In this edition of Ketogenic Diet News, we delve into the basic science of the diet, attempting to answer the question, “Why does it work?” Adam Hartman, MD, is a member of the John M. Freeman Pediatric Epilepsy Center at Johns Hopkins Hospital and also an integral part of our ketogenic diet team. Dr. Hartman is one of the many investigators interested in using animal research to help find out why the diet works. | Eric Kossoff MD

By Adam L. Hartman, MD

The ketogenic diet (KD) has been used for nearly 90 years. We still do not know how it prevents seizures, however, the KD, or substances related to it, has been used in animal models of other brain diseases, such as Alzheimer\'s disease, Parkinson\'s disease, and brain cancer. We will survey some laboratory studies published in 2007 looking at how the diet may work.

Garriga-Canut, Roopra, and their colleagues showed that a chemical called 2-deoxy-D-glucose (2-DG) prevents seizures in animals. These scientists suggested that using 2-DG, which prevents cells from using glucose (sugar), is similar to eating a low-carbohydrate diet, such as the KD. The KD raises levels of ketones in the blood, but it also has low amounts of sugar. Some researchers claim that dietary therapies may work by the latter, and this is one theory why the low glycemic index treatment may work. 2-DG may prevent seizures by decreasing amounts of a brain growth factor. Thus, this group has shown that 2-DG prevents certain seizures in animals. It is not known whether this also would be useful in humans. Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Daley TJ, Pfender RM, Morrison JF, Ockuly J, Stafstrom C, Sutula T, Roopra A.

One of the earliest ideas about the KD\'s anti-seizure effects is that ketones themselves are responsible for controlling seizures. Two groups recently showed some ketones may have beneficial effects that might be important for seizures and possibly other brain diseases. Maalouf, Rho, and colleagues showed these ketones decrease damage caused by chemicals that are increased during seizures. Ketones are believed to do this by affecting one of the cell’s ‘fuel gauges.’ This leads to an improvement in how cells react during a stress, like seizures. Therefore, these ketones protect brain cells, which may be important in other brain diseases where the ketogenic diet is useful.

This same group showed previously that one of these ketones does not protect against seizures in certain animals. Therefore, the role this idea plays in the KD’s ability to control seizures is still unclear. Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM.

Epilepsy involves increased brain cell activity. Ma, Berg, and Yellen showed that certain ketones decrease brain cell activity, due to their effect on a specific potassium channel. This is an attractive idea to explain how ketones regulate brain cell activity, but the exact role of this particular channel in epilepsy is unclear. Furthermore, this channel is more active when the cell\'s fuel levels are low. Most studies have shown that fuel levels are higher during the ketogenic diet. Nonetheless, this idea may help explain how the ketogenic diet works for other diseases. Ma W, Berg J, Yellen G.

Likhodii and his colleagues showed that a third ketone elevated during the ketogenic diet, acetone, also has anti-seizure properties. Likhodii SS, Serbanescu I, Cortez MA, Murphy P, Snead OC 3rd, Burnham WM. More recently, Gasior, Rogawski, and their colleagues showed that it was acetone, not other substances related to it, that produces this effect. Unfortunately, acetone levels that produce this effect were higher than those measured in animals eating a ketogenic diet. Acetone itself may prove to be useful in the treatment of seizures. Gasior M, French A, Joy MT, Tang RS, Hartman AL, Rogawski MA.

In summary, scientists have helped us understand the effects of KD factors on animal seizure models and protecting brain cells. The importance of these findings to the KD’s effects on seizures is not entirely clear. Some of these findings may point to new therapies for seizures. Two things are certain: the KD has been very useful for a number of patients, and scientists will continue exploring why it works.

References

• Garriga-Canut M, Schoenike B, Qazi R, Bergendahl K, Daley TJ, Pfender RM, Morrison JF, Ockuly J, Stafstrom C, Sutula T, Roopra A. 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nat Neurosci. 2006 Nov;9(11):1382-7.
• Maalouf M, Sullivan PG, Davis L, Kim DY, Rho JM. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience. 2007 Mar 2;145(1):256-64.
• Ma W, Berg J, Yellen G. Ketogenic diet metabolites reduce firing in central neurons by opening K(ATP) channels. J Neurosci. 2007 Apr 4;27(14):3618-25.
• Likhodii SS, Serbanescu I, Cortez MA, Murphy P, Snead OC 3rd, Burnham WM. Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. Ann Neurol. 2003 Aug;54(2):219-26.
• Gasior M, French A, Joy MT, Tang RS, Hartman AL, Rogawski MA. The anticonvulsant activity of acetone, the major ketone body in the ketogenic diet, is not dependent on its metabolites acetol, 1,2-propanediol, methylglyoxal, or pyruvic acid. Epilepsia. 2007 Apr;48(4):793-800.

Edited by Steven C. Schachter, MD
Submitted on October 1, 2007