Chen Guang, Manji Husseini K
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, Maryland 20892-3711, USA.
Curr Opin Psychiatry. 2006 May;19(3):313-23. doi: 10.1097/01.yco.0000218604.63463.cd.
There exists a growing appreciation that, though not classical neurodegenerative disorders, severe mood disorders are associated with regional impairments of structural plasticity and cellular resilience. Exciting recent data suggest that synaptic plasticity probably is involved in mechanisms of actions of mood stabilizers and antidepressants. Notably, the extracellular signal-regulated kinase pathway is a critical 'plasticity pathway' in the brain. The present review summarizes neurobiological, pharmacological, and behavioral data on the role of the extracellular signal-regulated kinase pathway in regulating some of the symptoms of bipolar disorder and as a therapeutically relevant target for mood stabilizers.
The extracellular signal-regulated kinase pathway is known to mediate neurotrophic actions and synaptic plasticity. Treatment with lithium and valproate activates the extracellular signal-regulated kinase pathway in cultured cells and in prefrontal cortex and hippocampus. In addition, lithium or valproate treatment promotes neurogenesis, neurite growth, and cell survival. The extracellular signal-regulated kinase pathway is also targeted by antipsychotics. Modulation of the central nervous system extracellular signal-regulated kinase pathway induces animal behavioral alterations reminiscent of manic symptoms; these complex behaviors probably depend on the effects of extracellular signal-regulated kinase on discrete brain regions and the presence of other interacting molecules.
The extracellular signal-regulated kinase pathway may represent a novel target for the development of improved therapeutics for bipolar disorder.
人们越来越认识到，严重情绪障碍虽非典型神经退行性疾病，但与结构可塑性和细胞弹性的区域损伤有关。最近令人兴奋的数据表明，突触可塑性可能参与了心境稳定剂和抗抑郁药的作用机制。值得注意的是，细胞外信号调节激酶通路是大脑中一条关键的“可塑性通路”。本综述总结了关于细胞外信号调节激酶通路在调节双相情感障碍某些症状中的作用以及作为心境稳定剂治疗相关靶点的神经生物学、药理学和行为学数据。
已知细胞外信号调节激酶通路介导神经营养作用和突触可塑性。锂盐和丙戊酸盐处理可在培养细胞以及前额叶皮质和海马体中激活细胞外信号调节激酶通路。此外，锂盐或丙戊酸盐处理可促进神经发生、神经突生长和细胞存活。抗精神病药物也作用于细胞外信号调节激酶通路。对中枢神经系统细胞外信号调节激酶通路的调节会诱发类似于躁狂症状的动物行为改变；这些复杂行为可能取决于细胞外信号调节激酶对离散脑区的影响以及其他相互作用分子的存在。
细胞外信号调节激酶通路可能是开发改善双相情感障碍治疗方法的新靶点。
