Raloxifene, a cannabinoid type-2 receptor inverse agonist, mitigates visual deficits and pathology and modulates microglia after ocular blast.

Visual deficits after ocular blast injury (OBI) are common, but pharmacological approaches to improve long-term outcomes have not been identified. Blast forces frequently damage the retina and optic nerves, and work on experimental animals has shown the pro-inflammatory actions of microglia can further exacerbate such injuries. Cannabinoid type-2 receptor (CB2) inverse agonists specifically target activated microglia, biasing them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state.

Raloxifene Modulates Microglia and Rescues Visual Deficits and Pathology After Impact Traumatic Brain Injury.

Mild traumatic brain injury (TBI) involves widespread axonal injury and activation of microglia, which initiates secondary processes that worsen the TBI outcome. The upregulation of cannabinoid type-2 receptors (CB2) when microglia become activated allows CB2-binding drugs to selectively target microglia. CB2 inverse agonists modulate activated microglia by shifting them away from the harmful pro-inflammatory M1 state toward the helpful reparative M2 state and thus can stem secondary injury cascades.

Amelioration of visual deficits and visual system pathology after mild TBI via the cannabinoid Type-2 receptor inverse agonism of raloxifene.

Visual deficits after traumatic brain injury (TBI) are common, but interventions that limit the post-trauma impairments have not been identified. We have found that treatment with the cannabinoid type-2 receptor (CB2) inverse agonist SMM-189 for 2 weeks after closed-head blast TBI greatly attenuates the visual deficits and retinal pathology this otherwise produces in mice, by modulating the deleterious role of microglia in the injury process after trauma. SMM-189, however, has not yet been approved for human use.

Amelioration of visual deficits and visual system pathology after mild TBI with the cannabinoid type-2 receptor inverse agonist SMM-189.

Mild TBI is often accompanied by visual system dysfunction and injury, which is at least partly caused by microglial neuroinflammatory processes initiated by the injury. Using our focal cranial blast mouse model of closed-skull mild TBI, we evaluated the ability of the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189, which biases microglia from the harmful M1 state to the beneficial M2 state, to mitigate visual system dysfunction and injury after TBI. Male C57BL/6 or Thy1-EYFP reporter mice received a closed-head blast of either 0-psi (sham) or 50-psi to the left side of the cranium.