The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells
The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells
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DOI：
10.1111/j.1471-4159.2004.02725.x
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发表时间：
2004-10-01
影响因子：
4.7
通讯作者：
Altar, CA
中科院分区：
文献类型：
--
作者：
Laeng, P;Pitts, RL;Altar, CA
丙戊酸是一种用于治疗双相情感障碍的抗惊厥药物，研究发现它能够促进胚胎大鼠皮层或纹状体原始干细胞的神经发生。暴露于丙戊酸6天后，微管蛋白β iii免疫阳性神经元的数量和百分比增加了5倍，神经突生长增加，星形胶质细胞数量减少了5倍，但细胞数量没有改变。丙戊酸盐还能促进人胎儿前脑干细胞培养中的神经元分化。丙戊酸盐对大鼠干细胞的神经源性作用超过了神经营养因子脑源性生长因子（BDNF）或NT-3，并略微超过了另一种情绪稳定剂锂的作用。卡马西平未见效果。大多数新形成的神经元是GABA能神经元，GABA和GABA合成酶GAD65/67免疫染色的神经元增加了10倍。溴脱氧尿苷和微管蛋白β III的双重免疫染色显示丙戊酸盐使大鼠干细胞衍生的神经祖细胞增殖增加4至5倍，并增加细胞周期蛋白D2的表达。丙戊酸盐在不同治疗时间对生存基因Bad和Bcl-2的表达也有调节作用。通过定量RT-PCR分析，早在丙戊酸治疗后6小时前列腺素E合成酶的表达就增加了9倍。通过增加神经干细胞的神经元分化，gaba能神经元数量、神经突生长和表型表达的增强可能有助于丙戊酸治疗双相情感障碍的治疗效果。
Valproate, an anticonvulsant drug used to treat bipolar disorder, was studied for its ability to promote neurogenesis from embryonic rat cortical or striatal primordial stem cells. Six days of valproate exposure increased by up to fivefold the number and percentage of tubulin beta III-immunopositive neurons, increased neurite outgrowth, and decreased by fivefold the number of astrocytes without changing the number of cells. Valproate also promoted neuronal differentiation in human fetal forebrain stem cell cultures. The neurogenic effects of valproate on rat stem cells exceeded those obtained with the neurotrophins brain-derived growth factor (BDNF) or NT-3, and slightly exceeded the effects obtained with another mood stabilizer, lithium. No effect was observed with carbamazepine. Most of the newly formed neurons were GABAergic, as shown by 10-fold increases in neurons that immunostained for GABA and the GABA-synthesizing enzyme GAD65/67. Double immunostaining for bromodeoxyuridine and tubulin beta III showed that valproate increased by four- to fivefold the proliferation of neuronal progenitors derived from rat stem cells and increased cyclin D2 expression. Valproate also regulated the expression of survival genes, Bad and Bcl-2, at different times of treatment. The expression of prostaglandin E synthase, analyzed by quantitative RT-PCR, was increased by ninefold as early as 6 h into treatment by valproate. The enhancement of GABAergic neuron numbers, neurite outgrowth, and phenotypic expression via increases in the neuronal differentiation of neural stem cell may contribute to the therapeutic effects of valproate in the treatment of bipolar disorder.