# Effects of dietary alpha-linolenic acid on SUDEP, seizures, and neural structure and function in mouse models of epilepsy

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2022 · $424,875

## Abstract

PROJECT SUMMARY
Currently available medications fail to control seizures in ~30% of epilepsy patients. This is a serious medical
problem because patients with severe progressive forms of drug-resistant epilepsy have a high risk of sudden
unexpected death in epilepsy (SUDEP). Thus, the need for novel and effective strategies for the prevention
and treatment of epilepsy is pressing. Among the potential adjunctive therapies for such refractory forms of
epilepsy, diet-based approaches hold great promise as they are often economical and associated with few ad-
verse side effects. Our long-term goal is to provide the scientific foundation necessary for developing new
effective interventions for combating drug-resistant epilepsy. To this end, it will be necessary to elucidate the
molecular and cellular mechanisms through which dietary modifications reduce seizures and SUDEP. The
overall objectives of this exploratory project are to determine 1) the beneficial effects of dietary
supplementation with -linolenic acid (ALA), an essential -3 polyunsaturated fatty acid (PUFA), on mouse
models of epilepsy, and 2) how “therapeutic diets” affect the morphology and physiological function of brain
neurons that are relevant to epilepsy. Our central hypothesis is that orally administered ALA and milk whey
reduce phenotypic severity in mouse models of epilepsy by inducing morphological and physiological changes
in brain GABAergic neurons. This hypothesis is based, in part, on our preliminary findings in fruit flies and
mice: 1) supplementation of diets with milk whey significantly suppresses neuronal and behavioral
hyperexcitability in Drosophila, as well as spontaneous seizures and SUDEP in epileptic mice, and 2) ALA in
milk whey mediates this diet-induced suppression of seizures in Drosophila. The current project will use mouse
voltage-gated sodium channel mutants, well-established models of human epilepsy. Aim #1 is to determine the
effects of ALA on SUDEP and seizures. Mice that model Dravet syndrome (Scn1aR1407X/+) and early infantile
epileptic encephalopathy (Scn8aN1768D/+) will be fed ALA daily after weaning, and spontaneous seizures and
SUDEP will be monitored under continuous video surveillance. Hyperthermia-induced seizures will also be
scored for frequency and severity in the presence or absence of ALA feeding. Aim #2 is to delineate diet-
induced morphological and physiological alterations in brain neurons. The effects of milk whey and ALA on the
morphology of neocortical GABAergic interneurons will be assessed by examining their numbers, dendritic
complexity, axonal projections, and terminal density in Scn1aR1407X/+ mutants. The effects of therapeutic diets
on the function of GABAergic neurons will also be determined, by patch clamp recordings from neocortical
slices. The proposed research is significant because it is expected to identify the beneficial effects of dietary
modifications on mouse models of genetic epilepsy under well-controlled condition...

## Key facts

- **NIH application ID:** 10527609
- **Project number:** 1R21NS125130-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** TOSHIHIRO KITAMOTO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $424,875
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527609

## Citation

> US National Institutes of Health, RePORTER application 10527609, Effects of dietary alpha-linolenic acid on SUDEP, seizures, and neural structure and function in mouse models of epilepsy (1R21NS125130-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10527609. Licensed CC0.

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