Melatonin attenuates isoproterenol‐induced protein kinase A overactivation and tau hyperphosphorylation in rat brain

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.

Estradiol Attenuates Tau Hyperphosphorylation Induced by Upregulation of Protein Kinase-A

“…After incubation for 10 min at 30°C, the reaction was stopped by addition of 25 ll of 300 mM O-phosphoric acid. Then, 10 ll of reactive solution was removed and spotted in triplicates onto phosphocellulose membrane [12,29]. The membrane was then washed five times in 1% phosphoric acid to remove nonprotein incorporated 32 P, dried and counted by Cerenkov counting [30,31].…”

Galantamine-loaded solid–lipid nanoparticles for enhanced brain delivery: preparation, characterization, in vitro and in vivo evaluations

“…Method described by Wang et al (2004) was used to administer ICV injection of isoproterenol. Isoproterenol (40 mM, ICV, 2 ml) previously standardized in our laboratory was injected bilaterally into the rat brain in the hippocample region using the coordinates 4.8 mm posterior to bregma; 2.2 mm lateral to sagittal suture and 3.0 mm beneath the surface of the brain (Paxinus 1985).…”

Amyloid-β Levels in Mice Hippocampus According to the ALDH2 Enzyme Activity followed Ethanol Exposure for 8-Weeks

“…알츠하이머 질환(Alzheimer's disease)은 인지능력과 행동 능력 두 가지에 모두 영향을 미치는 진행적 노인성 치매증의 일종으로 정확한 발병기전은 아직 알려져 있지 않으나 복잡한 신호전달체계(signal transduction)를 통해 뇌의 해마조직 부 위에 아밀로이드 베타(amyloid-beta, Aβ)가 다량 축적되고 이 로 인해 뇌세포의 사멸(apoptosis)이 유도되는 것으로 알려져 있다 [19,21,25]. 또한, 이 과정에 활성산소(Reactive oxygen species, ROS) 생성을 통한 산화적 스트레스가 중요한 역할을 할 가능성이 매우 크다 [3,4,16].…”