S. Ogle1,2,3, L. M. Law1,2, P. D. Adelson1,2, J. Lifshitz1,2, T. C. Thomas1,2,3, S. B. Johnson1,3 1University Of Arizona,College Of Medicine, Child Health,Phoenix, AZ, USA 2BARROW Neurological Institute @ Phoenix Children’s Hospital,Translational Neurotrauma Research Program,Phoenix, AZ, USA 3Banner University Medical Center- Phoenix,Surgery,Phoenix, AZ, USA
Introduction: Chronic neurological dysfunction occurs in 15-20% of mild diffuse traumatic brain injury (TBI) patients have been highlighted in athletic and military populations. Similar to light and sound hypersensitivity after TBI in humans, rodents develop a late-onset, gain-of-function hypersensitivity to whisker stimulation at 28 days following experimental diffuse TBI. Change in sensory sensitivity manifests, in part, as a consequence of injury-induced maladaptive circuit reorganization. Mechanistically, maladaptive circuit reorganization after TBI is not fully understood; however, bursts of new synapse formation can occur via astrocyte secreted thrombospondin-1 (TSP-1) interactions with α2δ-1-subunit on voltage-gated calcium channels. Preliminary data demonstrate an injury-induced increase in TSP-1 in the somatosensory relays of the whisker circuit. In seizure and focal injury models, gabapentin (GBP) inhibits TSP-1/ α2δ-1 interactions, inhibiting synaptogenesis and consequently attenuating morbidity, however this has never been addressed in diffuse TBI. Thus, we hypothesize that gabapentin therapy after experimental diffuse TBI will attenuate whisker hypersensitivity in a rodent model of diffuse TBI.
Methods: Adult male Sprague-Dawley rats underwent diffuse TBI by moderate midline fluid percussion brain injury. Vehicle (0.9% normal saline) or GBP (100mg/kg/day, dissolved in 0.9% normal saline) was delivered continuously via subcutaneous osmotic pumps. Animals were randomly assigned one of the following groups (n=12-15/group): naïve+vehicle, naïve+GBP, injured+vehicle, injured+GBP. Pumps were placed immediately after the injury procedure and continued for a total of 14 days post- injury (DPI). Whisker sensitivity was quantified via the whisker nuisance task (WNT) at 28 DPI. A Kruskal-Wallis non-parametric test followed by a Dunn’s multiple comparison post-test was used for statistical analysis of WNT scores.
Results:At 28 DPI, there were no significant differences between naïve+vehicle and naïve+GBP animals (p=0.95), thus these animals were combined for analysis. WNT scores significantly changed in response to injury (KW=11.36), where WNT scores in injured+vehicle rats were significantly greater than naïve rats (p<0.01), as previously reported. WNT scores of injured+GBP rats were not statistically different from naïve animals, albeit they were not significantly lower than the WNT scores of injured+vehicle.
Conclusion:These preliminary data indicate that treatment with gabapentin in the peri-traumatic period results in WNT scores statistically similar to naive animals, suggesting a prophylactic intervention for sensory hypersensitivity. Future studies necessitate a dose response evaluation and confirmation of TSP-1/ α2δ-1 mechanisms of action. Acute bolus gabapentin administration may be a FDA-approved approach to mitigate chronic neurological dysfunction after TBI.