B. Ebrahimi Behnam, S. Raeisi, N. Bakhtiari, MM. Abbasi and D. Shanehbandi (2025). Neurochemical and genetic effects of the ketogenic diet: alterations in brain GABA, glutamate, and related gene. Molecular biology reports, 52(1), 968. https://doi.org/10.1007/s11033-025-11077-y

PubMed 41026273

[Abstract]
BACKGROUND: A ketogenic diet (KD) is an effective nonpharmacological alternative therapy for managing drug-resistant epilepsy (DRE). We aimed to explore the potential effects of a KD on brain glutamate (Glu) and gamma-aminobutyric acid (GABA) neurotransmitters and their associated genes [glutamic acid decarboxylase (GAD) 65, GAD67, and GABA transaminase (GABA-T)] in rats as a possible antiseizure mechanism.

METHODS AND RESULTS: Eighteen male rats were divided into two weight-matched groups, namely, the normal diet (ND) group and the KD group. The ND group received a standard rat chow diet (10% protein, 80% carbohydrates, 10% fat; Kcal%). The KD group received a high-fat diet mimicking a clinical 4:1 fat to carbohydrate and protein ratio (8% protein, 2% carbohydrates, and 90% fat; Kcal%). The groups received diets for 30 days. The serum levels of beta-hydroxybutyric acid (BHB) in the KD group were significantly (p < 0.001) greater than those in the ND group. The brain concentrations of Glu and GABA in the KD group were lower (p = 0.001) and greater (p = 0.041), respectively. Compared with the ND group, the KD group presented increased GAD67 and decreased GABA-T levels (p = 0.036 and p = 0.035, respectively).

CONCLUSIONS: The elevated BHB observed with KD might be associated with changes in GABA and Glu levels in the brain, possibly reflecting alterations in GABA-T and GAD67 gene expression. These findings may provide preliminary insight into a mechanism that could contribute to the antiseizure effects of a KD.