Ketogenic diet, neuroprotection, and antiepileptogenesis

Abstract

High fat, low carbohydrate ketogenic diets (KD) have been in use for the treatment of epilepsy for almost a hundred years. Remarkably, seizures that are resistant to conventional anti-seizure drugs can in many cases be controlled by the KD therapy, and it has been shown that many patients with epilepsy become seizure free even after discontinuation of the diet. These findings suggest that KD combine anti-seizure effects with disease modifying effects. In addition to the treatment of epilepsy, KDs are now widely used for the treatment of a wide range of conditions including weight reduction, diabetes, and cancer. The reason for the success of metabolic therapies is based on the synergism of at least a dozen different mechanisms through which KDs provide beneficial activities. Among the newest findings are epigenetic mechanisms (DNA methylation and histone acetylation) through which KD exerts long-lasting disease modifying effects. Here we review mechanisms through which KD can affect neuroprotection in the brain, and how a combination of those mechanisms with epigenetic alterations can attenuate and possibly reverse the development of epilepsy.

Keywords: Antiepileptogenesis; Epigenetics; Epilepsy; Ketogenic diet; Neuroprotection.

Figure 1:. Epigenetic and Neuroprotective mechanisms of KD therapy.

The schematic is a simplistic representation of the two broader mechanisms thought to play a critical role in the neuroprotective and antiepileptogenesis functions of the KD therapy. The epigenetic mechanisms include restoration of (1) DNA methylation, (2) histone acetylation, and (3) non-coding RNA. Whereas, the neuroprotective mechanisms include (1) regulation of amino acids resulting in reduced glutamate and increased GABA neurotransmitters, (2) reduction in inflammation and oxidative stress via activation of mediators such as NF-kB, NLRP3 and PPAR, (3) reduction in oxidative stress via activation of Nrf2 pathway, glutathione (GHS) biosynthesis and expression of uncoupling proteins (UCPs), (4) inhibition of apoptotic factors such as BAD, Bax, and cytochrome C, and (5) release of neurotrophic factors such as BDNF and FGF21.

Figure 2:. Epigenetic mechanisms regulated by ketogenic diet.

The diagram represents the two major epigenetic alterations noted in patients and animal models of temporal lobe epilepsy and the mechanisms regulated by KD. DNA methylation: Global DNA hypermethylation induced by seizures is restored by KD via adenosine augmentation, shift in the SAH and SAM homeostasis and aiding DNA methylation by DNA methyltransferases (DNMT). Histone acetylation: Seizure-induced histone deacetylation is catalyzed by histone deacetylase (HDACs) resulting in closed chromatin structure and transcriptional gene repression. KD-induced increase in ketone bodies such as β-hydroxybutyrate, acetoacetate and acetone reverses histone deacetylation by inhibiting HDACs.