The ketogenic diet enhances the brain’s natural calmness to fight epilepsy

Recent Discovery of cells study investigates whether the ketogenic diet (KD) could alleviate epilepsy.

Study: β-Hydroxybutyric Acid Produced by Ketogenic Diet Accumulates GABA in Brain and Increases GABA/Glutamate Ratio to Inhibit Epilepsy. Image credit: SewCreamStudio / Shutterstock.com

Record

The ketogenic diet (KD) is a high-fat, very-low-carb, high-protein regimen. In this diet, the cells’ energy comes from the oxidation of fatty acids and amino acids, which creates 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 ketone body synthesis. Previously, KD has been associated with positive results in 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 approximately 1% of the world’s population. Many people with epilepsy are resistant to the current drugs available to treat the condition. However, KD has been found to be effective in treating children with refractory epilepsy.

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

GABA is produced in the central nervous system (CNS) by glutamate decarboxylase 1 (GAD1), whose main function is to decarboxylate glutamate within the GABAergic axon terminal. Previous studies have shown that epileptic activity in humans depends primarily 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 KD or normal diet (ND) for 12 weeks. Female mice were not used to avoid the effects of hormonal changes, which are important during puberty.

Before the start of the dietary intervention, all mice were treated with pentrazole (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 produced by KD was mainly responsible for the antiepileptic efficacy of this dietary regimen. BHB increases histone H3 lysine 27 (H3K27Ac) acetylation 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.

SIRT4 upregulation leads to glutamate dehydrogenase (GDH) decarbamylase. In addition, BHB inactivates GDH and accumulates glutamate, which is required for GABA production.

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

Activation of SIRT4 and GAD1 was found to be critical for the antiepileptic effects of BHB. SIRT4-negative experimental mice showed limited antiepileptic potency, while BHB enhanced GABA levels in the brain of mice. Inhibition of GDH and proportional increase of GABA and glutamate may result in limited antiepileptic activity.

A significantly high level of GABA is required to inhibit neurons, as there are many excitatory neurotransmitters besides glutamate. Studies in mammals have shown that BHB and ketone bodies could act as molecular signals to inhibit neuronal excitability.

Previous studies have also demonstrated the inhibitory effect of BHB against class I HDACs, while HDAC1/HDAC2-mediated histone deacetylation 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, over prolonged periods, could cause gastrointestinal problems, malnutrition, cardiovascular disease, 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 in turn upregulates SIRT4. Uploaded SIRT4 is related to the activities of adenosine diphosphate (ADP)-ribosyltransferase, decarbamylase, deacetylase, and lipoamidase, which lead to glutamate and GABA metabolism, along with regulation of neuronal activity. In the future, genetic epilepsy animal models are needed to confirm the effect of KD and BHB in alleviating epilepsy.