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Saturday, November 20, 2010

Epilepsy, Ketogenic Diet & The Mind

In this informative essay entitled "Epilepsy's Big, Fat Miracle" published online in The New York Times Nov. 17, 2010, Fred Vogelstein tells us how a ketogenic diet helped drastically diminish petit-mal seizures in his eight-year old son Sam who suffers from epilepsy. Medication is still needed. But Sam had suffered up to 130 seizures a day, producing short, at times frightening, pauses of consciousness. Since he has been on the diet, their frequency dropped by 75 percent. Experience with patients like Sam tells that he may not need it anymore at some point in the future. Why the diet provides this effect has remained little understand.

A ketogenic diet consists almost entirely of fatty foods and very low sugar. When we deprive our body of sugar for an extended period of time, we begin to metabolize fat. The liver converts fat into ketone bodies that all cells can use instead of glucose to produce the energy they need to function. Nerve cells in the brain do not only utilize the ketone bodies as sources of energy, but also may produce the neurotransmitter glutamate, as a derivative of the intermediate  α-ketoglutarate in the same metabolic energy pathway in the mitochondria that consumes the ketone bodies as well as glucose derivative pyruvate, known as Krebs cycle.

Krebs Cycle (courtesy: Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins)
Glutamate constitutes the most prevalent excitatory neurotransmitter in the brain. Neurotransmitters pass information across the contacts between nerve cells known as synapses.  Glutamate receptors, notably the N-methyl D-aspartate receptor, play a crucial role in the shaping of nerve cell connections. The kainate receptor is known to be excitatory when located postsynaptically and modulate inhibition when located presynaptically. Kainic acid triggers epileptic seizures. During a seizure nerve cells release glutamate in unusually large amounts causing waves of excitation that the nerve cells otherwise do not experience. Under normal conditions, nerve cells manage to adapt their responses to increasing stimulation, keeping the released amounts of glutamate low (read my post with title "Good News for Brain Energy Use" dated Sep. 12, 2009).

However, when we are on a ketogenic diet, the glutamate that can be derived from ketone bodies is at best half of that derived from glucose. The diminished availability of glutamate may make the difference (but also see Morris, 2005).

Addendum
  • A wise biochemist made me aware of the possibility that ketogenic diets may take advantage of yet another metabolic mechanism. By far not all α-ketoglutarate in the Krebs cycle is converted into glutamate. Rather, the larger fraction is turned into succinate in a reaction that also produces guanosine triphosphate (GTP) from guanosine diphosphate (GDP). Neurotransmitter receptors can be divided into two fundamentally two different types: ionotropic and metabotropic. The first type of receptor is coupled to channel proteins in the nerve cell membrane that control ion fluxes instrumental for the generation and propagation of the electrical impulses encoding the information processed in the brain. The afore-mentioned NMDA and kainate receptors are ionotropic. The second type of receptor is coupled to G-proteins that effect molecular signals regulating ionotropic receptor function, gene expression and energy metabolism.  Eight metabotropic glutamate receptors have been identified. The activation of G-proteins depends on GTP. In addition to curtailing the availability of glutamate per se, a ketogenic diet may therefore diminish glutamate's action indirectly, diminishing metabotropic glutamate receptor activity (12/07/10).
References
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