Inhibition of melatonin biosynthesis activates protein kinase a and induces Alzheimer-like tau hyperphosphorylation in rats.
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, 32P-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.


CONCLUSIONS
Decreased melatonin may be involved in Alzheimer-like tau hyperphosphorylation, and overactivation of PKA may play a crucial role in this process.
Zhu
Ling-qiang
LQ
Department of Pathophysiology, Institute of Neuroscience, Tongji Medical College, Huazhong University of Science and Technology, Wuhan.
Wang
Shao-hui
SH
Ling
Zhi-qun
ZQ
Wang
Qun
Q
Hu
Mao-qiong
MQ
Wang
Jian-zhi
JZ
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D000939:Epitopes; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D008550:Melatonin / Q000096:biosynthesis* / Q000097:blood; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
D000939:Epitopes; D016875:tau Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D006220:Haloperidol; D008550:Melatonin