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Melatonin attenuates isoproterenol-induced protein kinase A overactivation and tau hyperphosphorylation in rat brain
Dan-Ling Wang1, Zhi-Qun Ling, Fu-Yuan Cao
1Department of Pathophysiology, Institute of Neuroscience, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
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.
Insights
Melatonin (MT) protects against isoproterenol (ISO)-induced tau hyperphosphorylation in Alzheimer's disease models. MT suppresses both protein kinase A (PKA) overactivation and oxidative stress, key factors in tau pathology.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Hyperphosphorylation of tau protein is a hallmark of Alzheimer's disease (AD).
- Protein kinase A (PKA) plays a critical role in AD-like tau hyperphosphorylation.
- Oxidative stress is implicated in the pathogenesis of AD.
Purpose of the Study:
- To investigate the protective effects of melatonin (MT) against isoproterenol (ISO)-induced tau hyperphosphorylation in a rat hippocampus model.
- To elucidate the mechanisms underlying MT's protective effects, focusing on PKA activity and oxidative stress markers.
Main Methods:
- Bilateral hippocampal injection of ISO (a PKA activator) to induce tau hyperphosphorylation.
- Administration of MT (intraperitoneally) at various doses and durations.
- Measurement of PKA activity, tau phosphorylation at PHF-1 and tau-1 epitopes, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) levels.
Main Results:
- ISO injection led to PKA overactivation, tau hyperphosphorylation, elevated SOD activity, and increased MDA levels, indicating oxidative stress.
- MT preinfusion partially reversed ISO-induced tau hyperphosphorylation at both PHF-1 and tau-1 sites.
- MT (10 mg/kg for 2 wk) significantly antagonized PKA overactivation, enhanced SOD activity, and decreased MDA levels.
Conclusions:
- Isoproterenol induces tau hyperphosphorylation via PKA activation and increased oxidative stress.
- Melatonin confers protection against ISO-induced tau hyperphosphorylation by suppressing both PKA overactivation and oxidative stress.
- These findings suggest MT as a potential therapeutic agent for AD by targeting key pathological pathways.