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

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Abstract
1 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 (10−3M) or sodium cyanide (10−3M) 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× 10−7M), TTX (IC50 = 3 × 10−8 M) and nitrendipine (IC50 = 3 × 10−5 M). In contrast, (+)‐MK‐801 (up to 3 × 10−5 M) was ineffective against this insult.4 Glutamate‐induced neurotoxicity was inhibited by (+)‐MK‐801 (IC50 = 1.4 × 10 −8 M) and to a lesser extent by (−)‐MK‐801 (IC50 = 1 × 10−7 M), but was unaffected by lifarizine, TTX or nitrendipine (up to 10−6M).5 (+)‐MK‐801 was effective against sodium cyanide‐induced neurotoxicity (IC50= 1.9 × 10−8M), whereas lifarizine and TTX (up to 10−6 m) and nitrendipine (up to 3 × 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 of lifarizine observed in vivo may be mediated by inhibition of neuronal sodium currents.