Dysregulated Glucose Metabolism as a Therapeutic Target to Reduce Post-traumatic Epilepsy

2018
Jenny B. Koenig and Chris G. Dulla

Abstract

Traumatic brain injury (TBI) is a significant cause of disability worldwide and can lead to post-traumatic epilepsy. Multiple molecular, cellular, and network pathologies occur following injury which may contribute to epileptogenesis.

Efforts to identify mechanisms of disease progression and biomarkers which predict clinical outcomes have focused heavily on metabolic changes. Advances in imaging approaches, combined with well-established biochemical methodologies, have revealed a complex landscape of metabolic changes that occur acutely after TBI and then evolve in the days to weeks after.

Based on this rich clinical and preclinical data, combined with the success of metabolic therapies like the ketogenic diet in treating epilepsy, interest has grown in determining whether manipulating metabolic activity following TBI may have therapeutic value to prevent post-traumatic epileptogenesis.

Here, we focus on changes in glucose utilization and glycolytic activity in the brain following TBI and during seizures. We review relevant literature and outline potential paths forward to utilize glycolytic inhibitors as a disease-modifying therapy for post-traumatic epilepsy.

Introduction

While accounting for only 2% of the body’s weight, the human brain accounts for 20% of its energy utilization (Rolfe and Brown, 1997). In pathological states, such as following a brain injury or during a seizure, the brain’s energy usage is significantly disrupted. In this review, we explore brain metabolism and glucose utilization as therapeutic targets to prevent the pathophysiological changes that may cause epileptogenesis following brain injury.

The brain requires energy in the form of ATP to power its cellular processes. The ability of the brain to conduct electrical signals between cells requires a steep electrochemical gradient to be maintained across cellular membranes. Reestablishing the electrochemical gradient following synaptic activity accounts for ≈80% of the total brain energy costs (Alle et al., 2009), with action potential (AP) firing contributing to a smaller, but important, component of energy utilization. Active transport of neurotransmitter into presynaptic vesicles, as well as vesicle recycling (Rangaraju et al., 2014), also requires ATP. Thus, the brain has many energetically intensive tasks in addition to basic cellular functions.

The obligatory fuel of the brain is glucose, which is transported across the blood-brain-barrier by GLUT1 transporters (see Figure ​Figure11). The systemic delivery of multiple kinds of fuel (glucose, fructose, glycolytic end-products lactate and pyruvate, and ketone body β-hydroxybutyrate) results in an increase in extracellular glucose in the brain (Beland-Millar et al., 2017), suggesting that it is the preferred fuel.

Only in extreme cases, such as during starvation or in the condition of the anticonvulsant ketogenic diet (discussed below), does the brain switch to utilizing a different energy source (ketone bodies) to generate ATP. In addition to glucose, the brain also requires oxygen. Both glucose and oxygen are delivered to the brain parenchyma through the vasculature, a process which is dynamically regulated by regionally- and temporally-specific changes in vasoconstriction and vasodilation. Thus, there is coupling between brain function and local vascular supply (first proposed by Roy and Sherrington in 1890), such that ultimately, energy delivery and utilization are activity-dependent processes.

Conclusion

The challenges to treating TBI and preventing PTE are extensive. Heterogeneous injury categories, diverse metabolic responses to injury, and difficulty in powering both preclinical and clinical trials for PTE all make this a daunting translational problem. Based on the compelling evidence of metabolic changes following TBI, strong neuroprotective and anticonvulsant properties of the ketogenic diet, and multiple small molecule approaches to manipulate metabolism, we believe that therapeutic opportunities exist to harness metabolic systems to reduce PTE.

There are many outstanding questions the field must address, including identifying the cellular sites and types of glucose utilization during normal brain function and after TBI, developing diagnostic tools that provide molecular insight into brain metabolism, understanding how metabolism contributes to post-traumatic epileptogenesis, and identifying biomarkers to stratify the patients at highest risk of developing PTE.

We would recommend prioritizing the development of a quantitative assay to assess changes in glucose utilization in the brain following TBI. This assay could serve as both a prognostic and a predictive biomarker for PTE. Increased glucose utilization may be prognostic as it is likely associated with uncontrolled network activity, consistent with epileptogenesis. It may also serve as a predictive biomarker of which patients would respond best to a metabolically targeted therapy, such as glycolytic inhibition.

This is especially important as hyper-glycolysis may only occur in a brief temporal window and/or in a subset of patients following TBI. Developing new tools and biomarkers is critical, as the clinical needs of TBI patients are clear: to improve long-term quality-of-life and to prevent devastating TBI complications such as PTE.

Continued collaboration between basic scientists and clinicians will allow for better understanding of post-TBI pathophysiology and will ultimately advance novel interventional strategies to help these patients.