Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189

• Published in: International journal of molecular sciences 2014-12, Vol.16 (1), p.758-787
• Main Authors: Reiner, Anton, Heldt, Scott A, Presley, Chaela S, Guley, Natalie H, Elberger, Andrea J, Deng, Yunping, D'Surney, Lauren, Rogers, Joshua T, Ferrell, Jessica, Bu, Wei, Del Mar, Nobel, Honig, Marcia G, Gurley, Steven N, Moore, 2nd, Bob M
• Format: Article
• Language: English
• Subjects: Animals; Benzophenones - pharmacology; Brain damage; Brain Injuries - complications; Brain Injuries - drug therapy; Brain Injuries - pathology; Calcium-Binding Proteins - metabolism; CB2 receptors; Cells, Cultured; Chemokines - metabolism; Cytokines - metabolism; deficits; Depression - etiology; Depression - pathology; Disease Models, Animal; Drug Inverse Agonism; Genotype & phenotype; Humans; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins - metabolism; microglia; Microglia - cytology; Microglia - drug effects; Microglia - metabolism; Motor Activity - drug effects; Neurons; Phenotype; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - metabolism; Rodents; TBI; therapy; Traumatic brain injury; Vision Disorders - etiology; Vision Disorders - pathology
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms16010758

We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50-60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI. In vitro analysis indicated that SMM-189 converted human microglia from the pro-inflammatory M1 phenotype to the pro-healing M2 phenotype. Studies in mice showed that daily administration of SMM-189 for two weeks beginning shortly after blast greatly reduced the motor, visual, and emotional deficits otherwise evident after 50-60 psi blasts, and prevented brain injury that may contribute to these deficits. Our results suggest that treatment with the CB2 inverse agonist SMM-189 after a mild TBI event can reduce its adverse consequences by beneficially modulating microglial activation. These findings recommend further evaluation of CB2 inverse agonists as a novel therapeutic approach for treating mild TBI.