gw-6471 and Seizures

Docosahexaenoic acid (DHA) is the most bioactive fatty acid in the brain with well-known biological effects. Peroxisome proliferator-activated receptors (PPARs) underlie some therapeutic effects of DHA such as anti-inflammation, anti-apoptosis and immune regulation. We investigated probable involvement of PPARα in the anticonvulsant effect of DHA in pentylenetetrazole (PTZ) model of clonic seizures. DHA alone or along with the PPARα antagonist GW6471 were administered to mice by intracerebroventricular (i.c.v.) and/or intraperitoneal (i.p.) route. The incidence as well as the threshold of clonic seizures was determined by i.p. and intravenous infusion of PTZ, respectively. DHA, 0.3 mM inhibited the occurrence of seizures (6 out of 10 mice were protected compared to 0 out of 10 in control group, p < 0.01). The seizure threshold (mg/kg) in control group (43.3 ± 2.4) increased to 54.5 ± 2.8, by DHA 0.3 mM (n = 10, p < 0.01). GW6471 (1 mg/kg, i.p., or 4 and 10 μg/mouse, i.c.v.) prevented the anticonvulsant effect of DHA and the increase in seizure threshold, in a dose-dependent manner. GW6471 by itself had no effect on the threshold and the incidence of clonic seizures. PPARα is involved in the anticonvulsant effect of DHA in PTZ model of clonic seizures in mice.

Topics: Animals; Anticonvulsants; Docosahexaenoic Acids; Injections, Intraventricular; Male; Mice; Oxazoles; Pentylenetetrazole; PPAR alpha; Seizures; Tyrosine

Cannabinoid and PPAR receptors show well established interactions in a set of physiological effects. Regarding the seizure-modulating properties of both classes of receptors, the present study aimed to evaluate the roles of the PPAR-gamma, PPAR-alpha and CB1 receptors on the anticonvulsant effects of WIN 55,212-2 (WIN, a non selective cannabinoid agonist). The clonic seizure thresholds after intravenous administration of pentylenetetrazole (PTZ) were assessed in mice weighing 23-30 g. WIN increased the seizure threshold dose dependently. Pretreatment with pioglitazone, as a PPARγ agonist, potentiated the anticonvulsant effects of WIN, while PPARγ antagonist inhibited these anticonvulsant effects partially. On the other hand PPARα antagonist reduced the anticonvulsant effects of WIN significantly. Finally the combination of CB1 antagonist and PPARα antagonist could completely block the anticonvulsant properties of WIN. Taken together, these results show for the first time that a functional interaction exists between cannabinoid and PPAR receptors in the modulation of seizure susceptibility.

Topics: Anilides; Animals; Anticonvulsants; Benzoxazines; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Male; Mice; Morpholines; Naphthalenes; Oxazoles; Pentylenetetrazole; Peroxisome Proliferator-Activated Receptors; Pioglitazone; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Seizures; Thiazolidinediones; Tyrosine