title: Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189.
abstract: 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.
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. areiner@uthsc.edu.
authors.forename: Anton
authors.initials: A
authors.lastname: Reiner
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. sheldt@uthsc.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Heldt
authors.affiliation: Department of Pharmaceutical Sciences, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. cpresle4@uthsc.edu.
authors.forename: Chaela S
authors.initials: CS
authors.lastname: Presley
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. nhart2@uthsc.edu.
authors.forename: Natalie H
authors.initials: NH
authors.lastname: Guley
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. aelberge@uthsc.edu.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Elberger
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. ydeng@uthsc.edu.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. ldsurney@uthsc.edu.
authors.forename: Lauren
authors.initials: L
authors.lastname: D'Surney
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. jroger45@uthsc.edu.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Rogers
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. jferre13@uthsc.edu.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ferrell
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. wbu1@uthsc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Bu
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. ndelmar@uthsc.edu.
authors.forename: Nobel
authors.initials: N
authors.lastname: Del Mar
authors.affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. mhonig@uthsc.edu.
authors.forename: Marcia G
authors.initials: MG
authors.lastname: Honig
authors.affiliation: Department of Pharmaceutical Sciences, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. sngurley@comcast.net.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Gurley
authors.affiliation: Department of Pharmaceutical Sciences, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. bmoore@uthsc.edu.
authors.forename: Bob M
authors.initials: BM
authors.lastname: Moore
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D054314:Drug Inverse Agonism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D010641:Phenotype; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D014786:Vision Disorders / Q000209:etiology / Q000473:pathology
chemical_list: C491049:Aif1 protein, mouse; D001577:Benzophenones; D002135:Calcium-Binding Proteins; D018925:Chemokines; D016207:Cytokines; D008840:Microfilament Proteins; D043885:Receptor, Cannabinoid, CB2; C000601178:SMM-189