Ketogenic Diet and Epilepsy

A ketogenic diet, or keto diet, is a very low-carb diet, which is known to turn the body into a fat-burning machine, has many potential benefits for weight loss, health and performance, but also some potential initial side effects. The importance of the ketogenic diet (KD) has been acknowledged in the treatment of epilepsy, although the exact mechanisms, remains enigma.

They seem to be different from those of regular antiepileptic medications (AEDs), and is comprised of four elements, the changes of any of them can potentially result in loss of its anticonvulsant effect: (1) increased amount of fat, i.e., in a ratio of 3 to 4 grams of fat for each gram of protein and carbohydrates, (2) as low glucose consumption as possible, (3) caloric restriction, (4) fluid restriction. A keto diet is designed specifically to result in ketosis, with increased blood level of free fatty acids (FFAs). The FFAs are transferred into the mitochondria, by means of a carnitine shuttle system, where they are degraded into ketone bodies through β oxidation. These ketone bodies include β hydroxybutyrate, acetone and acetoacetate.

The degradation of these ketone bodies delivers Acetyl-CoA directly to the TCA cycle, thereby increasing its turnover while bypassing the essentiality to depend on acetyl-CoA coming from glycolysis to synthesize ATP. The ketone bodies penetrate it easily unlike glucose, which requires a transporter to cross the blood brain barrier. But, in case of glut 1 deficiency, the KD is the preferred way of antiepileptic treatment since it allows for bypassing the need for glucose. Also the population in whom the conversion of pyruvate to acetyl-CoA is blocked, for instance, in pyruvate dehydrogenase (PDH) deficiency, will also benefit from bypassing this route. β hydroxybutyrate being the predominant ketone body measured in the blood, is used to monitor the degree of ketosis during therapy. The degradation of βhydroxybutyrate leads to increased production of acetone. Acetone is one of the ketone bodies that have an anticonvulsant effect in several types of mouse seizure models. The mechanism of this effect is unknown, although an effect on K2p channels has been proposed.

Acetyl-CoA increases the level of the neurotransmitters glutamate and γ-aminobutyric acid (GABA) and the major excitatory and inhibitory neurotransmitters in brain, respectively. A net effect of enhanced GABAergic influence can be responsible for an anticonvulsant action. Another product of an elevated level of free fatty acids is polyunsaturated fatty acids (PUFAs) with potential ability of PUFAs to block seizure activity in the brain is associated with some rather more complicated mechanisms, including direct inhibition of voltage-gated sodium and calcium channels, activation of a lipid-sensitive potassium channel, enhanced activity of the sodium pump to limit neuronal excitability, activation of peroxisome proliferator-activated receptor-α (PPARα), and induction of expression and activity of brain specific uncoupling proteins in mitochondria, henceforth inducing a neuroprotective effect which works through limiting reactive oxygen species (ROS) generation. The ketogenic diet is primarily anticonvulsant but but in several aspects, is also neuroprotective. Neuroprotection can bring about anticonvulsant effect, but it may have other effects, which can lead to other clinical uses of the KD. Overall, the use of the KD enhances energy production in the brain. A product of βhydroxybutyrate dehydrogenation, acetoacetate, is transferred into acetyl-CoA which enters the tricarboxylic acid (TCA) cycle. The increased turnover generates protons and electrons that are channeled to ETC. This, in turn, drives the formation of ATP from adenosine diphosphate (ADP) by ATP synthase. Enhanced ATP can either be converted to phosphocreatine for energy storage or split into adenosine. Higher ATP levels provide energy reserves for a neuron to continue functioning under stress. Increased extracellular adenosine offers a neuroprotective buffer against insults, reduces excitation, and ward off excessive TP demands, thus providing local seizure control and neuroprotection.

It was also suggested that the KD influences toward an upregulation of transcripts encoding energy metabolism enzymes and increase in the density of mitochondria in neuronal process, leading to heightened energy reserves. An improved energetic status can help in seizure prevention, by supporting GABAergic inhibition. It is suggested that adaptive processes to the metabolic changes induced by the diet lead to changes in gene expression which in turn result in some of the above-noted changes. Another path of neuroprotection is modulated through decreased generation of ROS which is considered to be related to PUFAs effect on uncoupling proteins.



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