Effect of cyclooxygenase-2 (COX-2) inhibitors in various animal models (bicuculline, picrotoxin, maximal electroshock-induced convulsions) of epilepsy with possible mechanism of action.

Enzyme cyclooxygenase (COX) is reported to play a significant role in neurodegeneration and may play a significant role in the pathogenesis of epilepsy. Bicuculline (4 mg/kg; ip), picrotoxin (8 mg/kg; ip) and electroshock (60 mA for 0.2 sec) significantly induced convulsions in male Laka mice. COX-inhibitors viz. nimesulide (2.5 mg/kg; ip) and rofecoxib (2 mg/kg, ip) administered 45 minutes prior to an epileptic challenge prolonged mean onset time of convulsions, decreased duration of clonus and decreased % mortality rate against bicuculline- and picrotoxin-induced convulsions in mice. COX-2 inhibitors were ineffective towards maximal electroshock-induced convulsions. Nimesulide (1 mg/kg) and rofecoxib (1 mg/kg) also enhanced the effect of subprotective dose of muscimol against picrotoxin-induced convulsions. The result of the present study strongly suggests for a possible role of cyclooxygenase isoenzymes particularly, COX-2 in the pathophysiology of epilepsy and its GABAergic modulation.

The expression of an intraspecific aggressive reaction in the face of a stressor agent alters the immune response in rats

A repercussão sobre a resposta imune da expressão da agressividade intra-específica diante de um estressor foi investigada em ratos. Aos 90 dias de vida, os animais foram divididos em três grupos: grupo-controle (foram realizadas apenas mensurações imunológicas), choque nas patas (FS) (os animais receberam FS individualmente) e grupo resposta agressiva intra-específica (IAR) (os animais receberam FS e apresentaram IAR). Para as medições imunológicas, amostras de sangue foram coletadas imediatamente, 7 e 15 dias após FS ou IAR. O FS reduziu a quantidade total de leucócitos. Contudo, a agressividade foi acompanhada, além da redução do número de leucócitos, por diminuição de linfócitos e aumento de neutrófilos. Além disso, também foi observada elevação no número de leucócitos associada a aumento na resposta imune humoral uma semana após as IAR. Neste estudo, a expressão da agressividade intra-específica diante de um estressor parece ativar o sistema imune e potencializar a resposta humoral antígeno específica.

Anterograde effects of a single electroconvulsive shock on inhibitory avoidance and on cued fear conditioning

A single electroconvulsive shock (ECS) or a sham ECS was administered to male 3-4-month-old Wistar rats 1,2, and 4 h before training in an inhibitory avoidance test and in cued classical fear conditioning (measured by means of freezing time in a new environment). ECS impaired inhibitory avoidance at all times and, at 1 or 2 h before training, reduced freezing time before and after re-presentation of the ECS. These results are interpreted as a transient conditioned simulus (CS)-induced anxiolytic or analgesic effect lasting about 2 h after a single treatment, in addition to the known amnesic effect of the stimulus. This suggests that the effect of anterograde learning impairement is demonstrated unequivocally only when the analgesic/anxiolytic effect is over (about 4 h after ECS administration) and that this impairment of learning is selective, affecting inhibitory avoidance but not classical fear conditioning to a discrete stimulus.

Aspirin and anticonvulsant interaction.

Aspirin (360 mg/kg, po) per se had anticonvulsant activity in MES model. No effect was observed at lower doses and in other models. Aspirin 216 mg/kg, po (a subanticonvulsant dose) protected animals, receiving subanticonvulsant doses of phenytoin, phenobarbitone and carbamazepine against MES.

Effect of GABA analogues on various components of maximum electroshock-induced seizures in mice.

Out of fourteen compounds reported here only four [N-valproyl GABA (V.GABA), N-phthaloyl GABA (P.GABA), gamma-phthalimido N-amyl butyramide (PGA) and gamma-phthalimido N-phenyl butyramide (PGP)] gave significant protection to all the four components of maximal electroshock-induced seizures (MES) in mice. It appeared that substitution of either amino or carboxylic or both groups of gamma-aminobutyric acid (GABA) with bulkier groups like aliphatic or aromatic carbons usually produced effective anticonvulsant GABA derivatives. V.GABA and P.GABA were the most effective anticonvulsant GABA derivatives in protecting all the components of MES-induced seizures. They were 2.3 and 1.5 times potent than sodium valproate in molar ratio, but P.GABA has low therapeutic index when compared to V.GABA. The observed anticonvulsant activity may be due to enhanced GABA concentration in the CNS. Probably, the active compound (V.GABA) crossed the blood brain barrier and hydrolysed to GABA and valproic acid to bring about its anticonvulsant action.

Effect of calcium channel blockers on experimentally induced seizures in rats.

Chemically different classes of calcium channel blockers were examined in rats for their effects on behavior, tolerability and protection against maximal electroshock seizures (MES) and pentylenetetrazol (PTZ) induced seizures. In MES test at doses (mg/kg, ip) that were devoid of side effects, felodipine, 50, afforded 100% protection, while nimodipine, 5; pimozide, 10; and thioridazine, 25, showed 50 to 66% protection. Nifedipine, 10, and diltiazem, 50, showed 30 and 66% protection respectively, but were associated with side effects. Verapamil and loperamide were ineffective against MES and PTZ induced seizures. Nimodipine, 1 mg/kg, ip, was the most potent agent and produced 100% protection against PTZ. Equieffective doses were pimozide, 25, felodipine, 50, and thioridazine, 50. The rest of the calcium channel blockers showed marginal to moderate activity against chemoshock. The data obtained suggest that some calcium channel blockers possess anticonvulsant activity and may be considered as adjuvant therapeutic agents in epileptics refractory to conventional antiepileptic medication.