Effects of benzodiazepines and valproic acid on brain aldehyde reductase and a proposed mechanism of anticonvulsant action

Abstract

Benzodiazepines (clonazepam, diazepam, flurazepam, fosazepam, lorazepam, nitrazepam, oxazepam and R07-5205) were shown to inhibit the activity of brain aldehyde reductase obtained from DBA/2J mice with the ic 50 values (concentration of inhibitor at 50 per cent of control activity) ranging from 0.24 to 7.0 mM. ed 50 Values of these benzodiazepines for protection against maximal electroshock-induced convulsions were determined for DBA/2J mice which were pretreated with either saline or β-diethylaminoethyl diphenylpropylacetate (SKF-525A), an inhibitor of microsomal drug-metabolizing systems. Spearman rank order and Pearson correlation coefficients between the ic 50 values for inhibition of aldehyde reductase activity and the ed 50 values for protection against maximal electroshock-induced convulsions were calculated to be 0.62 and 0.82, respectively, for a group of eight benzodiazepines. When the animals were pretreated with SKF-525A, the correlation coefficients were 0.83 and 0.71, respectively. R m values, indicators of relative lipid solubility, were measured for these benzodiazepines. Correlations between R m values and ic 50 values or ed 50 values were not significant at the 95 per cent confidence level. Valproic acid inhibited DBA/2J mouse brain aldehyde reductase activity with an ic 50 value of 7 × 10 −5 M. Data presented in this study are consistent with the hypothesis that highly reactive aldehyde intermediates of biogenic amine metabolism may be implicated in anticonvulsant drug action.