RESPONSE TO NIMODIPINE IN CAFFEINE-INDUCED NEUROTOXICITY IN CEREBELLAR GRANULAR-CELL CULTURE OF RAT PUPS

Methylxanthines (theophylline, theobromine and caffeine) are widely us ed as central nervous system stimulants and caffeine is used in the tr eatment of apnea in newborns. Plasma therapeutic concentration of caff eine is around 110 mu M. Caffeine diffuses the blood brain barrier eas ily, increasing oxygen consumption in neurones and leading to cell dea th. In the present study, 4-7-day-old rats were used to obtain cerebel lar 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) caf feine concentrations. The role of voltage-dependent calcium channels i n 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 in effective in blocking neurotoxicity. Doses administered 45 min prior t o 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 nimodi pine administration into the cultures. A dose-dependent manner of nimo dipine in ischemic states is well-known. In the light of these results , nimodipine may be used in the treatment of newborn apneas together w ith caffeine to prevent neurotoxic side effects of high or repeated do ses of it. (C) 1998 The Italian Pharmacological Society.