Einat Haim, Yuan Peixiong, Gould Todd D, Li Jianling, Du JianHua, Zhang Lei, Manji Husseini K, Chen Guang
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-4405, USA.
J Neurosci. 2003 Aug 13;23(19):7311-6. doi: 10.1523/JNEUROSCI.23-19-07311.2003.
The neurobiological underpinnings of mood modulation, molecular pathophysiology of manic-depressive illness, and therapeutic mechanism of mood stabilizers are largely unknown. The extracellular signal-regulated kinase (ERK) pathway is activated by neurotrophins and other neuroactive chemicals to produce their effects on neuronal differentiation, survival, regeneration, and structural and functional plasticity. We found that lithium and valproate, commonly used mood stabilizers for the treatment of manic-depressive illness, stimulated the ERK pathway in the rat hippocampus and frontal cortex. Both drugs increased the levels of activated phospho-ERK44/42, activated phospho-ribosomal protein S6 kinase-1 (RSK1) (a substrate of ERK), phospho-CREB (cAMP response element-binding protein) and phospho-B cell lymphoma protein-2 antagonist of cell death (substrates of RSK), and BDNF. Inhibiting the ERK pathway with the blood-brain barrier-penetrating mitogen-activated protein kinase (MAP kinase)/ERK kinase (MEK) kinase inhibitor SL327, but not with the nonblood-brain barrier-penetrating MEK inhibitor U0126, decreased immobility time and increased swimming time of rats in the forced-swim test. SL327, but not U0126, also increased locomotion time and distance traveled in a large open field. The behavioral changes in the open field were prevented with chronic lithium pretreatment. SL327-induced behavioral changes are qualitatively similar to the changes induced by amphetamine, a compound that induces relapse in remitted manic patients and mood elevation in normal subjects. These data suggest that the ERK pathway may mediate the antimanic effects of mood stabilizers.
情绪调节的神经生物学基础、躁郁症的分子病理生理学以及情绪稳定剂的治疗机制在很大程度上尚不清楚。细胞外信号调节激酶（ERK）通路被神经营养因子和其他神经活性化学物质激活，以产生它们对神经元分化、存活、再生以及结构和功能可塑性的影响。我们发现，常用于治疗躁郁症的情绪稳定剂锂盐和丙戊酸盐可刺激大鼠海马体和额叶皮质中的ERK通路。两种药物均增加了活化的磷酸化ERK44/42、活化的磷酸化核糖体蛋白S6激酶-1（RSK1）（ERK的一种底物）、磷酸化CREB（环磷酸腺苷反应元件结合蛋白）和磷酸化B细胞淋巴瘤蛋白-2细胞死亡拮抗剂（RSK的底物）以及脑源性神经营养因子（BDNF）的水平。使用可穿透血脑屏障的丝裂原活化蛋白激酶（MAP激酶）/ERK激酶（MEK）激酶抑制剂SL327抑制ERK通路，但使用不可穿透血脑屏障的MEK抑制剂U0126则不能，这减少了强迫游泳试验中大鼠的不动时间并增加了游泳时间。SL327而非U0126还增加了大鼠在大的开放场地中的运动时间和移动距离。慢性锂盐预处理可预防开放场地中的行为变化。SL327诱导的行为变化在性质上类似于苯丙胺诱导的变化，苯丙胺是一种可诱发缓解期躁狂患者复发并使正常受试者情绪升高的化合物。这些数据表明，ERK通路可能介导情绪稳定剂的抗躁狂作用。
