Anticonvulsant profile and mechanism of action of propranolol and its two enantiomers

The anticonvulsant properties of the ss-adrenoceptor antagonist propranolol and its two enantiomers were examined in various screening tests in order to characterize the anticonvulsant profile as well as the possible molecular mechanism of action. These compounds dose-dependently raised the threshold for tonic electroshock seizures in mice and were effective in the traditional maximal electroshock test (ED (50)s 15- 20 mg kg (-1)i.p.). In combination with clinically used antiepileptics, the anticonvulsant effectiveness of the latter was significantly increased. In the pentylenetetrazol (85 mg kg (-1)s.c.) seizure threshold test, ( +/-)- and ( +)-propranolol were not effective in preventing clonic seizures. In unrestrained rats with chronically implanted electrodes in the dorsal hippocampus, propranolol and its ( +)-enantiomer equieffectively reduced the duration of electrically-evoked hippocampal afterdischarges (10 and 20 mg kg (-1)i.p.) and raised the focal stimulation threshold (20 mg kg (-1)i.p.). In amygdala-kindled rats, both drugs ( >or= 10 mg kg (-1)i.p.) reduced the seizure severity from stage 5 (generalized clonic-tonic) to stage 3 (unilateral forelimb) seizures. Furthermore, whole-cell patch-clamp experiments showed that ( +)- as well as ( -)-propranolol ( 10(-6)to 10(-4)M) depressed the fast inward sodium current in a concentration- and use-dependent manner in cultured rat cardiomyocytes and inhibited picrotoxin-induced burst firing activity of mouse spinal cord neurones in culture. In conclusion, propranolol and its two enantiomers have anticonvulsant effects in models for generalized tonic-clonic and complex partial seizures which may be accounted for by the sodium channel blocking and not by the ss-adrenoceptor blocking activity.