Abstracts

Activation of the CB[sub]1[/sub] receptors in the brain has been shown to be effective in various therapeutic targets, including epilepsy. The purpose of the present study was to further investigate the role of endocannabinoids on seizure activity in two acute seizure models using male CF-1 mice.
Threshold electroshock was delivered by corneal electrodes that produced a 15 mA current for 0.2 secs with a pulse train of 60 Hz. This type of corneal stimulation produced a tonic seizure manifested by hind limb extension (HLE). An anticonvulsant effect was manifested by the absence of HLE. Data were expressed in terms of percent protection (i.e. the percentage of animals without seizure manifested by HLE). 6 Hz electroshock was delivered by corneal electrodes that produced a 32 mA current for 3 secs with a pulse train of 6 Hz. This type of corneal stimulation produced a clonic seizure manifested by stun, forelimb clonus, twitching of the vibrissae, and Straub-tail. An anticonvulsant effect was manifested by the absence of a clonic seizure. Data were expressed in terms of percent protection (i.e. the percentage of animals without clonic seizure). All compounds were dissolved in a vehicle consisting of 2% DMSO, 2% cremefor EL, and 96% saline, and administered intraperitoneally. Animals were tested 20 or 30 mins-post injection of compound.
Cannabimimetic compounds such as WIN 55, 212-2 [ED[sub]50[/sub] (mg/kg): TES = 3.4, 6 Hz = 1.43] and CP-55, 940 [ED[sub]50[/sub] (mg/kg): TES = 2.3, 6 Hz = 0.03], partial and full (respectively) CB[sub]1[/sub] receptor agonists, were fully efficacious in both the threshold electroshock model and the 6 Hz electroshock model, with the 6 Hz model being more sensitive to the effects of these compounds. The effects of CP-55, 940, were fully reversed in both models by pretreatment with the CB[sub]1[/sub] receptor antagonist, SR141716A (1 [ndash] 10 mg/kg), thereby establishing the CB[sub]1[/sub] receptor-mediated anticonvulsant mechanism for CB[sub]1[/sub] receptor agonists. The endogenously occurring endocannabinoid, arachidonylethanolamide (anandamide) was ineffective when administered alone (1 [ndash] 300 mg/kg). Several other endocannabinoids, and analogs of anandamide were also evaluated in the threshold electroshock model, but were shown to be ineffective when given alone. The lack of effectiveness of these compounds may have been due to their high rate of metabolism, or lack of chemical stability. The putative anandamide re-uptake inhibitors, AM404 and arvanil were also evaluated alone and concomitantly with anandamide in the threshold electroshock model. AM404 was ineffective alone and concomitantly with anandamide. In contrast, arvanil (TES ED[sub]50[/sub] = 15.7 mg/kg) was not only effective alone, but also potentiated the effects of anandamide (TES ED[sub]50[/sub] = 1.87 mg/kg).
The present study provides further support of the hypothesis that endocannabinoids play a role in the modulation of seizure activity, and this effect is mediated through CB[sub]1 [/sub]receptors.
[Supported by: Lilly Research Laboratories]