Department of Neurology and Clinical Neurophysiology, Hannover Medical School, OE 7210, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
Cell Mol Neurobiol. 2010 Aug;30(6):891-900. doi: 10.1007/s10571-010-9518-8. Epub 2010 Apr 27.
Amyotrophic lateral sclerosis is a devastating motoneuron disorder for which no effective treatment exists. There is some evidence for neuroprotective effects of valproic acid (VPA). The beneficial effects, however, are limited due to the adverse effects of VPA. To overcome this problem, a number of VPA derivates with fewer side effects have been synthesized. In the present study, we investigated the viability of highly purified embryonic motoneurons cultured on glial feeder layers, composed of either astrocytes or Schwann cells, or in monoculture, in presence of VPA and its three derivates 3-propyl-heptanoic acid (3-PHA), PE-4-yn enantiomers (R- and S-PE-4-yn). An excitotoxic stimulus, kainate (KA), was added at day in vitro 9 (DIV9) and the neuroprotective effect of either simultaneous incubation (DIV9) or pre-incubation (DIV1) of VPA and its derivates was tested. The survival of motoneurons under simultaneous application of KA and VPA derivates was not remarkably increased. Pre-incubation with VPA and even more with the derivates before the addition of KA, however, significantly reduced their vulnerability against the KA-induced neurotoxic effect. Our data suggest that the neuroprotective capacities of VPA and its three derivates tested here drastically increase when they are added several days before KA. Most prominent neuroprotective effects were seen for the PE-4-yn enantiomers. Patch-clamp experiments revealed an antiexcitotoxic effect of the S-PE-4-yn enantiomer that reduces the frequency of postsynaptic currents and enhances the inhibitory postsynaptic transmission dependent on the co-culture condition.
肌萎缩性侧索硬化症是一种毁灭性的运动神经元疾病，目前尚无有效的治疗方法。丙戊酸（VPA）具有一定的神经保护作用。然而，由于 VPA 的不良反应，其有益作用受到限制。为了克服这个问题，已经合成了许多副作用较小的 VPA 衍生物。在本研究中，我们研究了在胶质细胞饲养层（由星形胶质细胞或施万细胞组成）或单培养物上培养的高度纯化的胚胎运动神经元的活力，存在 VPA 及其三种衍生物 3-丙基庚酸（3-PHA）、PE-4-yn 对映体（R-和 S-PE-4-yn）。在体外第 9 天（DIV9）添加兴奋性毒素海人酸（KA），并测试 VPA 及其衍生物同时孵育（DIV9）或预孵育（DIV1）的神经保护作用。同时应用 KA 和 VPA 衍生物时，运动神经元的存活率没有明显增加。然而，在添加 KA 之前，用 VPA 甚至更用其衍生物进行预孵育，显著降低了它们对 KA 诱导的神经毒性作用的易感性。我们的数据表明，当 VPA 和三种衍生物在 KA 添加前几天添加时，其神经保护能力会大大增加。最显著的神经保护作用见于 PE-4-yn 对映体。膜片钳实验显示 S-PE-4-yn 对映体具有抗兴奋毒性作用，可降低突触后电流的频率，并增强依赖于共培养条件的抑制性突触传递。
