Dept. of Physiology, Northwestern Univ. Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611, USA.
J Neurophysiol. 2012 Jan;107(1):484-92. doi: 10.1152/jn.00714.2011. Epub 2011 Oct 19.
Riluzole is the only FDA-approved drug to treat amyotrophic lateral sclerosis, but its long-term effects on motoneurons are unknown. Therefore, we treated primary mouse spinal cord cultures with 2 μM riluzole for 4-9 days and then used whole cell patch clamp to record the passive and active properties of both wild-type and SOD1(G93A) motoneurons. At this concentration, riluzole blocks >50% of the sodium component of a persistent inward current that plays a major role in determining motoneuron excitability. Prolonged riluzole treatment significantly decreased the amplitude of the persistent inward current. This effect was specific for SOD1(G93A) motoneurons, where the amplitude decreased by 55.4%. In addition, prolonged treatment hyperpolarized the resting membrane potential as well as the voltage onset and voltage maximum of the persistent inward current (∼2-3 mV in each case). These effects appeared to offset one another and resulted in no change in the firing properties. In a subset of cells, acute reapplication of 2 μM riluzole during the recording decreased repetitive firing and the persistent inward current, which is consistent with the normal effects of riluzole. The downregulation of the persistent inward current in response to prolonged riluzole administration is in contrast to the strong upregulation of this same current after descending neuromodulatory drive to the cord is lost following spinal injury. This dichotomy suggests that decreased activation of G protein-coupled pathways can induce upregulation in the persistent inward current but that direct channel block is ineffective.
利鲁唑是唯一被 FDA 批准用于治疗肌萎缩侧索硬化症的药物，但它对运动神经元的长期影响尚不清楚。因此，我们用 2μM 的利鲁唑处理原代小鼠脊髓培养物 4-9 天，然后用全细胞膜片钳记录野生型和 SOD1(G93A)运动神经元的被动和主动特性。在这个浓度下，利鲁唑阻断了持续内向电流的钠离子成分的>50%，而持续内向电流在决定运动神经元兴奋性方面起着主要作用。延长利鲁唑处理显著降低了持续内向电流的幅度。这种作用是 SOD1(G93A)运动神经元特有的，其幅度降低了 55.4%。此外，长期治疗使静息膜电位以及持续内向电流的电压起始和电压最大值超极化（每种情况约 2-3 mV）。这些效应似乎相互抵消，导致放电特性没有变化。在一小部分细胞中，在记录过程中急性再应用 2μM 的利鲁唑可降低重复放电和持续内向电流，这与利鲁唑的正常作用一致。与脊髓损伤后下行神经调节驱动丧失导致脊髓后，同一电流的强烈上调相反，长时间给予利鲁唑后持续内向电流的下调表明，G 蛋白偶联途径的激活减少可诱导持续内向电流的上调，但直接通道阻断无效。
