Ketogenic diet boosts brain's natural calm to combat epilepsy

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A recent Cell Discovery study investigates whether the ketogenic diet (KD) could alleviate epilepsy.

Study: Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy. Image Credit: SewCreamStudio / Shutterstock.com

Background

The ketogenic diet (KD) is a high-fat, very low carbohydrate, and adequate protein regimen. In this diet, cell energy is derived from fatty acid and amino acid oxidation, which generates ketone bodies, such as acetoacetate (AcAc) and β-hydroxybutyrate (BHB). 

Additional studies are needed to confirm whether the physiological effects of KD, such as reduced blood sugar, cholesterol levels, and body weight, are due to altered energy metabolism or synthesis of ketone bodies. Previously, KD has been associated with positive effects on the treatment of brain disorders, such as Alzheimer’s disease, Parkinson’s disease, sleep disorders, multiple sclerosis, and autism. 

Epilepsy is a common neurological disorder that affects about 1% of the global population. Many individuals with epilepsy are resistant to current drugs available to treat this condition; however, KD has been found to be effective in treating children with refractory epilepsy. 

Epileptic seizures often occur due to an imbalanced production of excitatory and inhibitory neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). This imbalance in neurotransmission leads to excessive firing of neurons in the brain, which subsequently causes seizures.

GABA is generated in the central nervous system (CNS) by glutamate decarboxylase 1 (GAD1), whose primary function is the decarboxylation of glutamate within the GABAergic axon terminal. Previous studies have shown that epileptic activity in humans is primarily dependent on GABA depolarization; therefore, GABA could be referred to as an inhibitory neurotransmitter.

About the study

In the current study, eight-week-old male mice were fed a KD or normal diet (ND) for 12 weeks. Female mice were not used to avoid the effects of hormonal changes, which are significant during puberty.

Prior to initiating the dietary intervention, all mice were treated with pentetrazol (PTZ), which is used to induce epilepsy in vivo. The stereotypic behaviors that develop during seizures in mice were monitored, and the severity of epilepsy was measured using the Racine scale.

Study findings

BHB generated from KD was primarily responsible for the antiepileptic efficacy of this diet regime. BHB increases histone H3 lysine 27 acetylation (H3K27Ac) levels by inhibiting histone deacetylase 1 (HDAC1)/HDAC2, subsequently facilitating the transcription of sirtuin 4 (SIRT4) and glutamate decarboxylase 1 (GAD1), which inhibit neuronal activation.

Upregulation of SIRT4 leads to the decarbamylase of glutamate dehydrogenase (GDH). Furthermore, BHB inactivates GDH and accumulates glutamate, which is required to produce GABA.

BHB also upregulates GAD1, which leads to the production of GABA from glutamate. The elevated GABA/glutamate ratio alleviates epilepsy.

Activation of SIRT4 and GAD1 was found to be crucial for the antiepileptic effects of BHB. The SIRT4-negative experimental mice exhibited limited antiepileptic potency, whereas BHB enhanced GABA levels in mouse brains. The inhibition of GDH and a proportional increase of GABA and glutamate may lead to a limited antiepileptic effect. 

A significantly high level of GABA is required for neuronal inhibition, as many excitatory neurotransmitters, in addition to glutamate, are present. Mammalian studies have indicated that BHB and ketone bodies could function as molecular signals to inhibit neuronal excitation.

Previous studies have also demonstrated the inhibitory effect of BHB against class I HDACs, whereas HDAC1/HDAC2-mediated histone de-acetylation also down-regulates BHB. These findings support the upregulation of GAD1 by KD or BHB. 

KD has been used to treat refractory epilepsy in children since the 1920s; however, KD, for prolonged periods, could cause gastrointestinal problems, malnutrition, cardiovascular diseases, poor growth, and kidney stones. These limitations could be overcome by replacing KD with BHB. 

Conclusions

The mechanism responsible for the antiepileptic effects of KD appears to be related to the ability of this diet to upregulate BHB levels, which subsequently upregulates SIRT4. Upregulated SIRT4 is associated with the activities of adenosine diphosphate (ADP)-ribosyltransferase, de-carbamylase, deacetylase, and lipoamidase, which lead to glutamate and GABA metabolism, along with regulation of neuronal activity. In the future, genetic animal epilepsy models are needed to confirm the effect of KD and BHB in alleviating epilepsy.

Journal reference:
  • Qiao, Y., Li, L., Hu, S., et al. (2024) Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy. Cell Discovery 10(1); 1-20. doi:10.1038/s41421-023-00636-x
Dr. Priyom Bose

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Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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