利法立嗪（RS - 87476）对培养的大鼠大脑皮质神经元的神经保护作用

Neuroprotective profile of lifarizine (RS-87476) in rat cerebrocortical neurones in culture.

作者信息

May G R, Rowand W S, McCormack J G, Sheridan R D

机构信息

Department of Pharmacology, Syntex Research Centre, Riccarton, Edinburgh.

出版信息

Br J Pharmacol. 1995 Apr;114(7):1365-70. doi: 10.1111/j.1476-5381.1995.tb13357.x.

DOI:10.1111/j.1476-5381.1995.tb13357.x

PMID:7606340

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1510289/

Abstract

The ability of the neuroprotective agent, lifarizine (RS-87476), to mitigate veratridine-, cyanide- and glutamate-induced toxicity in rat embryonic cerebrocortical neurones in primary culture has been compared with that of tetrodotoxin (TTX), nitrendipine, (+)-MK-801 and (-)-MK-801. Lactate dehydrogenase (LDH) released into the culture medium was used as the indicator of cell viability. 2. Incubation of cultures for 16 h in a medium containing veratridine (10(-4) M), sodium glutamate (10(-3) M) or sodium cyanide (10(-3) M) resulted in consistent elevations of LDH activity in the culture medium. The ability of compounds to attenuate these elevations was expressed as the concentration required to inhibit the increases in LDH release by 50% (IC50). 3. Neurotoxicity induced by veratridine was inhibited by lifarizine (IC50 = 4 x 10(-7) M), TTX (IC50 = 3 x 10(-8) M) and nitrendipine (IC50 = 3 x 10(-5) M). In contrast, (+)-MK-801 (up to 3 x 10(-5) M) was ineffective against this insult. 4. Glutamate-induced neurotoxicity was inhibited by (+)-MK-801 (IC50 = 1.4 x 10(-8) M) and to a lesser extent by (-)-MK-801 (IC50 = 1 x 10(-7) M), but was unaffected by lifarizine, TTX or nitrendipine (up to 10(-6) M). 5. (+)-MK-801 was effective against sodium cyanide-induced neurotoxicity (IC50 = 1.9 x 10(-8) M), whereas lifarizine and TTX (up to 10(-6) M) and nitrendipine (up to 3 x 10(-6) M) were without protective activity against this insult. 6. The results demonstrate that lifarizine potently protects rat cortical neurones in vitro against a neurotoxic insult that requires activation of sodium channels for its expression, and that the compound is ineffective against insults mediated by N-methyl-D-aspartate receptor activation. The weak efficacy of nitrendipine against veratridine-induced cell death argues against the involvement of L-type calcium channels in this insult. These data are consistent with the notion that the neuroprotective activity oflifarizine observed in vivo may be mediated by inhibition of neuronal sodium currents.

摘要

已将神经保护剂利法立嗪（RS - 87476）与河豚毒素（TTX）、尼群地平、（+） - MK - 801和（ - ） - MK - 801相比较，观察其减轻原代培养的大鼠胚胎大脑皮质神经元中由藜芦碱、氰化物和谷氨酸诱导的毒性的能力。释放到培养基中的乳酸脱氢酶（LDH）用作细胞活力的指标。2. 在含有藜芦碱（10⁻⁴ M）、谷氨酸钠（10⁻³ M）或氰化钠（10⁻³ M）的培养基中培养16小时，导致培养基中LDH活性持续升高。化合物减轻这些升高的能力以抑制LDH释放增加50%所需的浓度（IC50）表示。3. 利法立嗪（IC50 = 4×10⁻⁷ M）、TTX（IC50 = 3×10⁻⁸ M）和尼群地平（IC50 = 3×10⁻⁵ M）可抑制藜芦碱诱导的神经毒性。相比之下，（+） - MK - 801（高达3×10⁻⁵ M）对这种损伤无效。4. （+） - MK - 801（IC50 = 1.4×10⁻⁸ M）可抑制谷氨酸诱导的神经毒性，（ - ） - MK - 801（IC50 = 1×10⁻⁷ M）的抑制作用较小，但利法立嗪、TTX或尼群地平（高达10⁻⁶ M）对此无影响。5. （+） - MK - 801对氰化钠诱导的神经毒性有效（IC50 = 1.9×10⁻⁸ M），而利法立嗪和TTX（高达10⁻⁶ M）以及尼群地平（高达3×10⁻⁶ M）对这种损伤无保护活性。6. 结果表明，利法立嗪在体外能有效保护大鼠皮质神经元免受一种需要激活钠通道才能表达的神经毒性损伤，且该化合物对由N - 甲基 - D - 天冬氨酸受体激活介导的损伤无效。尼群地平对藜芦碱诱导的细胞死亡的微弱疗效表明L型钙通道不参与这种损伤。这些数据与利法立嗪在体内观察到的神经保护活性可能由抑制神经元钠电流介导的观点一致。