# Ketogenic Diet and Adenosine: Epigenetics and Antiepileptogenesis

> **NIH NIH R01** · TRINITY COLLEGE · 2020 · $546,933

## Abstract

PROJECT SUMMARY
Current epilepsy therapies are inadequate: at least 30% of epilepsy patients suffer residual or medically-
refractory seizures and/or comorbidities as well as significant side-effects from antiepileptic drugs. Some of
these patients are treated successfully with a ketogenic diet (KD), a poorly understood and potentially
underutilized metabolic therapy established in 1921. The consistent clinical success of the KD in suppressing
seizures in refractory adult and pediatric epilepsies has been verified in multi-center, international and
randomized prospective clinical studies. Clinical observations and recent translational work strongly suggest
that a KD has antiepileptogenic and disease-modifying properties, and recent work indicates that metabolic
therapy may benefit a greatly expanded spectrum of diseases including pain, autism, brain cancer, and
Alzheimer’s disease. Nevertheless, therapeutic use of the KD has been limited largely to pediatric refractory
epilepsy: there are virtually no data on using a metabolic therapy as a first-line therapy, and thus its true clinical
efficacy and ability to prevent epileptogenesis is unknown. Understanding key mechanisms by which the
clinical benefits of a KD are exerted is urgent and of the highest biomedical significance because it is
anticipated that these mechanisms will lead to the rapid genesis of effective new metabolism-based
therapeutics with disease-modifying capabilities for epilepsy. Here we test our OVERALL HYPOTHESIS that
epigenetic changes in DNA methylation are mobilized during epileptogenesis and provide a
therapeutic target for epilepsy prevention through diet-based metabolic therapy. In Aim 1 we will identify
epigenetic epileptogenic mechanisms that are (i) common to etiologically different rodent models of temporal
lobe epilepsy (TLE) and (ii) laboratory independent – thus fulfilling an unmet need in epilepsy research and
establishing a high degree of scientific rigor among our team. In Aim 2 we will quantify antiepileptogenesis and
test mechanisms mobilized by KD therapy, including increased adenosine as a key downstream
antiepileptogenic mechanism. Finally, in Aim 3 we will validate whether candidate epigenetic changes are
required for KD-based antiepileptogenic effects and thereby provide mechanistic evidence for a causal
relationship among metabolic therapy, epigenetic alterations, and antiepileptogenesis. Our approach
represents the first systematic and comprehensive mechanistic analysis of an understudied metabolic
treatment that can stop – and even permanently resolve – seizures. The expected outcome is the identification
and characterization of epigenetic mechanisms through which metabolic therapy interferes with the process of
epileptogenesis. In particular we will determine whether the expected antiepileptogenic effects are specific to
KD-therapy and dependent on identified epigenetic mechanisms. A thorough mechanistic understanding of the
KD may reveal an entirely...

## Key facts

- **NIH application ID:** 9912862
- **Project number:** 5R01NS065957-07
- **Recipient organization:** TRINITY COLLEGE
- **Principal Investigator:** Detlev Boison
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $546,933
- **Award type:** 5
- **Project period:** 2010-09-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9912862

## Citation

> US National Institutes of Health, RePORTER application 9912862, Ketogenic Diet and Adenosine: Epigenetics and Antiepileptogenesis (5R01NS065957-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9912862. Licensed CC0.

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