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

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. Brain ventricular and intraperitonea...

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Published inChinese medical sciences journal Vol. 20; no. 2; p. 83
Main Authors Zhu, Ling-qiang, Wang, Shao-hui, Ling, Zhi-qun, Wang, Qun, Hu, Mao-qiong, Wang, Jian-zhi
Format Journal Article
LanguageEnglish
Published China 01.06.2005
Subjects
Animals
Cyclic AMP-Dependent Protein Kinases - metabolism
Epitopes
Glycogen Synthase Kinase 3 - metabolism
Haloperidol - administration & dosage
Haloperidol - pharmacology
Hippocampus - enzymology
Hippocampus - metabolism
Injections, Intraperitoneal
Injections, Intraventricular
Male
Melatonin - biosynthesis
Melatonin - blood
Phosphorylation - drug effects
Rats
Rats, Wistar
tau Proteins - metabolism
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Summary: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. 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. 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. Decreased melatonin may be involved in Alzheimer-like tau hyperphosphorylation, and overactivation of PKA may play a crucial role in this process.
ISSN:1001-9294