Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat.
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.
Zhu
Ling Qiang
LQ
Department of Pathophysiology, Institute of Neuroscience, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Wang
Shao Hui
SH
Ling
Zhi Qun
ZQ
Wang
Dan Ling
DL
Wang
Jian-Zhi
JZ
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006220:Haloperidol / Q000008:administration & dosage; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008550:Melatonin / Q000096:biosynthesis*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016875:tau Proteins; D006220:Haloperidol; D008550:Melatonin