Ashton D, Willems R, Wynants J, Van Reempts J, Marrannes R, Clincke G
Department of Neuopsychopharmacology, Jansen Research Foundation, Beerse, Belgium.
Brain Res. 1997 Jan 16;745(1-2):210-21. doi: 10.1016/s0006-8993(96)01094-3.
Veratridine blocks Na(+)-channel inactivation and causes a persistant Na(+)-influx. Exposure of hippocampal slices to 10 microM veratridine led to a failure of synaptic transmission, repetitive spreading depression (SD)-like depolarizations of increasing duration, loss of Ca(+)-homeostasis, a large reduction of membrane potential, spongious edema and metabolic failure. Normalization of the amplitude of the negative DC shift evoked by high K+ ACSF 80 min after veratridine exposure was taken as the primary endpoint for neuroprotection. Compounds whose mechanisms of action includes Na(+)-channel modulation were neuroprotective (IC50-values in microM): tetrodotoxin 0.017, verapamil 1.18, riluzole 1.95, lamotrigine > or = 10, and diphenylhydantoin 16.1. Both NMDA (MK-801 and PH) and non-NMDA (NBQX) excitatory amino acid antagonists were inactive, as were NOS-synthesis inhibitor (nitro-L-arginine and L-NAME) Ca(2+)-channel blockers (cadmium, nimodipine) and a K(+)-channel blocker (TEA). Lubeluzole significantly delayed in time before the slices became epileptic, postponed the first SD-like depolarization, allowed the slices to better recover their membrane potential after a larger number of SD-like DC depolarizations, preserved Ca2+ and energy homeostasis, and prevented the neurotoxic effects of veratridine (IC50-value 0.54 microM). A concentration of lubeluzole, which was 40 x higher than its IC50-value for neuroprotection against veratridine, had no effect on repetitive Na(+)-dependent action potentials induced by depolarizing current in normal ACSF. The ability of lubeluzole to prevent the pathological consequences of excessive Na(+)-influx, without altering normal Na(+)- channel function may be of benefit in stroke.
藜芦碱可阻断钠通道失活并导致持续性钠内流。将海马切片暴露于10微摩尔的藜芦碱会导致突触传递失败、持续时间不断增加的重复性扩散性抑制（SD）样去极化、钙稳态丧失、膜电位大幅降低、海绵状水肿和代谢衰竭。以藜芦碱暴露80分钟后高钾人工脑脊液诱发的负向直流偏移幅度恢复正常作为神经保护的主要终点。作用机制包括钠通道调节的化合物具有神经保护作用（IC50值，单位为微摩尔）：河豚毒素0.017、维拉帕米1.18、利鲁唑1.95、拉莫三嗪≥10以及苯妥英16.1。NMDA（MK - 801和PH）和非NMDA（NBQX）兴奋性氨基酸拮抗剂均无活性，一氧化氮合酶合成抑制剂（硝基 - L - 精氨酸和L - NAME）、钙通道阻滞剂（镉、尼莫地平）以及钾通道阻滞剂（四乙铵）也无活性。鲁贝鲁唑能显著延迟切片癫痫发作的时间，推迟首次SD样去极化，使切片在经历大量SD样直流去极化后能更好地恢复膜电位，维持钙和能量稳态，并预防藜芦碱的神经毒性作用（IC50值为0.54微摩尔）。鲁贝鲁唑的浓度比其对藜芦碱神经保护的IC50值高40倍，对正常人工脑脊液中去极化电流诱导的重复性钠依赖性动作电位没有影响。鲁贝鲁唑在不改变正常钠通道功能的情况下预防过量钠内流病理后果的能力可能对中风有益。
