Abstracts

Rationale: Diclofenac, a commonly used antinociceptive, is a KCNQ2/Q3 potassium channel opener that has anticonvulsant properties in the mouse Maximal Electroshock Test (MES) model (1). To expand on this data in possible preparation for use in humans, diclofenac was tested in multiple rat and mouse models for anticonvulsant effect.Methods: Diclofenac sodium was screened through the NINDS Anticonvulsant Screening Program. Mice were tested at 30- 300 mg/kg in the MES, the Subcutaneous Metrazol Seizure Threshold Test (SCMET), and the rotarod test. Mice were tested at 50mg/kg in the Minimal Clonic Seizure (6Hz) Test. Rats were tested using the MES at 30mg/kg orally administered. Results: In the murine intraperitoneal MES model, diclofenac had an effective dose (ED50) of 70 mg/kg (95% CI 64-76) at 30 minutes. Median toxic dose (TD50) was determined to be 167 mg/kg (95%CI 145-181) by rotarod testing. There was protection from SCMET at 300mg/kg in 1 animal but not 100mg/kg and the ED50 was determined to be greater than 160mg/kg. At 300mg/kg the drug was fatal to one animal, causing myoclonic jerks, ataxia, and then death. In rats, the drug had no effect and no toxicity at the 30mg/kg oral dose. Conclusions: In two murine models of seizures, diclofenac sodium appears effective at doses between 69-300mg/kg. Rotarod testing suggests that at the lower effective dose, the drug is not toxic. This data is similar to previously published MES data suggesting that diclofenac has an ED50 of 43mg/kg(1). Diclofenac, a KCNQ2/Q3 potassium channel opener, appears non-toxic and effective in preventing MES seizures in mice but ineffective or incompletely absorbed in rat MES. The drug has CNS penetration in people, but it is usually used at a dose that is much lower than 100mg/kg. Diclofenac might be an effective anticonvulsant in people, but more studies are needed before it is used for this indication. Citations 1. Peretz A, Degani N, Nachman R, Uziyel Y, Gibor G, Shabat D, Attali B. Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties. Mol Pharmacol. 2005 Apr;67(4):1053-66