December 2018
Li‐Rong Shao, Jong M. Rho, and Carl E. Stafstrom

 

Summary

Conventional antiseizure medications reduce neuronal excitability through effects on ion channels or synaptic function. In recent years, it has become clear that metabolic factors also play a crucial role in the modulation of neuronal excitability. Indeed, metabolic regulation of neuronal excitability is pivotal in seizure pathogenesis and control.

The clinical effectiveness of a variety of metabolism‐based diets, especially for children with medication‐refractory epilepsy, underscores the applicability of metabolic approaches to the control of seizures and epilepsy. Such diets include the ketogenic diet, the modified Atkins diet, and the low‐glycemic index treatment (among others).

A promising avenue to alter cellular metabolism, and hence excitability, is by partial inhibition of glycolysis, which has been shown to reduce seizure susceptibility in a variety of animal models as well as in cellular systems in vitro. One such glycolytic inhibitor, 2‐deoxy‐d‐glucose (2DG), increases seizure threshold in vivo and reduces interictal and ictal epileptiform discharges in hippocampal slices.

Here, we review the role of glucose metabolism and glycolysis on neuronal excitability, with specific reference to 2DG, and discuss the potential use of 2DG and similar agents in the clinical arena for seizure management.

 

Key Points

  • Cellular metabolism plays a key role in the modulation of neuronal excitability
  • Inhibition of glycolysis (e.g., by 2‐deoxy‐D‐glucose, 2DG) reduces seizure occurrence and retards epilepsy progression in several animal seizure models, and abrogates epileptiform bursting in hippocampal slices
  • 2DG is taken up preferentially by metabolically active cells, making this compound especially attractive for suppressing seizure activity
  • 2DG appears to be safe, without long‐lasting cognitive, behavioral, or systemic effects
  • Inhibitors of glycolysis offer a potential novel method for suppressing seizures and epilepsy

Neuronal excitability has been traditionally thought to be mediated predominantly via ion channels and synaptic transmission. However, it is becoming increasingly clear that metabolic factors also play a role in the modulation of neuronal excitability.1, 2 Several examples of beneficial metabolic treatments for epilepsy and other neurologic disorders are already in clinical use, including the high‐fat, low‐carbohydrate ketogenic diet (KD) and its variants (e.g., medium‐chain triglyceride diet, modified Atkins diet, and low‐glycemic index treatment).3, 4, 5, 6

However, the mechanisms of action underlying these metabolic treatments are not fully understood. Possible mechanisms include reduction in excitability by ketone bodies or fatty acids, altered neurotransmitter synthesis or action, improved mitochondrial function, or a variety of other factors. The observation that carbohydrate ingestion by children receiving the KD resulted in loss of seizure control7 led to the hypothesis that carbohydrate restriction could protect against seizure occurrence.8

In addition to limiting carbohydrate intake, restricting total calorie intake also suppresses seizures and affords neuroprotection.8, 9, 10, 11 In fact, the original idea behind the KD was to mimic the physiologic effects of fasting, and some data support intermittent fasting for seizure control,12 but this strategy is not a pragmatic long‐term treatment option.