CB2 Receptor Therapy Using the FDA-Approved Drug Raloxifene to Mitigate Visual Deficits after Mild TBI and/or Ocular Trauma
Abstract
Head trauma from a blast, blow, or collision is an extremely common injury among military personnel deployed in recent wars. Although the vast majority survives these injuries, traumatic brain injury (TBI) from the blast event, even when mild, and/or non-rupturing ocular trauma can harm the visual system and impair visual functioning. The symptoms observed often include reductions in visual acuity and contrast sensitivity, retinal thinning, optic nerve neuropathy, and painful light sensitivity. The visual deficits can impair military performance, prevent redeployment, and greatly mar post-military functioning. The impaired military functioning adversely affects military capacity and preparedness. The diminished job-related functioning and dependence resulting from TBI or ocular trauma place particularly great financial and personal stress on the warriors themselves, and on their families, after military their service. Visual impairment from head trauma has become endemic among present and past warriors, and no treatments are known that can prevent or reduce their adverse consequences for visual functioning. The studies we propose here offer the promise of a therapy that can soon be used to curtail visual deficits after head trauma in warriors. In a mouse model in which we create mild TBI by a focal high-pressure air blast to the cranium (with skin and skull intact), we have identified a drug approach that reduces the visual deficits after TBI. The drug we have found successful is called SMM189, and it targets a type of cannabinoid (marijuana) receptor termed the CB2 type. It is important to note that this receptor type does not mediate the psychotropic effects of marijuana (cannabis) on brain, and thus our therapy does not involve a substance that has unwanted addictive psychotropic side effects. Rather, our drug appears to interact with the immune system of the brain to reduce the brain and visual system injury after trauma. Although this drug is not approved for human use, another drug, called raloxifene, that is Food and Drug Administration-approved was recently found to act on CB2 receptors in the same way as SMM189. We thus propose to test the effectiveness of raloxifene for reducing retinal and optic nerve damage and visual deficits stemming from mild TBI and non-rupturing ocular injury in mice. Our studies will involve three goals. As our first goal, we will determine if raloxifene reduces the visual deficits and pathology in our focal blast model of mild TBI in mice, when delivered daily after the TBI event. As our second goal, we will determine if raloxifene when delivered daily after the TBI event reduces the visual deficits and pathology in model in which mild TBI is created by a focal blow to the cranium. As our third goal, we will determine if raloxifene reduces the visual deficits and pathology in a blast model of non-rupturing ocular injury, when delivered daily after the event. As part of these studies, we will determine how much and for how long raloxifene should be administered to produce the greatest benefit. The studies proposed here may identify a drug (raloxifene) that reduces visual deficits after TBI and non-rupturing ocular injury in warriors. Given an encouraging outcome from these studies, raloxifene could next be tested in phase 2 human clinical trials to determine its effectiveness in treating visual injury after brain and/or eye trauma. If demonstrated as effective in phase 2 and eventually phase 3 human trials, raloxifene could be adopted as a standard treatment after trauma by medical personnel to prevent or reduce the harmful consequences of the trauma for vision and increase return to service and mitigate debilitating and costly long-term visual deficits. If all proceeds well, we expect that within 5 years from the successful completion of these studies, raloxifene could be used as therapy for visual deficits after TBI and closed-globe ocular injury. As there is no
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610076
Entities
People
- Anton Reiner
Organizations
- United States Army
- University of Tennessee Health Science Center