Manji H K, Chen G
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, MD 20892, USA.
Mol Psychiatry. 2002;7 Suppl 1:S46-56. doi: 10.1038/sj.mp.4001018.
The complexity of the unique biology of bipolar disorder--which includes the predisposition to episodic, and often progressive, mood disturbance--and the dynamic nature of compensatory processes in the brain, coupled with limitations in experimental design, have hindered our ability to identify the underlying pathophysiology of this fascinating neuropsychiatric disorder. Although we have yet to identify the specific abnormal genes in mood disorders, recent studies have implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of bipolar disorder. In particular, a converging body of preclinical data has shown that chronic lithium and valproate, at therapeutically relevant concentrations, regulate the protein kinase C signaling cascade. This has led to the investigation of the antimanic efficacy of tamoxifen (at doses sufficient to inhibit protein kinase C), with very encouraging preliminary results. A growing body of data also suggests that impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of bipolar disorder. It is thus noteworthy that mood stabilizers, such as lithium and valproate, indirectly regulate a number of factors involved in cell survival pathways--including cAMP response element binding protein, brain derived neurotrophic factor, bcl-2 and mitogen-activated protein kinases--and may thus bring about some of their delayed long-term beneficial effects via under-appreciated neurotrophic effects. The development of novel treatments, which more directly target molecules involved in critical central nervous system cell survival and cell death pathways, has the potential to enhance neuroplasticity and cellular resilience, thereby modulating the long-term course and trajectory of these devastating illnesses.
双相情感障碍独特生物学特性的复杂性——包括易患发作性且往往呈进行性的情绪紊乱——以及大脑中代偿过程的动态性质，再加上实验设计的局限性，阻碍了我们识别这种迷人的神经精神疾病潜在病理生理学的能力。尽管我们尚未确定情绪障碍中的具体异常基因，但最近的研究表明关键信号转导通路是双相情感障碍病理生理学和治疗的重要组成部分。特别是，越来越多的临床前数据表明，在治疗相关浓度下，慢性锂盐和丙戊酸盐可调节蛋白激酶C信号级联反应。这导致了对他莫昔芬（剂量足以抑制蛋白激酶C）抗躁狂疗效的研究，初步结果非常令人鼓舞。越来越多的数据还表明，神经可塑性和细胞弹性受损也可能是双相情感障碍病理生理学的基础。因此值得注意的是，锂盐和丙戊酸盐等心境稳定剂可间接调节细胞存活通路中涉及的一些因素——包括环磷酸腺苷反应元件结合蛋白、脑源性神经营养因子、bcl-2和丝裂原活化蛋白激酶——因此可能通过未被充分认识的神经营养作用产生一些延迟的长期有益效果。开发更直接靶向参与关键中枢神经系统细胞存活和细胞死亡通路的分子的新型治疗方法，有可能增强神经可塑性和细胞弹性，从而调节这些毁灭性疾病的长期病程和发展轨迹。
