Anti-Seizure Activity of 1-Adamantane Carboxylic Acid in Common Experimental Seizure Models: Role of Benzodiazepine-GABAA Receptors

Background: Despite introduction of modern antiepileptic drugs, 30% of epileptic patients are still drug resistant. Remarkable three-dimensional spatial structure of 1-Adamantane carboxylic acid (AdCA), yet the simplicity of the molecule, makes AdCA a promising lead compound. Methods: Sedative/motor impairment and 24-h mortality rate of AdCA were determined in mice. Impact of AdCA on (1) threshold and occurrence of clonic seizures induced by pentylenetetrazole (PTZ) in mice, (2) incidence of tonic seizures induced by maximal electroshock (MES) in mice, and (3) incidence of generalized seizures and duration of evoked afterdischarges in amygdala-kindled rats, were determined. The role of benzodiazepine receptors in the AdCA effect on clonic seizure threshold was also assessed. Results: AdCA showed sedative effect (median toxic dose [TD₅₀] = 224.5 [190.2-289.9] mg/kg). Median lethal dose (LD₅₀) = 805.5 (715.2–988.1) mg/kg was obtained for AdCA. The compound increased PTZ seizure threshold from 180 mg/kg (p < 0.05) and also inhibited the incidence of clonic seizures (ED₅₀ = 256.3 [107.4-417.3] mg/kg). AdCA also decreased afterdischarge duration (p < 0.01) and the incidence of generalized seizures (ED₅₀ < 50 mg/kg) in the kindled rats. However, AdCA did not protect mice against tonic seizures induced by MES. The benzodiazepine receptor antagonist flumazenil prevented the increase of seizure threshold by AdCA. Conclusion: AdCA possesses anticonvulsant activity in kindling and PTZ models through the activation of benzodiazepine/GABA_A receptors with acceptable therapeutic index.