Abstracts

During investigation of mechanisms of the ketogenic diet, the glycolysis inhibitor 2DG had unexpected anticonvulsant and antiepileptic effects in hippocampal slices and against seizures evoked by kindling of the perforant path. Anticonvulsant and antiepileptic properties of 2DG were further characterized by kindling of olfactory bulb and in screening models in cooperation with the NINDS Antiepileptic Screening Program (ASP). Cognitive and systemic toxicity was examined in rats receiving 2DG for as long as 6 months., Rats received olfactory bulb or perforant path kindling stimulation twice daily with 1-sec trains of 60-Hz 1-ms pulses at the lowest intensity evoking ADs by a standardized protocol. Interictal and ictal burst frequencies were examined in rat hippocampal slices in 7.5 mM [K⁺][sub]o[/sub]. 2DG was evaluated in NINDS ASP screening models in rats and mice including maximal electroshock, subcutaneous metrazol, 6-Hz stimulation, and Frings audiogenic mice. Cognitive effects were evaluated in rats in the Morris water maze., Application of 2DG (10mM) to hippocampal slices in 7.5 mM [K⁺][sub]o [/sub]reduced CA3 interictal bursts by [sim]40% and ictal bursts by 60%. 2DG (250 mg/kg) 30 min before kindling of perforant path in rats induced a 2-fold increase in AD threshold (an anticonvulsant effect) and a 2-fold increase in the number of ADs required to evoke Class V seizures (an antiepileptic effect). In contrast, 2DG prior to olfactory bulb kindling also resulted in 2-fold slowing of kindling progression, but had no effect on AD threshold. Initial evidence of anticonvulsant activity was observed in preliminary screening against seizures evoked by subcutaneous metrazol in rats, by 6-Hz stimulation in mice, and in Fring[apos]s audiogenic mice, but not against seizures evoked by maximal electroshock. Additional testing is underway to further characterize the activity found in these models. 2DG at 2 gm/kg daily for 2 weeks in rats had no effect on Morris water maze performance, and body weights of rats receiving 0.5 gm/kg daily for 6 months did not differ from controls., 2DG has novel anticonvulsant and antiepileptic activity against experimental seizures compared to currently available anticonvulsants and a favorable preclinical toxicity profile. [italic]Acute[/italic] anticonvulsant action was observed [italic]in vitro[/italic] against both interictal and ictal discharges. Robust [italic]chronic [/italic]antiepileptic action against kindling progression was independent of the seizure initiation site, but anticonvulsant action against AD threshold was stimulation site specific. The [italic]in vivo[/italic] chronic effects on kindled seizures have been associated with a novel mechanism of antiglycolytic metabolic suppression of seizure-induced BDNF and trkB expression by the NADH sensor CtBP and the transcription factor NRSF, which regulates neuronal gene expression., (Supported by NINDS R01 25020, the Wisconsin Alumni Research Foundation, and the NINDS Antiepileptic Screening Program.)