Abstracts

Seizures due to overdose with the bronchodilator, theophylline (THEO), can be life-threatening in humans. Mildly toxic doses of THEO did not produce seizures, but predisposed outbred mice to seizures induced by sound (THEO-induced audiogenic seizures; THEO-AGS). Here, we describe effects of several anticonvulsant drugs and static magnetic fields on THEO-AGS. ICR/CD1 male mice were obtained from Charles River Laboratories , Wilmington, MA. Animal handling conformed to NIH guidelines and was approved by the Vanderbilt Institutional Animal Care and Use Committee. THEO and anticonvulsant drugs were injected intraperitoneally (IP) before sound stimulation (recording of rattling keys; 90-110 dB). The device and methods for magnetic field stimulation have been published (McLean et al., Epi Res 55:105-116, 2003). Concomitant controls received THEO IP, but no other treatment. Audiogenic seizures (AGS) evolved from wild running (WR) to loss of righting (LOR), clonic jerks (CLO), tonic hindlimb extension (THE) and death (DEA) in [lt] 1 min. Sound stimulation did not result in seizures in ICR mice. Mice ([gt]90%) given 75 mg/kg THEO IP 10 minutes before sound stimulation (blood level [sim]71 mg/ml) had AGS. Pretreatment with anticonvulsant drugs (AED) prevented AGS manifestations to different degrees with the following order of potency: Non-toxic doses of gabapentin (ED50 vs CLO 60 mg/kg, 30 min before sound; [sim]36 mg/ml) and pregabalin ([sim]60 mg/kg, 30 min before sound) provided nearly complete control. Phenytoin provided nearly complete control at an intoxicating dose that produce abnormal movements (80 mg/kg, 2 hr before sound; [sim]170 mg/ml). Levetiracetam provided partial protection at high non-toxic doses (up to 500 mg/kg, 1 hour before sound; 361 mg/ml). Static magnetic fields effective against AGS in inbred DBA/2 mice ([sim]5 millitesla and 0.3-1 tesla/meter averaged over volume of mouse head) provided no protection against THEO-AGS. Intoxicating doses of THEO did not produce seizures, but had proconvulsant effects that resulted in seizures in response to sound. THEO-AGS in outbred mice were more severe than AGS in inbred DBA/2 mice. THEO-AGS were lethal if untreated. Seizure control required higher doses of certain AED than AGS in DBA/2 mice. Magnetic fields effective in DBA/2 mice were ineffective against THEO-AGS, perhaps due to greater seizure severity and widespread distribution of THEO. (Supported by a research grant from Pfizer and by funds from the Holcomb Medical Research Institute.)