Over the past decade, much progress has been made in understanding the mechanisms of ketogenic diet (KD) action. From the complex systemic and metabolic changes induced by the KD have emerged innovative hypotheses attempting to link biochemical adaptations to its clinical effects. Despite such developments, the fundamental question of how the KD works remains as elusive as ever. At present, it is unclear which of many potential mechanisms proposed thus far are directly relevant to the clinical effects of the KD. It is unlikely that these numerous hypotheses can be unified into a single mechanism (or a final common pathway). Nevertheless, it may be instructive to consider each of these putative mechanisms in turn and ask the following question: If the mechanism or target in question is a critical determinant of the anticonvulsant efficacy of the KD, then would a similar intervention known to be based on that mechanism yield a comparable effect? Perhaps answering this question for each mechanistic speculation might help substantiate (or invalidate) that particular hypothesis. Can the KD be packaged into a pill? At present, the answer is likely “no.” We have yet to discover a “magic bullet” that completely mirrors the anticonvulsant (and potential neuroprotective) effects of the KD. However, without a clearer understanding of the mechanistic elements comprising the complex metabolic puzzle posed by the KD, we would be left only with empiric observations, and to wonder curiously how a high-fat diet can exert such profound clinical effects.
While the relationships between seizure activity, oxidative stress and neuronal injury have yet to be clarified, previous studies have indicated that defects in antioxidant systems may contribute to seizure genesis and epileptogenesis (Cock, 2002; Patel, 2004; Liang & Patel, 2006; Shin et al, 2008). Earlier, the effects of a KD on mitochondrial ROS generation were discussed. Are there other mechanisms through which oxidative stress can be attenuated in epileptic brain?
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One potential explanation for the anticonvulsant action of the KD argues that increased ATP synthesis should produce a positive bioenergetic balance, allowing stabilization of the resting membrane potential via enhanced activity of Na+-K+-ATPase (Bough & Rho, 2007). Several decades ago, De Vivo and colleagues (1978) reported that the KD increased the total quantity of bioenergetic substrates (such as adenosine triphosphate, or ATP) and elevated the energy charge in rat brain. These changes were purported to stabilize the cell membrane, especially in the face of excessive excitation. Consistent with these observations, a later human study utilizing magnetic resonance spectroscopic techniques indicated that patients with epilepsy fed a KD had elevated phosphocreatine to creatine levels in the brain (Pan et al., 1999). Recently, using cDNA microarray technology, increased expression of the mitochondrial ATP synthase β,D subunit in mouse brain was reported after KD treatment (Noh et al., 2004). And in the most comprehensive study of this kind to date, the KD was found to enhance mitochondrial biogenesis and significantly increase the number of transcripts encoding energy metabolism genes in rats (Bough et al., 2006). This increase in bioenergetic capacity enabled hippocampal slices from these animals to better withstand metabolic challenge from low glucose exposure. Taken together, the prevailing notion has been that increased energy production and reserve capacity enable greater resistance to neuronal hyperexcitability and hypersynchrony.
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