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Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat
Ling Qiang Zhu1, Shao Hui Wang, Zhi Qun Ling
1Department of Pathophysiology, Institute of Neuroscience, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
We have found recently that melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity. In the present study, we further investigated the in vivo effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rats and the potential underlying mechanisms by using haloperidol, a specific inhibitor of 5-hydroxyindole-O-methyltransferase, and a key enzyme in melatonin biosynthesis. We have found that injection of haloperidol into the lateral ventricle and into peritoneal cavity compromises spatial memory retention of rats and induces hyperphosphorylation of microtubule-associated protein tau at tau-1 (Ser199/Ser202) and PHF-1 (Ser396/Ser404) epitopes. At mean time, the activity of protein phosphatase-2A (PP-2A), a deficit phosphatase in the Alzheimer's disease brain and superoxide dismutase decreases with an elevated level of malondialdehyde. Supplementation with melatonin by prior injection for 1 wk and reinforcement during the haloperidol administration significantly improves memory retention deficits, arrests tau hyperphosphorylation and oxidative stress, and restores PP-2A activity. These results strongly support the involvement of decreased melatonin in Alzheimer-like spatial memory impairment and tau hyperphosphorylation, and PP-2A may play a role in mediating aberrant melatonin-induced lesions.
Insights
Inhibiting melatonin biosynthesis in rats impaired spatial memory and increased tau phosphorylation. Melatonin supplementation reversed these effects, suggesting its role in Alzheimer-like cognitive decline.
Area of Science:
- Neuroscience
- Biochemistry
Background:
- Melatonin protects neuronal cells from neurotoxicity.
- Melatonin biosynthesis is crucial for its protective effects.
Purpose of the Study:
- Investigate the in vivo effects of inhibiting melatonin biosynthesis on spatial memory and tau phosphorylation in rats.
- Explore the underlying mechanisms, including oxidative stress and protein phosphatase-2A (PP-2A) activity.
Main Methods:
- Administered haloperidol, a 5-hydroxyindole-O-methyltransferase inhibitor, to rats to block melatonin synthesis.
- Assessed spatial memory retention, tau phosphorylation (tau-1 and PHF-1 epitopes), PP-2A activity, superoxide dismutase, and malondialdehyde levels.
- Supplemented with melatonin to evaluate its protective effects.
Main Results:
- Haloperidol administration impaired spatial memory retention and induced tau hyperphosphorylation.
- Inhibition of melatonin synthesis led to decreased PP-2A activity, reduced superoxide dismutase, and increased malondialdehyde.
- Melatonin supplementation significantly improved memory, reduced tau hyperphosphorylation, mitigated oxidative stress, and restored PP-2A activity.
Conclusions:
- Decreased melatonin levels are implicated in Alzheimer-like spatial memory impairment and tau hyperphosphorylation.
- Protein phosphatase-2A (PP-2A) activity may mediate the detrimental effects of reduced melatonin.
- Melatonin holds potential therapeutic value for neurodegenerative conditions characterized by memory deficits and tau pathology.
