Scientists Unlock Secret to Successful Dietary Therapy for Epilepsy

HARTFORD, CT -- A high-fat, low-carbohydrate “ketogenic” diet can stop seizures in mice by activating adenosine receptors, a finding that will serve as a catalyst for the development of adenosine-based therapies for epilepsy and other neurological disorders, according to a study featured on the cover of the July 2011 issue of The Journal of Clinical Investigation.

The article describing the link between ketogenic diets and adenosine was produced by an international research team led by Susan Masino, Charles A. Dana Research Associate Professor of Neuroscience and Psychology at Trinity College in Hartford, Conn., and Detlev Boison, Director of Basic and Translational Research at the Legacy Research Institute in Portland, Ore. Also contributing to the study were scientists from the University of Amsterdam in the Netherlands, the University of North Dakota, and the Karolinska Institute in Sweden.

Ketogenic diets have been used successfully to treat epilepsy in people, primarily in children, since 1921, and can sometimes stop seizures even when drugs are ineffective. The ketogenic diet has shown promise in treating diabetes and cancer, particularly brain cancer, in mice and people. It is also being explored for other neurological conditions, including autism and brain injury, and neurodegenerative disorders, such as Parkinson’s disease. In 2009, Masino’s research team showed for the first time that a ketogenic diet can reduce pain and inflammation in rats.

Adenosine -- the core of adenosine triphosphate (ATP), the main cell energy molecule -- acts on neurons to inhibit brain activity, and can be considered the brain’s own anti-seizure substance.

This groundbreaking research by an international team of scientists reveals for the first time a direct connection between ketogenic diets and adenosine. Until now, scientists have been unable to develop therapies without having to rely on strict ketogenic diets because they didn’t know how or why the diet was effective.

Adenosine-based therapies have shown promise in multiple neurological conditions based on research in animal models. Adenosine is similar to a ketogenic diet in that it can stop seizures that do not respond to medication. Adenosine also protects neurons from injury and can reduce pain. This new research demonstrating diet-induced changes in adenosine receptor activity in the brain will open doors for the development of adenosine therapies.

In their journal article, “A ketogenic diet suppresses seizures in mice through adenosine A1 receptors,” the research team used three types of genetically altered mice. All three groups had spontaneous ongoing electrographic seizures due to decreased inhibitory adenosine A1 receptor (A1R) signaling. The first group had no A1Rs; the second group had half the normal level; and the third group had normal receptor levels but high levels of an enzyme that metabolizes adenosine and reduces A1R activity.

In comparing the groups, the investigators found that treatment with a ketogenic diet virtually eliminated seizures in animals with normal A1Rs. Dietary treatment reduced seizures partially in mice with reduced A1Rs but had no effect on seizures in animals that lacked all A1Rs. Any anti-seizure effects of the diet were reversed with either an injection of glucose or a substance that blocked A1Rs. Together, the results showed that the A1Rs were necessary for the anti-seizure effects of the high-fat, low carbohydrate diet.

Dr. Eleonora Aronica, of the University of Amsterdam, analyzed brain tissue from people diagnosed with epilepsy. She found evidence for decreased adenosine, thus linking the ketogenic diet research in mice with changes in the brain found in human epilepsy. 

Many of the experiments were performed in the laboratory of Boison, an expert on adenosine and epilepsy, at the Legacy Research Institute. “This is an incredibly exciting advance for adenosine-based therapies for epilepsy. Adenosine is an ideal molecule to stop seizures, and the ketogenic diet seems to increase adenosine exactly where it is needed,” said Boison.

Masino, the lead author of The Journal of Clinical Investigation article, said, “We put together a dream team of scientists and research tools for this project. We are incredibly excited about the opportunities that this research opens up for adenosine and for metabolic therapies like the ketogenic diet.” 

A ketogenic diet is administered under medical supervision and was developed based on the historical observation that fasting reduces seizures. Because of restricted carbohydrate intake, ketones replace glucose as the body’s energy source; thus, the diet produces a similar metabolic state to fasting. 

The diet fell out of favor in the 1930s and 1940s with the advent of anticonvulsant drugs, but experienced a resurgence in the 1990s with the popularity of low carbohydrate diets and public awareness raised by the 1997 television movie, First Do No Harm, starring Meryl Streep. 

On average, ketogenic diet therapy is as effective as medication, even though it is often only considered as a last resort. The Charlie Foundation in the United States (www.charliefoundation.org) and Matthew’s Friends in the United Kingdom (www.matthewsfriends.org) are non-profits devoted exclusively to resources, education and awareness of ketogenic diet therapy for epilepsy and other disorders. 

The research was funded by the National Institutes of Health, the National Science Foundation, the Swedish Research Council, the CHDI Foundation, National Epilepsy Fund, the European Union, Trinity College, and the Legacy Good Samaritan Foundation. 

Founded in Hartford, CT in 1823, Trinity College (www.trincoll.edu) is an independent, nonsectarian liberal arts college with more than 2,200 undergraduates from 47 states and 49 countries. It is home to the eighth-oldest chapter of Phi Beta Kappa in the United States.  The faculty and alumni include recipients of the Pulitzer Prize, the MacArthur Award, Guggenheims, Rockefellers and other national academic awards.

Legacy Health (www.legacyhealth.org) is an Oregon-based not-for-profit, tax-exempt corporation comprising five full-service hospitals, a children's hospital, and the Legacy Research Institute, to bring the most advanced health care treatment modalities and cutting edge technologies quickly on-line, where they can be applied to the benefit of our patients and community. The Legacy Research Institute is home to 18 distinguished research scientists and their research teams conducting basic, translational, and clinical research in the areas of neurology, ophthalmology, neurotology, diabetes, and biomechanics.