Abstracts

Rationale: Following a traumatic brain injury (TBI), post-traumatic epilepsy (PTE) can occur. Chronic seizures can be a significant cause of disability for TBI patients, especially when the seizures are refractory to medical anticonvulsant therapies. The latent period between a TBI and the onset of PTE provides a therapeutic opportunity to prevent the pathophysiological changes that result in a seizure-prone network. Post-traumatic epileptogenesis may be explained by a loss of network inhibition resulting in an excitatory/inhibitory imbalance of the network. By targeting the metabolic changes following TBI, namely acute increases in glycolysis, we may be able to prevent the downstream loss of interneurons and resulting hyperexcitability. We hypothesize that 2-deoxyglucose (2DG), a glucose analog that competitively inhibits glycolysis at the rate-limiting enzyme hexokinase, is neuroprotective and anti-epileptogenic following TBI. Methods: To study TBI, we have used a model known as controlled cortical impact (CCI) in mice. Using this approach we found cortical network hyperexcitability, increased glutamatergic signaling, and a loss of parvalbumin and somatostatin interneurons following injury. We used 2DG in naﶥ or injured cortical tissue (either through treating acute cortical slices, or through systemic intraperitoneal injection daily for 7 days post-CCI). We use electrophysiological and immunohistochemical approaches to examine the excitability of the perilesional network, the presence of interneurons in the perilesional area, and the intrinsic excitability of different neuronal subtypes in the presence of 2DG. Results: In vitro 2DG application attenuated epileptiform activity in acute cortical slices from injured brains (% Epileptiform sweeps: CCI baseline = 90% versus CCI 2DG wash-on = 18%; n = 10 slices; Paired sample t-test, p = 2.2E-6). Additionally, in vivo 2DG treatment prevented the development of epileptiform activity following injury (% Epileptiform sweeps: CCI vehicle = 95% versus CCI 2DG = 13.3%; n = 10 slices, 9 slices; 2-sample t-test, p = 1.8E-9). In vivo 2DG treatment also attenuated the loss of parvalbumin-expressing interneurons in the region adjacent to the lesion site (PV+ cell density/10,000um^2: Sham vehicle = 2.498, Sham 2DG = 2.423, CCI vehicle = 1.341, CCI 2DG = 3.407; N = 4-6/group; ANOVA Sham vehicle vs. CCI vehicle, P = 0.03; CCI vehicle vs. CCI 2DG, P = 9.2E-5). Our preliminary data also suggests that glycolytic inhibition with 2DG has different effects on the excitability of different neuronal subtypes. Conclusions: Our research supports a role for glycolytic inhibition in the preservation of interneurons and the prevention of epileptogenesis following TBI. Additionally, it may reveal a novel cell type-specific coupling of metabolism to neuronal excitability. Funding: R01 NS076885 MSTP T32 GM008448 Tufts Pilot Award