Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy

Abstract

Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.

Characterization of β-Hydroxybutyrate as a Cell Autonomous Fuel for Active Excitatory and Inhibitory Neurons

“…For example, brain lactate has been observed to increase with fasting in tandem with BHB ( Pan et al, 2000 ), indicating that the body is able to provide these fuels to neurons in conditions of lower glucose availability. It remains possible that the metabolic perturbations of the ketogenic diet have minimal effects on synaptic transmission, given the many other proposed mechanisms of ketone action ( Masino et al, 2011 ; Youm et al, 2015 ; Qiao et al, 2024 ; Ma et al, 2007 ; Juge et al, 2010 ), but our recent results highlight a previously unconsidered therapeutic mechanism. Whether brain lactate levels similarly increase in prolonged ketogenic diet use represents an interesting topic for future study.…”

“…Ketone bodies are a notable example of an alternative mitochondrial fuel, as the ketogenic diet is in use as a therapy for medication-refractory cases of epilepsy ( El-Rashidy et al, 2023 ) and is effective in about 40% of these cases ( Ye et al, 2015 ). There are multiple proposed mechanisms for the therapeutic effect of the ketogenic diet including epigenetic modifications, neuroprotective signaling, antioxidant activity, and metabolic shifts leading to shifts in the ratio of excitation to inhibition ( Murugan and Boison, 2020 ; Ma et al, 2007 ; Juge et al, 2010 ; Qiao et al, 2024 ), each with varying amounts of supporting evidence. The efficacy of the ketogenic diet is relatively high for inherited metabolic disorders with impaired glycolysis ( Klepper et al, 2005 ; Sofou et al, 2017 ), supporting the notion that an underlying metabolic component contributes to the therapeutic impact.…”

Complete remission of depression and anxiety using a ketogenic diet: case series

“…Recent research shows that a ketogenic diet (KD) reduces neuronal firing rates, modulates ion channels and cell signaling cascades, and stimulates the biochemical synthesis and neurotransmission of GABA by inhibiting glutamate decarboxylase, a major inhibitory neurotransmitter involved in neuronal firing and anxiogenesis ( 25 , 26 ). BHB activates the transcription of antioxidant-related genes by inhibiting histone deacetylases, triggering long-term adaptive changes in gene expression.…”

“…BHB activates the transcription of antioxidant-related genes by inhibiting histone deacetylases, triggering long-term adaptive changes in gene expression. In addition, at physiologic concentrations, ketone bodies reduce neuroinflammation through direct action at G-protein coupled receptors ( 25 ). KD also favorably alters the gut microbiome ( 27 ).…”