Authors :
Canah McNeal, BS – East Tennessee State University
Raina Desai, na – East Tennessee State University
Presenting Author: Chad Frasier, PhD – East Tennessee State University
Rationale:
Traumatic brain injury (TBI) represents a major cause of death and permanent disability in the population. TBI patients also have increased risk to develop post-traumatic epilepsy (PTE). Following TBI, the occurrence of seizures has been categorized as immediate (< 24 h), early (days), or late (weeks). These immediate and early seizures are considered to reflect the severity of the injury itself, whereas the late seizures are thought to be the result from maturation of epileptogenic pathology. A full understanding of the pathways that lead to development and progression of PTE remain a priority. Mitochondrial function is known to be compromised following TBI and lead to increased tissue damage and cognitive deficits. The goal of this project is to determine if mitochondrial energetics are altered during the epileptogenic process following TBI in both the acute and chronic phases. Methods:
Mice underwent controlled cortical impact (CCI) injury (or sham) surgery to induce TBI and mitochondrial function was analyzed across acute timepoints. Mitochondria were isolated from both ipsilateral and contralateral cerebral and hippocampus. A subset of mice were implanted with EEG and ECG electrodes to measure seizure activity and cardiac rhythm. Telemetered mice were video-recorded and seizure detection was performed using custom written software to sync electrical recordings with video recordings for potential seizure events. Results:
Of the 12 TBI mice that underwent telemetry we have determined epileptic events were present 4 weeks post injury in 7 of them, while 0 of 4 sham mice showed evidence of epileptic events. Interestingly, we found that two of the mice consistently had evidence of AV block following events. Additionally, in mice telemetered with ECG leads we noticed large fluctuations in heart rate during seizure free periods, typically during the lights off period. Further analysis of seizure events suggest that they may be more likely to occur during the first 4 hours following lights off. Following 6 or 12 weeks of post injury recording tissue was saved for further analysis. We also looked at mitochondrial function acutely at 2-, 24-, and 72- hours post injury. This deficit is still observed at 7 days in the hippocampus. In general, mitochondria from mice subjected to TBI showed impaired respiration and decreased ADP phosphorylation. This result was particularly marked at 2h post injury. Respiration through both mitochondrial Complex I (glutamate/malate) and Complex II (succinate) tended to decrease, especially in the ipsilateral hemisphere, suggested that during the acute phase mitochondrial function is depressed. Conclusions:
Our results that following TBI, mitochoindrial function is depressed and that this affect may linger in the weeks following injury. This suggests that mitochondrial therapies may play a role in preventing progression of PTE. Our findings on ECG abnormalities mimics those we have observed in other models of epilepsy, suggesting that neuro-cardiac interactions in TBI warrant deeper investigation.
Funding: Congressionally Directed Medical Research (EP220018) to CRF.