The correlation between concentrations of anticonvulsive drugs in the brain and various parameters of maximal electroshock seizures in mice

Abstract

The relationship between concentrations of anticonvulsive drugs in the brain and various parameters of maximal electroshock seizures was investigated in mice. Maximal electroshock seizures were elicited with a current intensity (60 Hz, 50 mA for 0.2 sec) through corneal electrodes. Convulsive movements were detected by an accelerometer, amplified and recorded by a polygraph. Concentrations of anticonvulsive drugs in the whole brain were determined by the method of enzyme immunoassay. With various doses of phenobarbital (PB: 5-35 mg/kg, i.p.), duration of tonic flexion (TF) was prolonged, whereas duration of tonic extension (TE) and clonic convulsion (CL) was shortened in a dose-dependent manner. The correlation coefficient between the PB concentration and the duration of TF, TE or CL was 0.680, -0.882 or 0.409, respectively. The correlation coefficient between the PB concentration and the intensity of TE or CL, measured by the integrated curve of the accelerometer, was -0.847 or 0.440. The correlation coefficient between the PB concentration and the ratio of TE-duration/TF-duration (TE/TF ratio) was -0.901. After administration of phenytoin (PNT), carbamazepine (CBZ) or valproic acid (VPA), a highly negative correlation between the drug level in the brain and the TE/TF ratio was also obtained. In the case of diazepam, clonazepam, ethosuximide or trimethadione, the TE/TF ratio was decreased dose-dependently, but the slope of the dose-response regression line was less steep than that obtained by the administration of PB, PNT, CBZ, VPA or primidone. These results suggest that the TE/TF ratio may be the most reliable parameter for drug evaluation of the anticonvulsive efficacy against tonic-clonic seizures in human patients.