Abstracts

Energy supply is critical for essential functions in all cells. There is increasing evidence that dietary carbohydrate and caloric restriction moderate cellular responses to damage, alter ageing processes, enhance longevity and may have therapeutic affects in neurological disorders such as epilepsy, Alzheimer[apos]s Disease and Huntington[apos]s Chorea. Dietary regimes termed [apos]ketogenic diets[apos] which iso-calorically replaces carbohydrates with fats and proteins, can produce significant anticonvulsant effects in patients with epilepsy and have successfully been used therapeutically. The mechanisms behind the beneficial effects of [apos]]ketogenic diets[apos] are completely unknown. Using biochemical and in vivo approaches in cell lines and rats we assessed the role of chromatin modification around neuronal genes implicated in epileptogenesis in the therapeutic effects of dietary restriction in controlling epilepsy We show that the transcription factor NRSF confers metabolic control upon neuronal genes implicated in the progression of epilepsy by recruiting a redox sensitive transcriptional corepressor and propose that this mechanism underlies some of the beneficial effects of [apos]ketogenic diets[apos] in epilepsy. We have generated a molecular model that explains how regulation of cellular redox state can effect neuronal gene expression. This model has allowed the design and evaluation of metabolic modifiers to retard the process of epileptogenesis in animal models. (Supported by Start up package to AR; Epilepsy Foundation award to AR; NIH funding to TS.)