CB2 Receptor Therapy Using the FDA-Approved Drug Raloxifene to Mitigate Visual Deficits after Mild TBI and/or Ocular Trauma

Visual deficits after traumatic brain injury TBI or after non-rupturing ocular trauma are highly common in the military, but interventions that limit the post-trauma visual impairments have not been identified. We have found that treatment with a CB2 cannabinoid receptor inverse agonist for 2 weeks after closed-head blast TBI greatly attenuates the visual deficits and retinal pathology produced by mild traumatic brain injury in mice, apparently by modulating the otherwise deleterious role of microglia in the injury process after trauma. The drug we have used SMM189, however, has not yet been approved for human use. Raloxifene is an FDA approved estrogen receptor drug that is used to treat osteoporosis, but was recently found to show noteworthy CB2 inverse agonism. In the current studies, we are testing the benefit of raloxifene for reducing visual deficits and retinal and optic nerve damage from mild TBI and closed-globe ocular injury in mice. In the second year of the project, we have been determining if raloxifene reduces visual deficits and pathology, when delivered daily after TBI produced using our focal cranial blast injury or an impact injury model. Visual system injury and its abatement with raloxifene is being assessed by functional testing visual acuity, contrast sensitivity, the scotopic electroretinogram, pupil light response, and light aversion and morphological analysis of retina, optic nerve, optic tract, central visual structures and oculomotor nerves. We have found that raloxifene for both TBI models does reduce visual deficits, and for blast we have completed studies showing it abates light aversion, and mitigates the underlying visual system pathology and inflammatory response, seemingly by modulating microglia to a more beneficial state.