Anticonvulsant effect of 2-ethylthio-7-methyl-4-(4-methylphenyl) pyrazolo[1,5-a][1,3,5]triazine

Martín Estrada2, Henry Insuasty1, Luis E Cuca2, Mario F Guerrero2. 1Universidad de Nariño, Pasto, Nariño, Colombia, 2Universidad Nacional de Colombia, Bogotá, D.C., Colombia. Carrera 45 No 26-85 - Edificio Uriel Gutierréz, Bogotá D.C. – Colombia.

The anticonvulsant activity of some 4-aryl-2-ethylthio-7-methylpyrazolo[1,5-a][1,3,5]triazines (MH4a-c) was evaluated by two methods namely, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) models. Phenytoin (20 mg/Kg) and clonazepam (0,5 mg/Kg) were used as standard drugs for comparison. ICR male mice weighing 25-30 g were used as experimental animals.

The maximal electroshock seizures were elicited by delivering a 60 Hz, 50 mA electrical stimuli via corneal electrodes for 0,1 s. Abolition of tonic hind limb extensor component of convulsion was considered as positive criterion.

The scPTZ test was performed by administering PTZ (80 mg/Kg) dissolved in 0,9% NaCl dissolution. A time of 30 min subsequent to the administration of PTZ was used for detection seizures lasting for a period of at least five seconds.

Test compounds were orally administered at a dose of 100 mg/Kg 60 minutes before the administration of PTZ and at 30 and 300 mg/Kg where positive results were observed. The compounds were prepared as suspension in tween 80, propyleneglycol, glycerin and water (5, 10, 10 and 75%)

Among the evaluated compounds, only 2-ethylthio-7-methyl-4-(4-methylphenyl) pyrazolo[1,5-a][1,3,5]triazine (MH4b) was effective against seizures in the MES test (0.7 and 0.9 index protection at doses of 100 and 300 mg/Kg, respectively). Neurotoxicity was evaluated in the rota rod test. The mice were trained to stay on a rota rod of 3 cm diameter, rotating at 12 rpm for a period of 30 seconds. Control animals were administered with vehicle. The average time of each group at 0, 60 and 120 minutes after administration were compared to establish the toxic effects of the compounds. No differences were observed between the test compounds and the vehicle.

Compounds MH4a-c do not posses protective activity in the scPTZ test which is a model of the absence crisis or petit mal in humans.

Only compound MH4b protect mice against the tonic seizures in the MES test, which is a model of the grand mal epilepsy in humans

Taking into account that MH4b protected the animals in the MES test but not in the scPTZ test, the authors suggest that, perhaps, the Benzodiazepine/GABAergic receptor is not involved in the mechanism of action.