stimulation of mitochondrial biogenesis, and enhancement of alternative energy substrates (Bough, 2008; Bough et al., 2006; Davis et al., 2008; Gasior et al., 2006). The ketogenic diet is also hypothesized to promote neuroinhibitory actions. One aspect of this hypothesis is an associated modification of the tricarboxylic acid cycle to increase the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA), leading to neuronal hyperpolarization (Bough and Rho, 2007). GABA is the primary inhibitor of neurotransmission, making a neuron more refractory to abnormal firing due to hyperpolarization. Seizures can be decreased by effects on GABA such as increasing its synthesis or decreasing its metabolism and breakdown. For this reason, GABA effects are an important target for some anticonvulsant drugs. Polyunsaturated fatty acid (PUFA) levels are likewise increased in patients on the ketogenic diet, and consequently induce the expression of neuronal uncoupling proteins (UCPs) (Fraser et al., 2003; Freeman et al., 2006). In one experimental study, mice fed a ketogenic diet were found to have increased UCPs, thus limiting the generation of ROS (Sullivan et al., 2004). Other mechanisms that possibly contribute to neuroprotection and enhanced mitochondrial function include, but are not limited to, promoting synthesis of adenosine triphosphate (ATP), interfering with glutamate toxicity, and bypassing the inhibition of complex I in the mitochondrial respiratory chain (Gasior et al., 2006; Prins, 2008; Zhao et al., 2006). Premature electron leakage occurs at complex I; moreover, it is one of the main sites of production of harmful superoxide and resultant apoptosis. Bypassing complex I can therefore reduce production of ROS and nonlytic cell death.

There have been two studies demonstrating evidence of neuroprotection against glutamate excitotoxicity, reduced mitochondrial ROS production, chronic hypoglycemia, and oxygen-glucose deprivation with in vitro exposure to beta-hydroxybutyrate of rat brain hippocampal slice cultures that were subsequently subjected to chronic hypoglycemia, oxygen-glucose deprivation, and N-methyl-D-aspartate-induced excitotoxicity (Maalouf et al., 2009; Samoilova et al., 2010).


Because ketone bodies are typically developed as an alternative energy source during intervals of fasting or starvation, they are not considered an essential nutrient nor has their absence been considered a nutritional deficiency. The traditional ketogenic diet consists of four parts fat to one part protein, with the fat components derived primarily from long-chain fatty acids. Modifications to the ketogenic diet have included a change of ratio to three parts fat to one part protein, the use of medium-chain triglycerides (MCT) for the fat component, and substitution of a modified Atkins diet or low-glycemic-index diet.

The most well-known clinical application of the ketogenic diet is in pediatric epilepsy syndromes, whose patients generally tolerate the special diet well with only mild side effects. Long-term use in the pediatric population has sometimes been associated with growth retardation, kidney stones, bone fractures due to osteopenia, and hypercholesterolemia; short-term side effects include low-grade acidosis, constipation, dehydration, vomiting or nausea, and hypoglycemia (if there is an initial fasting period) (Prins, 2008).

Consideration of adverse effects should take into account complications that may arise from the associated state of starvation or fasting that may lead to formation of ketone bodies. Such starvation is typically designed to provide 80–90 percent of the estimated caloric needs, based on age and weight (Kossoff et al., 2009). When diet is the primary means of achieving ketosis, there may be a need to consider an intermittent timing schedule. There have been some studies utilizing exogenous administration of ketone body precursors such as 1,3-butanediol or MCT, but there have been reports of adverse gastrointestinal symptoms

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