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Summary: Purpose: 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.
Zonisamide (ZNS) is a novel antiepileptic drug (AED) developed in Japan (1–3). In a large number of clinical trials, including controlled comparative studies with carbamazepine (CBZ) and valproate (VPA), this compound was shown to be effective in patients with various types of intractable epilepsies. ZNS has been widely used in Japan since 1989 and in South Korea since 1992 (4,5); in the United States, some trials were conducted in the mid-1980s, until occurrences of renal calculi led to suspension of these investigations. However, after completion of new studies and approval by the Food and Drug Administration, the drug is now available in the United States (6,7).
Because ZNS has a sulfonamide group on its side chain, an initial hypothesis held that its anticonvulsive effect would have a basis similar to that of acetazolamide (AZM): inhibition of carbonic anhydrase (CA) activity. However, ZNS was found to be 100–1,000 times less potent as a CA inhibitor than was AZM (8), suggesting that its anticonvulsant action would have a different mechanism. Furthermore, clinical reports have described these drugs as having differing antiepileptic effects: ZNS is a major AED appropriate for symptomatic, localization-related, and generalized epilepsies (4–7), whereas AZM is used as adjunctive therapy in partial epilepsies and in idiopathic generalized epilepsies, especially those with absence seizures (9–11). Therefore, judging from clinical experience, ZNS and AZM may have different anticonvulsive mechanisms of action, as shown in experimental animals, even though these drugs have been reported to exhibit similar anticonvulsive properties in conventional acute seizure models (1,8–11).
In our previous study of amygdala (AM) kindling in rats, ZNS showed a potent anticonvulsive effect comparable to that of phenytoin (PHT), CBZ, and phenobarbital (PB) (12). Conversely, some reports comparing the therapeutic effects of conventional AEDs in AM-kindled rats failed to show a potent anticonvulsive effect with AZM (13,14). To help elucidate the antiepileptic features of ZNS and AZM, we used a standardized protocol comparing the acute and chronic therapeutic effects of the two drugs in AM-kindled rats. We also examined the prophylactic effects of ZNS and AZM.