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Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189.
Int J Mol Sci 2014; 16(1):758-87IJ

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+Show Affiliations

Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. areiner@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. sheldt@uthsc.edu.Department of Pharmaceutical Sciences, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. cpresle4@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. nhart2@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. aelberge@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. ydeng@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. ldsurney@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. jroger45@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. jferre13@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. wbu1@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. ndelmar@uthsc.edu.Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. mhonig@uthsc.edu.Department of Pharmaceutical Sciences, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. sngurley@comcast.net.Department of Pharmaceutical Sciences, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. bmoore@uthsc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25561230

Citation

Reiner, Anton, et al. "Motor, Visual and Emotional Deficits in Mice After Closed-head Mild Traumatic Brain Injury Are Alleviated By the Novel CB2 Inverse Agonist SMM-189." International Journal of Molecular Sciences, vol. 16, no. 1, 2014, pp. 758-87.
Reiner A, Heldt SA, Presley CS, et al. Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189. Int J Mol Sci. 2014;16(1):758-87.
Reiner, A., Heldt, S. A., Presley, C. S., Guley, N. H., Elberger, A. J., Deng, Y., ... Moore, B. M. (2014). Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189. International Journal of Molecular Sciences, 16(1), pp. 758-87. doi:10.3390/ijms16010758.
Reiner A, et al. Motor, Visual and Emotional Deficits in Mice After Closed-head Mild Traumatic Brain Injury Are Alleviated By the Novel CB2 Inverse Agonist SMM-189. Int J Mol Sci. 2014 Dec 31;16(1):758-87. PubMed PMID: 25561230.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189. AU - Reiner,Anton, AU - Heldt,Scott A, AU - Presley,Chaela S, AU - Guley,Natalie H, AU - Elberger,Andrea J, AU - Deng,Yunping, AU - D'Surney,Lauren, AU - Rogers,Joshua T, AU - Ferrell,Jessica, AU - Bu,Wei, AU - Del Mar,Nobel, AU - Honig,Marcia G, AU - Gurley,Steven N, AU - Moore,Bob M,2nd Y1 - 2014/12/31/ PY - 2014/10/29/received PY - 2014/12/22/accepted PY - 2015/1/7/entrez PY - 2015/1/7/pubmed PY - 2015/9/15/medline SP - 758 EP - 87 JF - International journal of molecular sciences JO - Int J Mol Sci VL - 16 IS - 1 N2 - 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. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/25561230/Motor_visual_and_emotional_deficits_in_mice_after_closed_head_mild_traumatic_brain_injury_are_alleviated_by_the_novel_CB2_inverse_agonist_SMM_189_ L2 - http://www.mdpi.com/resolver?pii=ijms16010758 DB - PRIME DP - Unbound Medicine ER -