Phenylbutyric acid prevents rats from electroconvulsion-induced memory deficit with alterations of memory-related proteins and tau hyperphosphorylation
Phenylbutyric acid prevents rats from electroconvulsion-induced memory deficit with alterations of memory-related proteins and tau hyperphosphorylation
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DOI：
10.1016/j.neuroscience.2010.03.060
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发表时间：
2010-06
期刊：
影响因子：
3.3
通讯作者：
Zhao-Hui Yao;Ziyuan Guo;Chun Yang;Qing Tian;C. Gong;Gang Liu;Junhan Wang
中科院分区：
文献类型：
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作者：
Zhao-Hui Yao;Ziyuan Guo;Chun Yang;Qing Tian;C. Gong;Gang Liu;Junhan Wang
电休克疗法已广泛应用于难治性抑郁症的治疗，但其认知副作用受到重视，限制了其应用。副作用背后的分子机制仍然难以捉摸，也没有有效的预防措施。采用公认的电惊厥(ECS)大鼠模型，我们发现ECS导致空间记忆障碍，同时N-甲基-D-天冬氨酸受体2A/B(NR2A/B)和突触后密度95(PSD95)、即刻早期基因c-Fos和cAMP反应元件结合(CREB)蛋白的突触蛋白减少，这些都是记忆相关蛋白。在阿尔茨海默病相关的多个磷酸化位点上，ECs还引起tau过度磷酸化，激活糖原合成酶-3β(GSK-3β)、AKT和磷酸化PKR样内网(PERK)，抑制蛋白磷酸酶-2A(PP)-2A。苯丁酸(PBA)是一种具有分子伴侣功能的芳香族短链脂肪酸，可预防ECS诱导的大鼠记忆障碍、记忆相关蛋白的改变和tau蛋白的过度磷酸化。我们的数据表明，PBA可能被用于减轻电惊厥治疗引起的副作用。
Electroconvulsive therapy has been commonly applied in the treatment of refractory depression, but its cognitive side effects are noticed and restrict its application. The molecular mechanisms underlying the side effects remain elusive, and there is no efficient prevention. By employing a recognized electroconvulsive shock (ECS) rat model, we found in the present study that ECS induced spatial memory deficits with simultaneous decreases in synaptic proteins of N-methyl-D-aspartate receptor 2A/B (NR2A/B) and postsynaptic density 95 (PSD95), the immediate early gene c-Fos and cAMP response element binding (CREB) proteins, all of which are memory-related proteins. ECS also caused tau hyperphosphorylation at multiple Alzheimer-related phosphorylation sites with activation of glycogen synthase kinase-3β (GSK-3β), Akt and phospho-PKR-like endoreticulum (PERK), and inhibition of protein phosphatase-2A (PP)-2A. Intraperitoneal injection of phenylbutyric acid (PBA), an aromatic short chain fatty acid with the functions of molecule chaperon, prevented rats from the ECS-induced memory deficits, alterations of the memory-associated proteins, and tau hyperphosphorylation. Our data suggest that PBA may be potentially used for attenuating the side effects caused by electroconvulsive therapy.