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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.

Reiner A, Heldt SA, Presley CS, Guley NH, Elberger AJ, Deng Y, D'Surney L, Rogers JT, Ferrell J, Bu W, Del Mar N, Honig MG, Gurley SN, Moore BM - Int J Mol Sci (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. areiner@uthsc.edu.

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.

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Related in: MedlinePlus

Graph showing the effects of 50-psi blasts compared to 0-psi blasts in vehicle-treated mice on the tail suspension test of depression six to eight weeks after blast. Data are presented as cumulative immobility per consecutive one-minute block. Note that immobility, reflecting a depression-like behavior, is increased in 50-psi mice compared to 0-psi mice. By contrast, depression is normalized in 50-psi mice treated with SMM-189. The asterisk indicates a significant difference between vehicle-treated 50-psi and sham mice.
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ijms-16-00758-f010: Graph showing the effects of 50-psi blasts compared to 0-psi blasts in vehicle-treated mice on the tail suspension test of depression six to eight weeks after blast. Data are presented as cumulative immobility per consecutive one-minute block. Note that immobility, reflecting a depression-like behavior, is increased in 50-psi mice compared to 0-psi mice. By contrast, depression is normalized in 50-psi mice treated with SMM-189. The asterisk indicates a significant difference between vehicle-treated 50-psi and sham mice.

Mentions: We have previously shown that mild TBI in mice produced by our approach yields increased depression when assessed one-two months after blast by the tail suspension test [15]. This was also true in a cohort of vehicle-treated mice with 50-psi blast compared to vehicle-treated mice with sham blast (Figure 10), in which depression was significantly greater in vehicle-treated 50-psi mice than in vehicle-treated sham blast mice (p = 0.012). SMM-189 treatment alleviated the depression (immobility) observed in 50-psi mice, normalizing it to a level that was statistically indistinguishable from that in the sham-blasted vehicle-treated mice (p = 0.951), and significantly less than in the vehicle-treated 50-psi mice (p = 0.011).


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

Reiner A, Heldt SA, Presley CS, Guley NH, Elberger AJ, Deng Y, D'Surney L, Rogers JT, Ferrell J, Bu W, Del Mar N, Honig MG, Gurley SN, Moore BM - Int J Mol Sci (2014)

Graph showing the effects of 50-psi blasts compared to 0-psi blasts in vehicle-treated mice on the tail suspension test of depression six to eight weeks after blast. Data are presented as cumulative immobility per consecutive one-minute block. Note that immobility, reflecting a depression-like behavior, is increased in 50-psi mice compared to 0-psi mice. By contrast, depression is normalized in 50-psi mice treated with SMM-189. The asterisk indicates a significant difference between vehicle-treated 50-psi and sham mice.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307274&req=5

ijms-16-00758-f010: Graph showing the effects of 50-psi blasts compared to 0-psi blasts in vehicle-treated mice on the tail suspension test of depression six to eight weeks after blast. Data are presented as cumulative immobility per consecutive one-minute block. Note that immobility, reflecting a depression-like behavior, is increased in 50-psi mice compared to 0-psi mice. By contrast, depression is normalized in 50-psi mice treated with SMM-189. The asterisk indicates a significant difference between vehicle-treated 50-psi and sham mice.
Mentions: We have previously shown that mild TBI in mice produced by our approach yields increased depression when assessed one-two months after blast by the tail suspension test [15]. This was also true in a cohort of vehicle-treated mice with 50-psi blast compared to vehicle-treated mice with sham blast (Figure 10), in which depression was significantly greater in vehicle-treated 50-psi mice than in vehicle-treated sham blast mice (p = 0.012). SMM-189 treatment alleviated the depression (immobility) observed in 50-psi mice, normalizing it to a level that was statistically indistinguishable from that in the sham-blasted vehicle-treated mice (p = 0.951), and significantly less than in the vehicle-treated 50-psi mice (p = 0.011).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy and Neurobiology, the University of Tennessee Health Science Center, Memphis, TN 38163, USA. areiner@uthsc.edu.

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.

Show MeSH
Related in: MedlinePlus