Department of Child Health Care, Soochow University Affiliated Children's Hospital, No. 303, Jingde Road, Suzhou, China.
Neurosci Lett. 2011 Jun 22;497(2):122-7. doi: 10.1016/j.neulet.2011.04.044. Epub 2011 Apr 27.
Human studies of neurodevelopment suggest that children exposed in utero to certain antiepileptic drugs (AEDs) suffer a variety of brain-behavior sequelae, such as neural tube defects, developmental delays, cognitive deficits, etc. Valproic acid (VPA), a commonly used AED, has greater risk for these side effects compared with other AEDs. However, the detailed molecular mechanisms underlying this developmental neurotoxicity of VPA is unclear despite previous research demonstrating that VPA could induce widespread apoptotic neurodegeneration in developing brains of animal models. This study characterizes the role of astrocytes in VPA-induced neurodegeneration. In developing brains, we evaluated the developmental neurotoxicity of VPA on differentiating neurons and astrocytes from neural progenitor cells cultured from the hippocampus of human fetuses. Exposure of a neuron-enriched culture to VPA at 250μM or 500μM did not cause neuronal apoptosis, but at 1mM and 7 days exposure, a slight increase in the percentage of apoptotic cells was observed. In contrast, VPA at 250μM to 1mM, selectively induced neuronal apoptosis in a neuron-astrocyte mixed cell culture model. The VPA-treated astrocytes showed morphological changes, and the level of tumor necrosis factor-α (TNF-α) was elevated in the supernatant. Both neuronal apoptosis and TNF-α release from astrocytes increased with concentration and exposure time to VPA, suggesting a synergism between the two cell types. Treatment of the neuron-astrocyte mixed culture exposed to VPA with TNF-α antibody partly prevented neuronal apoptosis, while the addition of exogenous TNF-α induced apoptosis in both cultures. Moreover, this pro-apoptotic effect was specific to VPA, as another AED, valpromide, failed to mimic this pro-apoptotic effect, nor did an inhibitor of histone deacetylase (iHDAC), sodium butyrate (NaB). We report a novel finding that astrocytes participate in VPA induced neurodegeneration by releasing TNF-α.
人类神经发育研究表明，胎儿在子宫内暴露于某些抗癫痫药物（AEDs）会导致各种脑-行为后遗症，如神经管缺陷、发育迟缓、认知缺陷等。与其他 AEDs 相比，丙戊酸（VPA）这种常用的 AED 具有更大的此类副作用风险。然而，尽管先前的研究表明 VPA 可诱导动物模型发育中大脑广泛的凋亡性神经退行性变，但 VPA 这种发育神经毒性的确切分子机制尚不清楚。本研究旨在阐明星形胶质细胞在 VPA 诱导的神经退行性变中的作用。在发育中的大脑中，我们评估了 VPA 对从人胎海马神经祖细胞培养的分化神经元和星形胶质细胞的发育神经毒性。将富含神经元的培养物暴露于 250μM 或 500μM 的 VPA 中不会引起神经元凋亡，但在 1mM 和 7 天暴露时，观察到凋亡细胞的百分比略有增加。相比之下，在神经元-星形胶质细胞混合细胞培养模型中，250μM 至 1mM 的 VPA 选择性诱导神经元凋亡。VPA 处理的星形胶质细胞表现出形态变化，上清液中肿瘤坏死因子-α（TNF-α）水平升高。随着 VPA 的浓度和暴露时间的增加，神经元凋亡和 TNF-α 从星形胶质细胞中的释放均增加，提示两种细胞类型之间存在协同作用。用 TNF-α 抗体处理暴露于 VPA 的神经元-星形胶质细胞混合培养物部分阻止了神经元凋亡，而外源性 TNF-α诱导两种培养物中的凋亡。此外，这种促凋亡作用是 VPA 特有的，因为另一种 AED 丙戊酸钠不能模拟这种促凋亡作用，组蛋白去乙酰化酶抑制剂（iHDAC）丁酸钠（NaB）也不能。我们报告了一个新发现，即星形胶质细胞通过释放 TNF-α 参与 VPA 诱导的神经退行性变。
