NEUROPROTECTION AGAINST NMDA INDUCED CELL-DEATH IN RAT NUCLEUS BASALIS BY CA2+ ANTAGONIST NIMODIPINE, INFLUENCE OF AGING AND DEVELOPMENTAL DRUG-TREATMENT

In the current study the neuroprotective effect of the L-type calcium channel antagonist nimodipine in rat brain was investigated in N-methyl-D-aspartate-induced neuronal degeneration in vivo. In the present model NMDA was unilaterally injected in the magnocellular nucleus basalis and the neurotoxic impact assessed by measuring cortical cholinergic fibre loss as a percentage of fibre density of the intact control hemisphere. This procedure proved to be a reproducible model in which the degree of damage was almost linearly proportional to the NMDA dose. Neuroprotection by nimodipine was determined in a number of conditions. First, the effect of nimodipine treatment in adult animals starting two weeks prior to neurotoxic injury was compared with neuroprotection provided by perinatal treatment of the mother animals with the calcium antagonist. Surprisingly, the degree of protection was in both cases similar, yielding almost 30% reduction of fibre loss. The neuroprotective effect in adulthood of perinatal nimodipine treatment may be explained by developmentally enhanced calcium binding proteins or persistent developmental changes in calcium channel characteristics. Protection by nimodipine was also investigated in aged, 26 month old rats. Compared to young adult cases, aged animals proved to be less vulnerable to NMDA exposure, while nimodipine application was more potent, thus yielding a reduction of nearly 50% in nerve fibre damage induced by NMDA infusions. Possible mechanisms of differential calcium influx in the various experimental conditions will be discussed. (C) 1995 Academic Press Limited