Insights into the Cellular Interactions and Molecular Mechanisms of Ketogenic Diet for Comprehensive Management of Epilepsy

Abstract

A high-fat diet with appropriate protein and low carbohydrate content, widely known as the ketogenic diet (KD), is considered as an effective non-pharmacotherapeutic treatment option for certain types of epilepsies. Several preclinical and clinical studies have been carried out to elucidate its mechanism of antiepileptic action. Ketone bodies produced after KD's breakdown interact with cellular excito-inhibitory processes and inhibit abnormal neuronal firing. The generated ketone bodies decrease glutamate release by inhibiting the vesicular glutamate transporter 1 and alter the transmembrane potential by hyperpolarization. Apart from their effect on the well-known pathogenic mechanisms of epilepsy, some recent studies have shown the interaction of KD metabolites with novel neuronal targets, particularly adenosine receptors, adenosine triphosphate-sensitive potassium channel, mammalian target of rapamycin, histone deacetylase, hydroxycarboxylic acid receptors, and the NLR family pyrin domain containing 3 inflammasomes to suppress seizures. The role of KD in augmenting gut microbiota as a potential mechanism for epileptic seizure suppression has been established. Furthermore, some recent findings also support the beneficial effect of KD against epilepsy- associated comorbidities. Despite several advantages of the KD in epilepsy management, its use is also associated with a wide range of side effects. Hypoglycemia, excessive ketosis, acidosis, renal stones, cardiomyopathies, and other metabolic disturbances are the primary adverse effects observed with the use of KD. However, in some recent studies, modified KD has been tested with lesser side effects and better tolerability. The present review discusses the molecular mechanism of KD and its role in managing epilepsy and its associated comorbidities.

Keywords: Epilepsy-associated comorbidities; gut microbiota; mammalian target for rapamycin; medium-chain triglyceride; neuronal activity; vesicular glutamate transporters.

Fig. (1)

Effect of KD and its metabolites on glutamatergic functions. KD undergoes β-oxidation of fatty acids and results in the formation of ketone bodies, ACA and β-HB, in the liver. Homeostatically, VGLUT-1 loads the glutamate in synaptic vesicles and controls its release. Ketone bodies cross the blood-brain barrier through MCT-1 and inhibit VGLUT-1 in synaptic vesicles, thus reducing the excitatory neurotransmitter release that hyperpolarizes the postsynaptic neuron. Abbreviations: ACA: Acetoacetate; β-HB: β-hydroxybutyrate; GABA: Gamma-aminobutyric acid; VGLUT-1: Vesicular glutamate transporter 1; MCT-1: Monocarboxylate transporter-1.

Fig. (2)

Effect of KD and its metabolites on the synaptic neurotransmission. Ketone bodies act diversely on various neurotransmitters to alter the movement of ions across the cell membrane. Ketone bodies interact directly/indirectly with receptors, including GABA, NMDA, AMPA, 5-hydroxytryptamine, and A1K. Ketone bodies increase the production of ATP, which ultimately acts on A1R and affects neurotransmission. MCT increases the synthesis of tryptophan, which results in increased production of 5-hydroxytryptamine. ACA inhibits glutamate transmission, which affects the NMDA functions. Abbreviations: ACA: Acetoacetate; ATP: Adenosine triphosphate; A1R: Adenosine receptor-1; NMDA: N-Methyl-D-aspartate; GABA: Gamma aminobutyric acid; AMPA: α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid; MCT: Medium-chain triglyceride.

Fig. (3)

Interaction of KD and its metabolites with the mTOR pathway. Ketone bodies lower the insulin levels, which act on tyrosine kinase (TK) receptors following the activation of downstream signaling cascades. This results in activation of AKT, which inhibits mTOR. Energy and nutrient deprivation results in the activation of LKβ1 and the AMPK pathway, which also alters mTOR downstream signaling. Abbreviations: AKT: Protein kinase B; AMPK: AMP-activated protein kinase; PI3K: Phosphoinositide 3-kinases; LKβ1: Liver kinase β1; TK: Tyrosine kinase; TSC: Tuberous sclerosis complex; mTOR: Mammalian target of rapamycin.

Fig. (4)

Molecular basis of KD and its metabolites-associated adverse effects. The detailed process is described in the main text. Abbreviations: PEP: Phosphoenolpyruvate; CPT: Carnitine transporter; VLDL: Very low-density lipoprotein; LDL: Low-density lipoprotein.