Melatonin attenuates isoproterenol-induced protein kinase A overactivation and tau hyperphosphorylation in rat brain.
Hyperphosphorylation of microtubule-associated protein tau at specific sites is a recognized pathological process in Alzheimer's disease (AD), and protein kinase A (PKA) is a crucial kinase in AD-like tau hyperphosphorylation. In the present study, isoproterenol (ISO) was injected bilaterally into hippocampus of rat brain; ISO is a specific PKA activator and it induces tau hyperphosphorylation. With this system, melatonin (MT) was shown to protect against ISO-induced tau hyperphosphorylation. We found that hippocampal injection of ISO (0.02 microm) induced PKA overactivation and tau hyperphosphorylation at both paired helical filament (PHF)-1 and tau-1 sites. ISO injection also resulted in activation of superoxide dismutase (SOD) and elevation of malondialdehyde (MDA), parameters suggesting elevated oxidative stress. Preinfusion of MT intraperitoneally partially reversed ISO-induced tau hyperphosphorylation at the PHF-1 epitope (1 and 10 mg/kg continuously for 4 wk or 10 mg/kg for 1, 2 or 3 wk) and tau-1 epitope (10 mg/kg for 2 wk). Furthermore, MT (10 mg/kg for 2 wk) obviously antagonized ISO-induced PKA overactivation, as well as enhanced SOD activity and decreased the level of MDA. It is suggested from these data that ISO may induce abnormal hyperphosphorylation of tau through not only the activation of PKA but also because of the fact that it increases oxidative stress; MT may protect against ISO-induced tau hyperphosphorylation through suppression of both PKA overactivation and oxidative stress.
Wang
Dan-Ling
DL
Department of Pathophysiology, Institute of Neuroscience, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ling
Zhi-Qun
ZQ
Cao
Fu-Yuan
FY
Zhu
Ling-Qiang
LQ
Wang
Jian-Zhi
JZ
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001921:Brain / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D007545:Isoproterenol / Q000008:administration & dosage*; D008297:Male; D008550:Melatonin / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013566:Sympathomimetics / Q000008:administration & dosage*; D016875:tau Proteins / Q000378:metabolism*
D000975:Antioxidants; D013566:Sympathomimetics; D016875:tau Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D008550:Melatonin; D007545:Isoproterenol