Animal models of the ketogenic diet: what have we learned, what can we learn?
Introduction
The ketogenic diet (KD) remains a therapy in search of an explanation. In 1921, when the KD was first introduced as a treatment for childhood seizures (Wilder, 1921), the only other available antiepileptic drug (AED) was phenobarbital (and to a lesser extent, bromides). Over the ensuing decades, the KD was used commonly, but its popularity declined as other AEDs were developed. AEDs, in pill form, were more convenient than the KD, which required tremendous effort on the part of the patient’s family to accommodate the exacting requirements of the diet. Despite the greater popularity of standard AEDs, the KD never really died out, a testimony to its effectiveness in certain severe cases.
Despite this long history of clinical use, it is not known how the KD works. Part of this ignorance is due to the startling lack of animal studies. From 1966 to 1990, only six animal studies of the KD were published. The infrequent use of the KD in recent decades and concerns about its efficacy are factors which may have contributed to the dearth of experimental studies. However, the KD is not an outlandish fad diet; it is a legitimate antiepileptic therapy that clearly works in some children (Freeman et al., 1998a, Roach, 1998). Our challenge is to define the optimal circumstances for its success. The resurgence of interest in the KD in the 1990s mandates a better understanding of the KD mechanism.
The goals of this chapter are to review the earlier published animal studies using experimental KDs, to describe some recent attempts to study the diet experimentally, and to discuss opportunities for additional animal studies. If the mechanism of KD action were known, it might be possible to modify or simplify the existing KD protocols (which have changed little since their inception in 1921), in terms of formulation, administration, or monitoring. Toward this end, it is important for investigators in this field to coordinate their studies so as to enhance comparisons and interpretations of key variables, which has hampered previous research on the KD.
Why is an animal model of the ketogenic diet important? A better understanding of the KD’s mechanism of action should lead to improved clinical utilization and effectiveness. Using an animal model, one can manipulate variables that cannot be altered in the clinical setting (Table 1). Many of the persistent clinical questions about the KD could be approached with animal models. Ideally, an animal model of the KD would mimic clinical observations, including the pattern of human ketogenesis, developmental effectiveness and sensitivity to the KD, and seizure suppression with regard to seizure type, age, and onset and termination of the KD’s beneficial action.
In this review, studies are divided into those which primarily address the effectiveness of the KD and those which concentrate on the mechanism(s) by which the diet works. While such a division is somewhat arbitrary, it conveniently separates the studies in which an animal model was designed to test whether the KD would raise seizure threshold or prevent convulsions (Table 2) from studies which sought to determine how brain biochemistry or physiology was altered by the KD. Some studies address both aspects. The review concludes with an attempt to integrate past studies into experimentally testable hypotheses.
Section snippets
Overview of ketones and cerebral metabolism
The KD was originally formulated to mimic the effects of fasting, as it had been known since biblical times that fasting had a beneficial effect on epilepsy. It has been assumed ever since that fasting and the KD share a common mechanism in alleviating seziures, although this assumption has not been tested rigorously. Whether the effectiveness of fasting or the high fat diet in epilepsy are related to the level of ketosis is a lingering controversy (see below).
Dietary fats are ordinarily broken
Early studies (pre–1990)
Table 2 lists the major animal studies of KD efficacy. The studies are marked by major differences in methods, including animal age, sex, and species, KD formulation, duration and route of administration, methods of monitoring ketosis and inducing seizures, and outcome measures. These discrepancies make it difficult to draw general conclusions, and point to the need for greater experimental uniformity in this field. Nevertheless, some clinically relevant trends have emerged.
About a decade after
Ketosis and fasting
In addition to establishing the efficacy of the KD in preventing seizures, another goal of animal studies is to elucidate the diet’s mechanism of action. Theories of KD action have evolved over time, as summarized by Withrow (1980), and none is yet accepted universally. Many of the early ideas about KD mechanism were inferred from clinical studies (Bridge and Iob, 1931). The earliest theory held that the protective effect was due to a sedative effect of ketones, akin to that of phenobarbital;
Future directions
These are exciting and challenging times for those interested in the ketogenic diet. From the back burner of anticonvulsant therapy to a well accepted alternative, interest in the KD has blossomed in the past several years. While recent studies of clinical efficacy have substantiated early reports, the persistent questions of how and why the diet works remain just as puzzling now as earlier in the century. Some particularly fruitful avenues of investigation are listed in Table 4; a few of these
Conclusion
There is still no consensus as to the mechanism of the KD antiepileptic effect, and many avenues need to be explored in parallel (Fig. 1). Of the various theories proposed, current data support the view that ketosis is central to the mechanism, and may be necessary but not sufficient to explain the antiseizure effect. Both acute and chronic effects may be involved, each of which may be modulated by other factors. Many of these variables are age dependent. Hopefully, data from varied models will
Acknowledgements
The author is grateful to Drs Kris Bough, Doug Eagles and Patty Vining for sharing unpublished data, and to Dr Dan Cook for valuable discussion of ATP-sensitive K+ channels. Work in the author’s laboratory is supported by the International Life Sciences Institute N.A., and The Charlie Foundation.
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2017, Journal of Trace Elements in Medicine and BiologyCitation Excerpt :The evidence shows, moreover, that KD may also improve long-term outcome in epileptic children beyond the period of the diet [11,12]. Although KD has been used in medical practice for many decades [13,14], the mechanisms of its therapeutic action are still rather obscure [15,16]. Therefore further study is necessary for better understanding of these mechanisms.
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2011, NeuroToxicologyCitation Excerpt :Similar to prolonged fasting, the KD has been shown to function as an effective treatment for epilepsy in clinical applications (for review see Bough and Rho, 2007). Furthermore, using a variety of animal models of epileptic disorders (6 Hz audiogenic seizures, pentylenetetrazole [PTZ], kainic acid [KA], pilocarpine, etc.), the KD has been shown to elevate seizure thresholds and/or have anticonvulsant properties (Stafstrom, 1999). The mechanism(s) by which the KD exerts its effects is unclear (Rho and Sankar, 2008).