September 2006
Maciej Gasior, Michael A. Rogawski, and Adam L. Hartman
Abstract
The ketogenic diet has been in clinical use for over 80 years, primarily for the symptomatic treatment of epilepsy. A recent clinical study has raised the possibility that exposure to the ketogenic diet may confer long-lasting therapeutic benefits for patients with epilepsy. Moreover, there is evidence from uncontrolled clinical trials and studies in animal models that the ketogenic diet can provide symptomatic and disease-modifying activity in a broad range of neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, and may also be protective in traumatic brain injury and stroke.
These observations are supported by studies in animal models and isolated cells that show that ketone bodies, especially β-hydroxybutyrate, confer neuroprotection against diverse types of cellular injury.
This review summarizes the experimental, epidemiological and clinical evidence indicating that the ketogenic diet could have beneficial effects in a broad range of brain disorders characterized by the death of neurons. Although the mechanisms are not yet well defined, it is plausible that neuroprotection results from enhanced neuronal energy reserves, which improve the ability of neurons to resist metabolic challenges, and possibly through other actions including antioxidant and anti-inflammatory effects.
As the underlying mechanisms become better understood, it will be possible to develop alternative strategies that produce similar or even improved therapeutic effects without the need for exposure to an unpalatable and unhealthy, high-fat diet.
Conclusions
A wide variety of evidence suggests that the ketogenic diet could have beneficial disease-modifying effects in epilepsy and also in a broad range of neurological disorders characterized by death of neurons. Although the mechanism by which the diet confers neuroprotection is not fully understood, effects on cellular energetics are likely to play a key role. It has long been recognized that the ketogenic diet is associated with increased circulating levels of ketone bodies, which represent a more efficient fuel in the brain, and there may also be increased numbers of brain mitochondria.
It is plausible that the enhanced energy production capacity resulting from these effects would confer neurons with greater ability to resist metabolic challenges. Additionally, biochemical changes induced by the diet – including the ketosis, high serum fat levels, and low serum glucose levels – could contribute to protection against neuronal death by apoptosis and necrosis through a multitude of additional mechanisms, including antioxidant and antiinflammatory actions.
Theoretically, the ketogenic diet might have greater efficacy in children than in adults, inasmuch as younger brains have greater capacity to transport and utilize ketone bodies as an energy source (Rafiki et al., 2003; Vannucci and Simpson, 2003; Pierre and Pellerin, 2005).
Controlled clinical trials are required to confirm the utility of the diet as a disease-modifying approach in any of the conditions in which it has been proposed to be effective. A greater understanding of the underlying mechanisms, however, should allow the diet to be more appropriately studied. Indeed, there are many as yet unanswered questions about the use of the diet.
For example, in epilepsy, how long an exposure to the diet is necessary? Do short periods of exposure to the diet confer long-term benefit? Why can the protective effects of the diet be readily reversed by exposure to carbohydrates in some but not all patients? In situations of acute neuronal injury, can the diet be administered after the neuronal injury, and if so, what time window is available? Does monitoring the diet through measurements of biochemical parameters improve efficacy and, if so, what is the best marker to monitor? Finally, the most fundamental research questions are what role ketosis plays, if any, in the therapeutic effects of the diet, and whether low glucose levels contribute to or are necessary for its symptomatic or proposed disease-modifying activity.
Moreover, a better understanding of the mechanisms may provide insights into ketogenic diet-inspired therapeutic approaches that eliminate the need for strict adherence to the diet, which is unpalatable, difficult to maintain, and is associated with side effects such as hyperuricemia and nephrolithiasis, and adverse effects on bone health and the liver (Freeman et al., 2006). A variety of approaches have been devised that allow ketosis to be obtained without the need to consume a high fat, low carbohydrate diet. The simplest is the direct administration of ketone bodies, such as through the use of the sodium salt form of β-hydroxybutyrate.
Toxicological studies in animals have demonstrated that β-hydroxybutyrate sodium is well tolerated, and that theoretical risks such as acidosis and sodium and osmotic overload can be avoided by careful monitoring of blood parameters (Smith et al., 2005). Intravenous β-hydroxybutyrate has the potential to provide neuroprotection against ischemia during some surgical procedures, such as cardiopulmonary bypass.
Owing to its short half-life, β-hydroxybutyrate sodium is, however, not suitable for long-term therapy in the treatment of chronic neurodegenerative disorders. In these circumstances, orally bioavailable polymers of β-hydroxybutyrate and its derivatives with improved pharmacokinetic properties may be of utility (Veech, 2004; Smith et al., 2005).
Another interesting alternative to the ketogenic diet is the administration of metabolic precursors of ketone bodies. Among potential precursor molecules, 1,3-butanediol and 1,3-butanediol acetoacetate esters have been most extensively studied.
These compounds are metabolized in a chain of enzymatic reactions in the plasma and liver to the same ketone bodies that are produced during the ketogenic diet (Desrochers et al., 1992, 1995; Ciraolo et al., 1995). Although each of the aforementioned alternatives is still early in development, the idea of developing the ketogenic diet in a ‘pill’ is very attractive and may be approachable.
