Contrasting effects of zonisamide and acetazolamide on amygdaloid kindling in rats.
OBJECTIVE
Zonisamide (ZNS) and acetazolamide (AZM) are two antiepileptic drugs (AEDs) that differ in clinical efficacy. To elucidate the mechanisms of action of these compounds, we investigated their therapeutic and prophylactic effects in rats by using a kindling model of partial epilepsy.


METHODS
Electrodes were implanted into the left amygdala of adult male Wistar rats. The animals were stimulated at the afterdischarge threshold until five stage 5 seizures were induced. The generalized seizure threshold was then determined. Therapeutic effects were examined in rats manifesting successive convulsions with near-threshold stimulation. To test prophylactic effects, drugs were administered intraperitoneally before daily kindling stimulation until the animal had a stage 5 seizure or reached day 18.


RESULTS
ZNS (10-40 mg/kg; n=6) suppressed kindled seizures in a dose-dependent manner. Repeated administration for 7 days produced tolerance to anticonvulsive effects. AZM (25-200 mg/kg; n=7) showed limited therapeutic effect, alleviating only the clonic convulsion in stage 5 seizures and reducing afterdischarge duration. Secondary generalization was not significantly suppressed during repeated treatment (50-200 mg/kg; n=6). ZNS, 25 or 40 mg/kg (n=8), significantly retarded seizure development; 15.0 or 17.0 daily stimulations were required to produce a stage 5 seizure. AZM, 50-200 mg/kg (n=6), also retarded seizure development, with 14.0-14.8 stimulations required.


CONCLUSIONS
ZNS exhibited modest therapeutic and prophylactic effects, whereas AZM showed mainly prophylactic effects. Hypotheses are presented that may explain the mechanisms of action of these drugs.
Hamada
K
K
National Epilepsy Center, Shizuoka Higashi Hospital, Shizuoka, Japan. khamada@m.kufm.kagoshima-u.ac.jp
Song
H K
HK
Ishida
S
S
Yagi
K
K
Seino
M
M
D000086:Acetazolamide / Q000494:pharmacology* / Q000627:therapeutic use; D000679:Amygdala / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004828:Epilepsies, Partial / Q000188:drug therapy / Q000517:prevention & control*; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D000078305:Zonisamide
D000927:Anticonvulsants; D002257:Carbonic Anhydrase Inhibitors; D007555:Isoxazoles; D000078305:Zonisamide; D000086:Acetazolamide