Nevertheless, it might be instructive to consider each of these putative mechanisms one by one and ask a simple comparative question. It would be far too difficult to integrate these numerous possibilities into a single unifying hypothesis (or a final common pathway), or to consider them simultaneously. At present, it is unclear which of many potential mechanisms reviewed in this supplement are relevant to the clinical effects of the KD. The mechanistic bases for their effectiveness have typically been elucidated post-hoc. Historically, many anticonvulsant medications have resulted from structural modifications of lead compounds that had themselves been discovered serendipitously. While many intriguing concepts and research data have been reviewed systematically in the context of the international symposium from which this supplement stems, the fundamental question of how the KD works remains as tantalizing as ever. The complex systemic and metabolic changes induced by a high-fat, low-carbohydrate diet – not surprisingly – provide fertile ground for very innovative and speculative hypotheses linking certain adaptations to a net anticonvulsant effect, ones that by necessity take researchers back to the earlier days of introductory biochemistry and human physiology. Over the past decade, much progress has been made in dissecting apart the mechanisms underlying the anticonvulsant (and potentially, neuroprotective) effects of the KD ( Gasior et al., 2006 Bough & Rho, 2007). Henceforth, until the mid 1990’s, clinicians – for obvious practical reasons – found it simpler to prescribe a pill rather than an exacting diet. Although the KD experienced an initial surge of interest following its introduction in the early 1920’s, it was relegated to near obscurity by the emergence of a familiar drug known as phenytoin. If achieved, this result would represent an ironic recapitulation of the early history of the KD in the United States. Researchers in the field of the ketogenic diet (KD) have also embraced these tenets and recently embarked on that all-too-familiar Quixotic journey, with the ultimate aim of reducing the “difficult” KD regimen to a simple pill. Moreover, in epilepsy research, disease prevention or modification has become the “holy grail”, such that we are no longer complacent with symptomatic treatment and increasing attention is being given to understanding the processes of anti-epileptogenesis itself. The scientific rationale for elucidating mechanisms of disease pathogenesis or of therapeutic interventions has been traditionally based upon the lofty goal of discovering novel treatments, ones that would be more efficacious than existing options and also be devoid of side-effects altogether. 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. 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. 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. It is unlikely that these numerous hypotheses can be unified into a single mechanism (or a final common pathway). At present, it is unclear which of many potential mechanisms proposed thus far are directly relevant to the clinical effects of the KD.
Despite such developments, the fundamental question of how the KD works remains as elusive as ever.
From the complex systemic and metabolic changes induced by the KD have emerged innovative hypotheses attempting to link biochemical adaptations to its clinical effects. Over the past decade, much progress has been made in understanding the mechanisms of ketogenic diet (KD) action.
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