Inhibition of melatonin biosynthesis activates protein kinase a and induces Alzheimer-like tau hyperphosphorylation in rats
Zhu, L-qiang.; Wang, S-hui.; Ling, Z-qun.; Wang, Q.; Hu, M-qiong.; Wang, J-zhi.
Chinese Medical Sciences Journal 20(2): 83-87
2005
ISSN/ISBN: 1001-9294 PMID: 16075743 Document Number: 586209
Objective To investigate effect of inhibiting melatonin biosynthesis on activities of protein kinase A (PKA), glycogen synthase kinase-3 (GSK-3) and tau phosphorylation at PS214 and M4 epitopes using haloperidol, a specific inhibitor of 5-hydroxyindole-O-methyltransferase.Methods Brain ventricular and intraperitoneal injections were used for haloperidol administration, Western blots for tau phosphorylation, P-32-labeling for PKA and GSK-3 activity, and high performance liquid chromatograph for detection of serum melatonin levels.Results Haloperidol injection through the lateral ventricle and intraperitoneal reinforcement significantly stimulated PKA activity with a concurrent hyperphosphorylation of tau at M4 (Thr231/Ser235) and PS214 (Ser214) sites. Prior treatment of the rats using melatonin supplement for one week and reinforcement during the haloperidol administration arrested PKA activity and attenuated tau hyperphosphorylation. GSK-3 activity showed no obvious change after haloperidol injection, however, melatonin supplements and reinforcements during haloperidol infusion inactivated basal activity of GSK-3.Conclusion Decreased melatonin may be involved in Alzheimer-like tau hyperphosphorylation, and overactivation of PKA may play a crucial role in this process.