Institute for Clinical Neurobiology, University of Wuerzburg, Josef-Schneider-Str. 11, D-97080 Wuerzburg, Germany.
Neurobiol Dis. 2009 Dec;36(3):477-87. doi: 10.1016/j.nbd.2009.08.014. Epub 2009 Sep 4.
Valproic acid (VPA), an antiepileptic drug and HDAC inhibitor, has been identified as a drug candidate for spinal muscular atrophy (SMA), a motoneuron disorder for which currently no effective therapy is available. Based on its potential to up-regulate SMN expression from the SMN2 gene in fibroblasts and lymphoblastoid cell lines from SMA patients, we analysed the effects of VPA in isolated motoneurons from Smn(-/-);SMN2 mice, a model for SMA type I. Treatment with VPA increased Smn expression but unexpectedly also led to reduced growth cone size and reduced excitability in axon terminals of mutant motoneurons. Analysis of Ca2+ currents and distribution of voltage-gated Ca2+ channels revealed an inhibitory function of VPA on voltage-gated Ca2+ channels and possibly also other ion channels that contribute to presynaptic excitability of motoneurons. Our data indicate effects of VPA which might aggravate disease-specific symptoms in SMA patients.
丙戊酸（VPA）是一种抗癫痫药物和组蛋白去乙酰化酶抑制剂，已被确定为脊髓性肌萎缩症（SMA）的候选药物，目前尚无有效的治疗方法。基于其在成纤维细胞和来自 SMA 患者的淋巴母细胞系中上调 SMN2 基因表达的潜力，我们分析了 VPA 对 Smn(-/-);SMN2 小鼠分离的运动神经元的影响，Smn(-/-);SMN2 小鼠是 SMA Ⅰ型的模型。VPA 的治疗增加了 Smn 的表达，但出人意料的是，这也导致突变运动神经元的生长锥大小减小和轴突末梢兴奋性降低。对 Ca2+电流和电压门控 Ca2+通道分布的分析表明，VPA 对电压门控 Ca2+通道具有抑制作用，可能对运动神经元的突触前兴奋性有贡献的其他离子通道也具有抑制作用。我们的数据表明 VPA 可能会加重 SMA 患者的疾病特异性症状。
