CB2 Receptor Therapy Using the FDA-Approved Drug Raloxifene to Mitigate Visual Deficits after Mild TBI and/or Ocular Trauma
Abstract
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 also shows noteworthy CB2 inverse agonism. In our studies, we tested the benefit of raloxifene for reducing visual deficits and visual system damage from TBI or closed-globe ocular injury in mice, when delivered daily after TBI produced using left side focal cranial blast or dorsal cranial impact injury or after single or repeat ocular blast injury (OBI). Visual system injury and its abatement with raloxifene was 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, and central visual structures. We found that raloxifene delivered by this regimen reduced the functional deficits and mitigated the underlying visual system pathology caused by focal cranial blast TBI, dorsal cranial impact TBI,single OBI or repeat OBI. The benefit could be obtained even with treatment delayed for 48 hours. Neurochemical analysis showed that the benefit stemmed from modulating microglia to a more beneficial M2 state, and thereby arresting the secondary injury caused by pro-inflammatory microglial M1 activation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2021
- Accession Number
- AD1124990
Entities
People
- Anton Reiner
Organizations
- University of Tennessee