Visual deficits in mice after mild traumatic brain injury produced by primary overpressure blast are alleviated by the novel CB2 drug SMM189

Abstract

Purpose: We have developed a blast model of closed-head mild traumatic brain injury (TBI) in mice using an air pressure wave. As in humans with mild TBI, visual impairments occur in our model. Because of the reported role of microglial activation in TBI and the evidence microglia can be modulated by their CB2 cannabinoid receptors, we tested the efficacy of the novel CB2 receptor modulator SMM189 for preventing these deficits.

Methods: Overpressure 50-psi or sham blasts were delivered to a 7.5 mm diameter area of the left side of the cranium in anesthetized 3-month old C57BL/6 male mice. SMM189 or vehicle were administered daily for two weeks beginning after blast. Optomotor testing assessed visual acuity and contrast sensitivity one month after blast, and histological methods assessed injury to retina (thin plastic sections). In vitro analysis had shown that SMM189 reduced production of pro-inflammatory cytokines by activated human microglia, and biochemical analysis had shown that SMM189 reduced cerebral expression of pro-inflammatory cytokines after 50-psi blasts in mice.

Results: Following 50-psi blasts, both eyes showed an acuity deficit, but more so the right eye. Both eyes also exhibited reduced contrast sensitivity, but in this case more so the left eye. The left retina was significantly thinner after blast (10-15% of sham), but the right retina was not. Thus, left eye functional deficits may stem from injury to left retina or optic nerve, while right eye functional deficits may stem from disruption of visual areas on the blasted left side of the brain. Daily administration of SMM189 for two weeks beginning shortly after blast greatly improved the visual outcome after 50-psi blasts. The left retina was no longer thinned, and left eye visual acuity and contrast sensitivity were notably improved, especially contrast sensitivity. Similarly, the right eye visual acuity and contrast sensitivity deficits were greatly reduced, with contrast sensitivity normalized.

Conclusions: Our mouse model recapitulates central visual system injury and visual abnormalities that occur after mild TBI in humans. Our results suggest that treatment with the novel CB2 modulator SMM189 during the two-week window just after a mild TBI event can greatly reduce the adverse visual consequence of the concussive event, apparently by beneficially modulating microglial activation.

Keywords: 742 trauma • 637 pathology: experimental • 615 neuroprotection