Abstracts

T-type calcium channels contribute to neuronal excitability (Chemin et al., J. Physiol. 540: 1, 2002), the regulation of oscillatory firing of thalamic neurons (Perez-Reyes, Physiol. Rev. 83: 1, 2003), and generation of absence seizures (Huguenard, Epil. Curr. 2: 2, 2002). In addition, T-type channel blockers, such as ethosuximide, display antinociceptive effects (Barton et al., Eur. J. Pharmacol. 521: 1-3, 2005). These channels may serve as unique targets for the treatment of epilepsy or neuropathic pain. In the present investigation, the novel T-type calcium channel blocker, ICM-1-40N (3, 3, 3-trifluoro-2-hydroxy-2-phenyl-propionamide; Choudhury-Mukherjee et al., J. Med. Chem. 46: 12, 2003) was evaluated for its ability to block therapy-resistant psychomotor seizures in the 6 Hz model and to limit formalin-induced inflammatory pain in the formalin test. At 32 and 44 mA, the 6 Hz model displays resistance to phenytoin, carbamazepine, lamotrigine, and topiramate and thus can be used to differentiate novel AEDs (Barton et al., Epil. Res. 47: 3, 2001)., Varying doses of ICM-1-40N were administered i.p. to male CF-1 mice. At the time of test (30 min), mice were evaluated for rotorod (6 rpm) toxicity before corneal stimulation (6 Hz, 3 s duration, 32 or 44 mA). Mice not displaying minimal clonic seizures and stereotyped automatistic behaviors were considered protected. Antinociceptive effects were evaluated in the formalin test. Formalin (0.5%) or 0.5% methylcellulose was injected s.c. under the plantar surface of the right hind paw and the time spent licking was compared between experimental and control groups. The total area under the curve (AUC) and percent of control AUC were calculated. Significance was defined as p [lt] 0.05 when compared by one-way ANOVA., ICM-1-40N was effective at both 32 and 44 mA [ED50[apos]s and (95% CI[apos]s): 18.5 (8.4 - 27.8) mg/kg and 45.1 (37.6 - 54.7) mg/kg, respectively]. Based on an observed TD50 of 59.4 (40 - 136) mg/kg, the protective index was 3.2 and 1.3 for 32 and 44 mA, respectively. At 70 mg/kg, ICM-1-40N displayed significant activity against the acute (46.1 [plusmn] 17.2% control) and inflammatory (43.8 [plusmn] 10.2% control) phases of formalin-induced pain., The results obtained in the present study demonstrate that the T-type calcium channel blocker ICM-1-40N possesses anticonvulsant activity in a model of pharmacoresistant epilepsy and antinociceptive activity in a mouse model of tonic pain. These findings support the further development of this novel therapeutic., (Supported by NO1-NS-4-2359 (MDSY [amp] HSW); RO1 CA105435-01 (MLB [amp] MKP).)