Abstracts

RATIONALE: Glutamate is the major excitatory neurotransmitter within the CNS which acts on ionotropic and metabotropic receptors: N-methyl-D-aspartate (NMDA), [alpha]-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate (KA), and mGluRs 1-8, respectively. Antagonists at the NMDA and AMPA/KA receptors as well as mGluR agonists/antagonists have been shown to possess anticonvulsant activity in a number of traditional animal seizure models, e.g., MES and DBA/2 sensory induced seizures. The 6 Hz model of partial seizures, recently described by Barton et al., 2001, is an alternative low frequency, long duration stimulation paradigm resulting in a seizure characterized by jaw and forelimb clonus, stun, and Straub tail. The unique aspect of this model is that it is the only acute seizure model in which levetiracetam has displayed anticonvulsant activity, suggesting that the 6 Hz seizure model may be useful in identifying compounds with unique anticonvulsant profiles. The purpose of the present study was to examine the role glutamate receptors play in the 6 Hz seizure using a number of NMDA, AMPA/KA, and mGluR modulators.
METHODS: Tonic extension seizures were induced in CF-1 mice via corneal stimulation at 60 Hz, 0.2-s duration, and 50 mA. Partial seizures were induced via corneal stimulation at 6 Hz, 3-s duration, and 32 mA. Various doses (0.1-100 mg/kg) of NMDA, AMPA/KA, or mGluR modulators were administered to animals prior to 60 Hz or 6 Hz stimulation. Behavioral toxicity was evaluated prior to electrical stimulation by a trained observer.
RESULTS: Complete tonic extension protection was obtained with the NMDA receptor antagonists LY235959 and MK-801, and AMPA/KA antagonists LY293558 and LY300168. The seizure protection afforded by NMDA and AMPA/KA antagonists, however, was only at doses producing behavioral impairment marked by ataxia and sedation. In contrast, LY235959, MK-801, LY293558, and LY300168 were only partially effective in blocking the 6 Hz seizure (0%, 60%, 0%, and 30% protection, respectively) at doses devoid of behavioral impairment. The mGluR2/3 agonists LY379268 and LY389795 were effective in blocking both the tonic extension and 6 Hz seizures at doses devoid of behavioral impairment. In addition, the mGluR5 antagonist, MPEP, was effective in blocking both the tonic extension and 6 Hz seizures at doses devoid of behavioral toxicity.
CONCLUSIONS: Previous studies have demonstrated the anticonvulsant potential of glutamate receptor modulators against the electroshock-induced tonic extension. In the present study however, NMDA and AMPA/KA antagonists were not effective in blocking the electrically induced 6 Hz seizure at doses devoid of behavioral impairment. These results suggest that NMDA and AMPA/KA receptor antagonists may not be a useful therapeutic strategy for the treatment of partial seizures. In contrast, the block of partial seizures by modulation of mGluRs may prove to be useful in treating partial seizures and supports their further development.
[Supported by: Eli Lilly and Company.]; (Disclosure: Salary - Employed by Eli Lilly and Company.)