activated GSK-3beta and p38 MAPK isoforms (p38alpha, p38beta, p38delta).
- Melatonin pre-treatment significantly inhibited SIN-1-induced tau hyperphosphorylation and kinase activation.
- Melatonin also reduced peroxynitrite-induced oxidative stress.
Conclusions:
- Melatonin effectively inhibits peroxynitrite-induced tau hyperphosphorylation in vivo.
- The mechanism involves scavenging reactive species and suppressing GSK-3beta and p38 MAPK activation.
- Melatonin shows potential therapeutic value in conditions associated with peroxynitrite-mediated neurotoxicity.
