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

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 ic₅₀ values (concentration of inhibitor at 50 per cent of control activity) ranging from 0.24 to 7.0 mM. ed₅₀ 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 ic₅₀ values for inhibition of aldehyde reductase activity and the ed₅₀ 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 ic₅₀ values or ed₅₀ values were not significant at the 95 per cent confidence level. Valproic acid inhibited DBA/2J mouse brain aldehyde reductase activity with an ic₅₀ 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.