The ω-3 endocannabinoid docosahexaenoyl ethanolamide reduces seizure susceptibility in mice by activating cannabinoid type 1 receptors.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most recognized omega-3 unsaturated fatty acids showing neuroprotective activity in animal and clinical studies. Docosahexaenoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA) are non-oxygenated endogenous metabolites of DHA and EPA, which might be in charge of the anti-seizure activity of the parent molecules. We examined the effect of these metabolites on the threshold of clonic seizures induced by pentylenetetrazole (PTZ). DHEA and EPEA possess similar chemical structure to the endogenous cannabinoids. Therefore, involvement of cannabinoid (CB) receptors in the anti-seizure effect of these metabolites was also investigated. DHA, DHEA, EPEA, AM251 (CB1 receptor antagonist), and AM630 (CB2 receptor antagonist) were administered to mice by intracerebroventricular (i.c.v.) route. Threshold of clonic seizures was determined 10 and/or 15 min thereafter by intravenous infusion of PTZ. The effect of DHA and DHEA on seizure threshold was then determined in mice, which were pretreated with AM251 and/or AM630. DHA (300µM), and DHEA (100 and 300 µM) significantly increased seizure threshold, 15 (p < 0.05) and 10 min (p < 0.01) after administration, respectively. DHEA was more potent than its parent lipid, DHA in decreasing seizure susceptibility. EPEA (300 and 1000 µM) did not change seizure threshold. AM251 fully prevented the increasing effect of DHA and DHEA on seizure threshold (p < 0.05). AM630 did not inhibit the effect of DHA and DHEA on seizure threshold. This is the first report indicating that DHEA but not EPEA, possesses anti-seizure action via activating CB1 receptors. DHEA is more potent than its parent ω-3 fatty acid DHA in diminishing seizure susceptibility.

Cannabinoid receptors and the proconvulsant effect of toxoplasmosis in mice.

Toxoplasmosis is an infectious disease caused by the intracellular parasite Toxoplasma gondii that harms the brain and increases the risk of epilepsy acquisition. It is well known that cannabinoid (CB) signaling is activated following brain insults and protects the neurons from excitotoxicity and inflammation. We examined the role of CB neurotransmission in the proconvulsant effect of Toxoplasmosis in mice. Toxoplasmosis was established in mice by intraperitoneal injection of T. gondii cysts. The mice with acute and/or chronic Toxoplasma infection were pretreated (through intracerebroventricular injection) with CB1 and CB2 receptor agonists (ACEA and HU308) and antagonists (AM251 and AM630), as well as JZL184 (the irreversible inhibitor of mono acyl glycerol lipase, enzyme degrading the endogenous cannabinoid 2-Acyl glycerol). The seizure threshold was then measured by tail vein infusion of pentylenetetrazole. In healthy uninfected mice JZL184, ACEA, and AM630 increased the seizure threshold in a dose-dependent manner, whereas AM251 and HU308 showed dose-dependent proconvulsant effect. Mice with acute and/or chronic infection had a substantial lower seizure threshold than the uninfected mice. JZL 184, ACEA and AM630 inhibited proconvulsant effect of Toxoplasmosis, while AM251 and HU308 intensified proconvulsant effect of Toxoplasmosis. CB receptors play a role in proconvulsant effect of Toxoplasmosis in mice.