Einat Haim, Chen Guang, Manji Husseini
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, HHS, Bethesda, USA.
Harefuah. 2004 Jun;143(6):420-5, 462.
Over the past decade, the focus of research into the pathophysiology of bipolar disorder has shifted from an interest in the biogenic amines to an emphasis on second messenger systems within cells. Emerging evidence implicates protein kinase C (PKC) intracellular signaling cascade in the pathophysiology and treatment of bipolar disorder. This review explores the possible involvement of PKC in bipolar disorder summarizing results from laboratory and clinical studies. Bipolar patients were demonstrated to have altered PKC levels, activity or distribution in platelets and in the brain. Chronic administration of lithium and valproate produced a striking reduction in protein kinase C (PKC) human cells and in rats. PKC inhibition in animals resulted in altered affective-like behavior and in a small study, tamoxifen (a PKC inhibitor) had marked antimanic efficacy. The results of studies at the molecular, cellular, animal and clinical levels all suggest that regulation of PKC signaling pathways may play a major part in the pathophysiology and treatment of bipolar disorder. Therefore, this pathway may be a promising candidate for the development of new, more specific drugs for the disease.
在过去十年中，双相情感障碍病理生理学的研究重点已从对生物胺的关注转向对细胞内第二信使系统的重视。新出现的证据表明蛋白激酶C（PKC）细胞内信号级联反应与双相情感障碍的病理生理学及治疗有关。本文综述探讨了PKC在双相情感障碍中的可能作用，总结了实验室和临床研究的结果。双相情感障碍患者被证明在血小板和大脑中PKC水平、活性或分布发生了改变。长期给予锂盐和丙戊酸盐可使人类细胞和大鼠体内的蛋白激酶C（PKC）显著减少。动物体内PKC抑制导致情感样行为改变，在一项小型研究中，他莫昔芬（一种PKC抑制剂）具有显著的抗躁狂疗效。分子、细胞、动物和临床水平的研究结果均表明，PKC信号通路的调节可能在双相情感障碍的病理生理学和治疗中起主要作用。因此，该通路可能是开发针对该疾病的新型、更特异性药物的有希望的候选靶点。
