2-Deoxyglucose and Beta-Hydroxybutyrate: Metabolic Agents for Seizure Control.

Jong M Rho,Carl E Stafstrom,Li-Rong Shao

doi:10.3389/fncel.2019.00172

Abstract

Current anti-seizure drugs (ASDs) are believed to reduce neuronal excitability through modulation of ion channels and transporters that regulate excitability at the synaptic level. While most patients with epilepsy respond to ASDs, many remain refractory to medical treatment but respond favorably to a high-fat, low-carbohydrate metabolism-based therapy known as the ketogenic diet (KD). The clinical effectiveness of the KD has increasingly underscored the thesis that metabolic factors also play a crucial role in the dampening neuronal hyperexcitability that is a hallmark feature of epilepsy. This notion is further amplified by the clinical utility of other related metabolism-based diets such as the modified Atkins diet and the low-glycemic index treatment (LGIT). Traditional high-fat diets are characterized by enhanced fatty acid oxidation (which produces ketone bodies such as beta-hydroxybutyrate) and a reduction in glycolytic flux, whereas the LGIT is predicated mainly on the latter observation of reduced blood glucose levels. As dietary implementation is not without challenges regarding clinical administration and patient compliance, there is an inherent desire and need to determine whether specific metabolic substrates and/or enzymes might afford similar clinical benefits, hence validating the concept of a “diet in a pill.” Here, we discuss the evidence for one glycolytic inhibitor, 2-deoxyglucose (2DG) and one metabolic substrate, β-hydroxybutyrate (BHB) exerting direct effects on neuronal excitability, highlight their mechanistic differences, and provide the strengthening scientific rationale for their individual or possibly combined use in the clinical arena of seizure management.

Highlights

The mechanistic focus in the field of epilepsy research has been on ion channels and transporters that regulate neuronal excitability at the synapse
The steadily increasing scientific arena of metabolic control of neuronal excitability has been catalyzed by the clinical success and evidence-based validation of the high-fat, lowcarbohydrate ketogenic diet (KD) and its variants [i.e., mediumchain triglyceride (MCT), modified Atkins diet (MAD), and low-glycemic index treatment (LGIT)] (Neal et al, 2008; Rho and Stafstrom, 2012; Lutas and Yellen, 2013; Gano et al, 2014)
2-Deoxyglucose and Beta-Hydroxybutyrate for Seizure Control enhanced mitochondrial biogenesis and respiration (DeVivo et al, 1978; Bough et al, 2006; Kim et al, 2010). Another explanation for ketone body action on KATP channels was provided by Kawamura et al (2010) who showed that low-glucose conditions lead to opening of pannexin channels and efflux of ATP through these channels on CA3 pyramidal neurons, subsequent conversion of ATP to adenosine via extracellular ectonucleotidases, and activation of adenosine A1 inhibitory receptors, which are coupled to KATP channels (Kawamura et al, 2010)

Summary

KEY POINTS

• Cellular metabolism plays a key role in the modulation of neuronal excitability. • 2-Deoxyglucose (2DG), an inhibitor of glycolysis, abrogates seizure activity and retards epilepsy progression both in vitro and in vivo. • Beta-hydroxybutyrate (BHB), a by-product of fatty acid oxidation, exerts both anti-seizure and neuroprotective effects. • 2DG and BHB offer potential novel avenues for suppressing seizure activity and possibly epileptogenesis.

INTRODUCTION

Findings

CONCLUSION