Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis
Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis
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DOI：
10.1523/jneurosci.5747-03.2004
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发表时间：
2004-07-21
影响因子：
5.3
通讯作者：
Chen, G
中科院分区：
文献类型：
--
作者：
Hao, YL;Creson, T;Chen, G
躁狂抑郁症被认为是一种神经化学疾病。然而，脑成像和尸检研究显示，躁狂抑郁症患者的灰质减少，以及神经元和神经胶质萎缩和离散脑区域的损失。这种脑形态缺陷在神经病理生理学和躁狂抑郁症治疗机制中的作用尚不清楚。丙戊酸盐（2-丙基戊酸盐）是一种常用的情绪稳定剂。ERK（细胞外信号调节激酶）通路被神经营养因子用于调节神经发生、神经突生长和神经元存活。我们发现，丙戊酸盐长期给药大鼠增加了前扣带回神经元中活化磷酸化ERK 44/42的水平，在该区域，我们发现丙戊酸盐诱导ERK通路调节基因bcl-2表达增加。丙戊酸盐时间和浓度依赖性增加培养的皮质细胞中活化的磷酸化ERK 44/42和磷酸化RSK 1（核糖体S6激酶1）水平。这些增加被Raf和MEK（促分裂原活化蛋白激酶/ERK激酶）抑制剂减弱。尽管丙戊酸盐影响GSK-3（糖原合成酶激酶-3）和组蛋白脱乙酰酶（HDAC）的功能，但其对ERK通路的影响未被GSK-3或HDAC的选择性抑制剂完全模拟。与神经营养因子相似，丙戊酸盐可增强ERK通路依赖性皮质神经元生长。丙戊酸盐还促进神经干细胞增殖-成熟（神经发生），表现为溴脱氧尿苷（BrdU）掺入和BrdU与巢蛋白、Tuj 1或神经元核标记物NeuN（神经元特异性核蛋白）的双重染色。丙戊酸盐长期治疗可增强海马齿状回的神经发生。总之，这些数据表明丙戊酸盐激活ERK通路并诱导ERK通路介导的神经营养作用。这一连串的事件提供了一个潜在的机制，使情绪稳定剂减轻与躁狂抑郁症相关的脑形态学缺陷。
Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase ( HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation ( neurogenesis), demonstrated by bromodeoxyuridine ( BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness.