Raloxifene Mitigates Emotional Deficits after Mild Traumatic Brain Injury in Mice

Abstract

Persons with mild traumatic brain injury (TBI) often exhibit persistent emotional impairments, particularly depression, fearfulness, and anxiety, that significantly diminish quality of life. Studying these mood disorders in animal models of mild TBI can help provide insight into possible therapies. We have previously reported that mice show increased depression, fearfulness, and anxiety, as well as visual and motor deficits, after focal cranial blast and that treatment with the cannabinoid type 2 receptor (CB2) inverse agonist, SMM-189, reduces these deficits. We have further shown that raloxifene, which is U.S. Food and Drug Administration approved as an estrogen receptor modulator to treat osteoporosis, but also possesses CB2 inverse agonism, yields a similar benefit for visual deficits in this model of TBI. Here, we have extended our studies of raloxifene benefit and show that it similarly reverses depression, fearfulness, and anxiety after focal cranial blast TBI in mice, using standard assays of these behavioral end-points. These results indicate the potential of raloxifene in the broad rescue of deficits after mild TBI and support phase 2 efficacy testing in human clinical trials.

Keywords

• anxiety
• CB2 inverse agonist therapy
• depression
• fear
• raloxifene
• traumatic brain injury