Effects of Mild Blast Traumatic Brain Injury on Cerebral Vascular Function, Histopathological and Behavioral Outcomes in Rats
Impact traumatic brain injury (i.e. non-blast TBI) is often associated with reduced cerebral perfusion and impaired cerebrovascular function due, in part, to the generation of reactive oxygen (ROS) and reactive nitrogen species (RNS) (e.g. peroxynitrite, ONOO‾). Although blast TBI (bTBI) also reduces cerebral perfusion, less is known about other cerebral vascular effects of bTBI. To determine the effects of mild bTBI on cerebral vascular function with and without the administration of the ONOO‾ scavenger penicillamine methyl ester (PenME), we subjected isoflurane-anesthetized rats to sham bTBI, bTBI alone or bTBI + PenME in five experiments using a compressed air shock tube. Dilator responses to reduced intravascular pressure were assessed in isolated middle cerebral arterial (MCA) segments collected 30 or 60 minutes post-blast in one study. Mean arterial blood pressure (MAP), relative cerebral perfusion (laser Doppler flowmetry, LDF) and cerebral vascular resistance (CVR) were monitored for two hours post-blast in a second study. To assess the effects of bTBI on neuronal injury, numbers of FluoroJade-C (FJC) positive cells were counted in brain sections obtained 24 or 48 hours post-bTBI in a third study. Vestibulomotor (beam balance/beam walk) and working memory (Morris water maze, MWM) function were evaluated up to two weeks post-bTBI in the fourth study. Lastly, MAP, relative cerebral perfusion and CVR were monitored in rats treated with PenME or a vehicle five minutes after mild bTBI. Shock wave overpressures of 20.9 psi ± 1.14 (138 kPa ± 7.9) produced mild bTBI, based on righting reflex (RR) suppression for 5.2 minutes (Sham bTBI = 4.3 minutes). Mild bTBI resulted in reductions in cerebral perfusion and MCA dilator responses, increases in CVR and numbers of FJC-positive cells and significantly impaired working memory. Treatment with PenME resulted in significant reductions in CVR and a trend towards increased cerebral perfusion. These results that bTBI increased CVR, reduced cerebral perfusion and impaired cerebral dilator responses to reduced intravascular pressure indicate that mild bTBI is associated with significant cerebral arterial dysfunction. Furthermore, the significant reduction of CVR after treatment with PenME indicated that blast-induced cerebral vascular dysfunction may be due, in part, to the generation of ONOO‾.