Epilepsy affects approximately 1% of the population across all age groups and is one of the most prevalent chronic neurological disorders. Unfortunately, current pharmacological treatments do not control seizures adequately in up to 35% of persons with epilepsy. As an alternative, therapy with a high-fat low-carbohydrate (ketogenic) diet can be highly effective in medically-refractory epilepsy, and the mechanisms underlying its success can offer insight into other neurological disorders with metabolic underpinnings. Despite intense interest, key mechanisms underlying the clinically- established anticonvulsant success of ketogenic diet therapy remain unknown. Adenosine, the core molecule of ATP, is an inhibitory neuromodulator that links cell metabolism directly to neuronal activity. Understanding how to regulate adenosine, an endogenous anticonvulsant and neuroprotectant, offers powerful therapeutic benefits. Akin to a ketogenic diet's success with refractory epilepsy, adenosine is an effective anticonvulsant in models of drug- resistant epilepsy. The central hypothesis is that ketogenic diets increase adenosine A1 receptor activation, and that this increased inhibitory influence of adenosine is critical for the anticonvulsant success of ketogenic diet therapy. To test this hypothesis, bioenergetic, neurochemical, electrophysiological and behavioral techniques will be applied after ketogenic diet therapy in rats and mice with normal or genetically-altered adenosine signaling. Experiments using the most accurate bioenergetic and neurochemical techniques will quantify changes in energy molecules, adenosine, adenosine receptors, and ketone bodies (Aim 1). Changes in adenosine's influence on synaptic transmission and neuronal excitability will be quantified using detailed electrophysiology and electrochemistry (Aim 2). Experiments using behavioral paradigms of genetically-based seizures or modeled epilepsy will quantify changes in seizure frequency and severity (Aim 3). Preliminary and published data from others and us support the hypothesis that ketogenic strategies increase levels and actions of adenosine. The proposed experiments will measure levels of adenosine and test the role of adenosine acting at adenosine A1 receptors in the anticonvulsant success of dietary therapy in vitro and in vivo. Our expertise in bioenergetics, adenosine regulation and epilepsy, coupled with unique and complementary methodological approaches, will yield clear experimental outcomes. The long-term goal of this research is to understand critical mechanisms underlying metabolic strategies and yield new options in the treatment of epilepsy and other conditions such as brain injury and stroke, where adenosine offers therapeutic benefits.

Public Health Relevance

Low carbohydrate """"""""ketogenic"""""""" diets prevent epileptic seizures and protect neurons, but the reason why dietary therapy is successful is unknown. We hypothesize that ketogenic diets increase adenosine, the brain's own seizure-control molecule. Ultimately, understanding the relationship between adenosine and ketogenic diet therapy will facilitate development of an entirely new family of treatments for epilepsy that are easy to administer, effective and well-tolerated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065957-03
Application #
8333420
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
2010-09-15
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$424,047
Indirect Cost
$46,791
Name
Trinity College
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
069259950
City
Hartford
State
CT
Country
United States
Zip Code
06106
Kawamura, Masahito Jr; Ruskin, David N; Masino, Susan A (2016) Metabolic Therapy for Temporal Lobe Epilepsy in a Dish: Investigating Mechanisms of Ketogenic Diet using Electrophysiological Recordings in Hippocampal Slices. Front Mol Neurosci 9:112
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Blaise, J Harry; Ruskin, David N; Koranda, Jessica L et al. (2015) Effects of a ketogenic diet on hippocampal plasticity in freely moving juvenile rats. Physiol Rep 3:
Kawamura Jr, Masahito; Ruskin, David N; Geiger, Jonathan D et al. (2014) Ketogenic diet sensitizes glucose control of hippocampal excitability. J Lipid Res 55:2254-60
Diogenes, Maria Jose; Neves-Tome, Raquel; Fucile, Sergio et al. (2014) Homeostatic control of synaptic activity by endogenous adenosine is mediated by adenosine kinase. Cereb Cortex 24:67-80
Flaten, Vanessa; Laurent, Cyril; Coelho, Joana E et al. (2014) From epidemiology to pathophysiology: what about caffeine in Alzheimer's disease? Biochem Soc Trans 42:587-92
Ruskin, David N; Svedova, Julia; Cote, Jessica L et al. (2013) Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS One 8:e65021
Masino, Susan A; Ruskin, David N (2013) Ketogenic diets and pain. J Child Neurol 28:993-1001

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