Preventing PTE Using Inhibitors of Glycolysis: Cell Type-Specific Approaches to Maintaining Inhibitory Cortical Networks
Abstract
Traumatic brain injuries (TBI) are the leading cause of death and disabilities in children and the aged. Post-traumatic epilepsy (PTE) often occurs following TBI, which significantly impairs rehabilitation and impacts patient quality of life. There are limited therapeutic options for TBI, none of which have proven to be efficacious in improving neurological outcomes across diverse groups of TBI patients. Therefore, developing new therapeutic tools based on mechanistic rationale is critical to developing treatments to improve patient outcome following TBI. Recently, we reported that the controlled cortical impact (CCI) model of TBI resulted in many changes consistent with neurological dysfunction and seizures. Specifically, we found a significant loss of parvalbumin-positive inhibitory interneurons in the cortex. Parvalbumin-positive interneurons provide a bulk of cortical inhibition, which constrains neuronal activity. When parvalbumin-positive interneurons were lost following TBI, uncontrolled glutamatergic activity was seen along with increased excitation. These changes are consistent with increased excitation and decreased inhibition following TBI, both of which would increase the likelihood of brain dysfunction, neurological deficits, and seizures. Based on these findings, we set out to develop new approaches to preserve interneurons following TBI. Based on published data showing areas of increased glycolytic activity in the brain following TBI (indicative of elevated energy usage) and known linkages between glycolysis and neuronal activity, we set out to determine if inhibiting glycolysis following TBI would attenuate loss of parvalbumin interneurons. This concept is consistent with the longstanding use of the ketogenic diet, which is powerfully anti-convulsant as well as neuroprotective, and decreases glycolysis in the brain. We hypothesized that TBI leads to glycolysis-dependent increases in excitatory neuron activity. This would lead to hyperactivation of inhibitory interneurons and their subsequent cell death due to overexcitation. We propose to interrupt glycolysis to attenuate excitatory neuronal activity following TBI. Using 2-deoxyglucose (2DG), an inhibitor of hexokinase (the rate-limiting enzyme of glycolysis), we have begun to test this hypothesis. Our preliminary data suggest that 2DG can acutely attenuate cortical hyperexcitability in brain slices 2-4 weeks following TBI and that in vivo treatment with 2DG following TBI attenuates both network hyperexcitability and parvalbumin-positive interneuron loss. Our preliminary data also suggest that 2DG attenuates excitatory, but not inhibitory, neuron excitability. Here we propose to further these studies by demonstrating that 2DG mediates its effect via inhibition of glycolysis, reduces parvalbumin-positive interneuron cell death, and reduces changes in synaptic communication in the cortex following injury. Additionally, we will directly test if treatment with 2DG following TBI reduces later seizures. As part of these studies, we propose that inhibition of glycolysis attenuates excitatory, but not inhibitory, cell excitability. This would be an extremely novel finding and would provide a mechanistic understanding of how glycolytic inhibition inhibits neuronal activity. Furthermore, we aim to determine whether there is differential expression of glycolytic and related proteins in excitatory neurons vs. inhibitory interneurons. This aspect of the proposal is both high-risk and high-reward. Our studies will determine if 2DG is able to preserve interneurons following TBI, will begin to establish 2DG’s mechanism of action, and will potentially demonstrate a novel form of cell type-specific coupling of metabolic and electrical activity. Based on these studies, we will be better able to manipulate neuronal excitability with cell type-specific metabolic disruption and design therapeutic strategies to reduce PTE following TBI. In summary, these
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710531
Entities
People
- Chris G Dulla
Organizations
- Tufts University School of Medicine
- United States Army