Comparison of blood-brain barrier permeability changes in gyrencephalic (ferret & non-human primate) and lissencephalic (rat) models following blast overpressure exposures

Abstract

Blast wave (BW)-associated brain injury criteria to assess risk of Warfighters are currently inadequate due to lack a suitable animal model that does not represent human blast injury pathology. We hypothesize that animal models with brain structures more closely resemble the human brain (e.g. gyrencephalic models) could better translate to recreate and identify human blast pathology. As a one-of-a kind evaluation, this study compared the blood brain barrier (BBB) integrity, gliovascular changes and neuroinflammation in lissencephalic (rats) and gyrencephalic (ferrets) models exposed to blast waves at varying overpressures (10, 15 and 20 psig) with a validation study in non-human primates exposed to a single BW at 20 psig. BBB disruption was measured by Evans blue extravasation. The extent of gliosis in brain sections was measured by immunofluorescence analysis of glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba-1), and neurodegeneration was determined by silver staining. Ferrets exposed to BW had a statistically significant increase in extravasation of Evans blue in different brain regions while a no such changes were observed in the rat model. Blast also induced a significant reactive astrogliosis and microglial activation in ferrets. NHPs exposed to a single BW at 20 psig showed a significant increase in EB extravasation in only thalamus. These results suggest that gyrencephalic brain structures may be more vulnerable to vascular disruption compared to lissencephalic models and these models may have better translatability to human blast injuries and potentially better suited to identify injury thresholds.