A Role for the PKC Signaling System in the Pathophysiology and Treatment of Mood Disorders: Involvement of a Functional Imbalance?
A Role for the PKC Signaling System in the Pathophysiology and Treatment of Mood Disorders: Involvement of a Functional Imbalance?
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DOI：
10.1007/s12035-011-8210-4
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发表时间：
2011-12-01
影响因子：
5.1
通讯作者：
Lambas-Senas, Laura
中科院分区：
文献类型：
--
作者：
Abrial, Erika;Lucas, Guillaume;Lambas-Senas, Laura
情绪障碍，如双相情感障碍和严重抑郁障碍，是一种常见的、严重的、往往使人致残的神经精神疾病，影响着全球数百万人。现有的情绪稳定剂和抗抑郁药仍然不能令人满意，因为它们的治疗效果延迟和部分。因此，迫切需要开发更快、更有效的靶向疗法。在此背景下，蛋白激酶C(PKC)信号系统，调节与情绪调节有关的多个神经元过程，可以构成一个新的治疗靶点。本文综述了目前有关PKC信号通路在心境障碍病理生理学中的作用以及PKC调节剂的治疗潜力的现有知识。目前的抗抑郁药和情绪稳定剂已被证明可以调节PKC通路，而抑制这种细胞内信号级联导致动物模型中的抗躁狂性质。在情绪障碍患者的死后大脑和血小板中都发现了PKC活性中断。最后，PKC抑制剂他莫昔芬最近在几个临床试验中显示出强大的抗躁狂特性。总体而言，来自临床前和临床研究的新数据表明，在情绪障碍中，PKC信号系统存在失衡。因此，PKC可能是发展创新疗法的关键分子靶点。
Mood disorders, such as bipolar and major depressive disorders, are frequent, severe, and often disabling neuropsychiatric diseases affecting millions of individuals worldwide. Available mood stabilizers and antidepressants remain unsatisfactory because of their delayed and partial therapeutic efficacy. Therefore, the development of targeted therapies, working more rapidly and being fully effective, is urgently needed. In this context, the protein kinase C (PKC) signaling system, which regulates multiple neuronal processes implicated in mood regulation, can constitute a novel therapeutic target. This paper reviews the currently available knowledge regarding the role of the PKC signaling pathway in the pathophysiology of mood disorders and the therapeutic potential of PKC modulators. Current antidepressants and mood stabilizers have been shown to modulate the PKC pathway, and the inhibition of this intracellular signaling cascade results in antimanic-like properties in animal models. Disrupted PKC activity has been found both in postmortem brains and platelet from patients with mood disorders. Finally, the PKC inhibitor tamoxifen has recently demonstrated potent antimanic properties in several clinical trials. Overall, emerging data from preclinical and clinical research suggest an imbalance of the PKC signaling system in mood disorders. Thus, PKC may be a critical molecular target for the development of innovative therapeutics.