Response to nimodipine in caffeine-induced neurotoxicity in cerebellar granular cell culture of rat pups

Methylxanthines (theophylline, theobromine and caffeine) are widely used as central nervous system stimulants and caffeine is used in the treatment of apnea in newborns. Plasma therapeutic concentration of caffeine is around 110 mu M. Caffeine diffuses the blood brain barrier easily, increasing oxygen consumption in neurones and leading to cell death. In the present study, 4-7-day-old rats were used to obtain cerebellar granular cell cultures. Caffeine was used 50, 150, 250 and 350 mu M concentrations and the most toxic dose for it was found to be 350 mu M. Death cell scores were 0.9 +/- 0.63 for control, 1.1 +/- 0.63 for 50 mu M, 0.89 +/- 0.47 for 150 mu M (P > 0.05 for both), 3.84 +/- 0.8 for 250 mu M (P = 0.024) and 6.2 +/- 0.86 for 350 mu M (P = 0.001) caffeine concentrations. The role of voltage-dependent calcium channels in caffeine-induced neurotoxicity was tested with the doses of 100 and 200 mu M nimodipine 45 min before or after the 350 mu M caffeine. Both doses of nimodipine after caffeine administration were found to be ineffective in blocking neurotoxicity. Doses administered 45 min prior to caffeine,, reduced death cell score to 0.89 +/- 0.23 (P = 0.000) for 100 mu M nimodipine and 2.35 +/- 0.96 (P = 0.000) for 200 mu M nimodipine administration into the cultures. A dose-dependent manner of nimodipine in ischemic states is well-known. In the light of these results, nimodipine may be used in the treatment of newborn apneas together with caffeine to prevent neurotoxic side effects of high or repeated doses of it. (C) 1998 The Italian Pharmacological Society.