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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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Comparison of the effects of 0-psi blast in vehicle-treated mice, 50-psi blast in vehicle-treated mice, and 50-psi blast in SMM-189-treated mice on rotarod motor performance (A); maximum speed in open field (B); and turn radius in open field (C). Note that motor performance is impaired for vehicle-treated 50-psi mice on all three tests, and restored by SMM-189. Red asterisks for a given time point indicate a significant difference between vehicle-treated 50-psi mice and vehicle-treated 0-psi mice for that time point, while a red asterisk to the right indicates a significant overall difference between vehicle-treated 50-psi mice and vehicle-treated 0-psi mice. At no time point did SMM-189-treated 50-psi mice differ from vehicle-treated 0-psi mice, nor did they show an overall difference. A green # indicates a significant difference between SMM-189 and vehicle-treated 50-psi mice.
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ijms-16-00758-f007: Comparison of the effects of 0-psi blast in vehicle-treated mice, 50-psi blast in vehicle-treated mice, and 50-psi blast in SMM-189-treated mice on rotarod motor performance (A); maximum speed in open field (B); and turn radius in open field (C). Note that motor performance is impaired for vehicle-treated 50-psi mice on all three tests, and restored by SMM-189. Red asterisks for a given time point indicate a significant difference between vehicle-treated 50-psi mice and vehicle-treated 0-psi mice for that time point, while a red asterisk to the right indicates a significant overall difference between vehicle-treated 50-psi mice and vehicle-treated 0-psi mice. At no time point did SMM-189-treated 50-psi mice differ from vehicle-treated 0-psi mice, nor did they show an overall difference. A green # indicates a significant difference between SMM-189 and vehicle-treated 50-psi mice.

Mentions: We used our blast model to characterize the motor deficits produced by 50-psi blasts in three-month old male C57BL/6 mice, and their alleviation by SMM-189 treatment for the two weeks commencing just after blast. A significant overall rotarod deficit across test sessions was observed by ANOVA in 50-psi blast mice receiving vehicle (Figure 7), compared to 0-psi mice receiving vehicle (p = 0.013), but not in SMM-189-treated 50-psi mice (p = 0.366). Deficits were also seen after 50-psi blast in maximum speed and turn radius in open field (Figure 7). For example, vehicle-treated sham-blasted mice showed significant improvement in maximum speed compared to pre-blast by the first week post blast (p = 0.0056), but the vehicle-treated 50-psi mice did not (p = 0.5279). By contrast, SMM-189-treated 50-psi mice (Figure 7) did show significant improvement in maximum speed compared to pre-blast by the first week after blast (p = 0.0355). Moreover, a significant overall deficit in maximum speed was observed across test sessions by ANOVA in 50-psi blast mice receiving vehicle (Figure 7), compared to 0-psi mice receiving vehicle (p = 0.046), but not in SMM-189-treated 50-psi mice (p = 0.454). Similarly, post blast mean turn radius was significantly less in vehicle-treated 50-psi mice than in vehicle-treated 0-psi mice (p = 0.028) across test sessions by ANOVA, but SMM-189-treated 50-psi mice did not differ from sham mice (p = 0.944), but did differ significantly from vehicle-treated 50-psi mice (p = 0.038).


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)

Comparison of the effects of 0-psi blast in vehicle-treated mice, 50-psi blast in vehicle-treated mice, and 50-psi blast in SMM-189-treated mice on rotarod motor performance (A); maximum speed in open field (B); and turn radius in open field (C). Note that motor performance is impaired for vehicle-treated 50-psi mice on all three tests, and restored by SMM-189. Red asterisks for a given time point indicate a significant difference between vehicle-treated 50-psi mice and vehicle-treated 0-psi mice for that time point, while a red asterisk to the right indicates a significant overall difference between vehicle-treated 50-psi mice and vehicle-treated 0-psi mice. At no time point did SMM-189-treated 50-psi mice differ from vehicle-treated 0-psi mice, nor did they show an overall difference. A green # indicates a significant difference between SMM-189 and vehicle-treated 50-psi mice.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-00758-f007: Comparison of the effects of 0-psi blast in vehicle-treated mice, 50-psi blast in vehicle-treated mice, and 50-psi blast in SMM-189-treated mice on rotarod motor performance (A); maximum speed in open field (B); and turn radius in open field (C). Note that motor performance is impaired for vehicle-treated 50-psi mice on all three tests, and restored by SMM-189. Red asterisks for a given time point indicate a significant difference between vehicle-treated 50-psi mice and vehicle-treated 0-psi mice for that time point, while a red asterisk to the right indicates a significant overall difference between vehicle-treated 50-psi mice and vehicle-treated 0-psi mice. At no time point did SMM-189-treated 50-psi mice differ from vehicle-treated 0-psi mice, nor did they show an overall difference. A green # indicates a significant difference between SMM-189 and vehicle-treated 50-psi mice.
Mentions: We used our blast model to characterize the motor deficits produced by 50-psi blasts in three-month old male C57BL/6 mice, and their alleviation by SMM-189 treatment for the two weeks commencing just after blast. A significant overall rotarod deficit across test sessions was observed by ANOVA in 50-psi blast mice receiving vehicle (Figure 7), compared to 0-psi mice receiving vehicle (p = 0.013), but not in SMM-189-treated 50-psi mice (p = 0.366). Deficits were also seen after 50-psi blast in maximum speed and turn radius in open field (Figure 7). For example, vehicle-treated sham-blasted mice showed significant improvement in maximum speed compared to pre-blast by the first week post blast (p = 0.0056), but the vehicle-treated 50-psi mice did not (p = 0.5279). By contrast, SMM-189-treated 50-psi mice (Figure 7) did show significant improvement in maximum speed compared to pre-blast by the first week after blast (p = 0.0355). Moreover, a significant overall deficit in maximum speed was observed across test sessions by ANOVA in 50-psi blast mice receiving vehicle (Figure 7), compared to 0-psi mice receiving vehicle (p = 0.046), but not in SMM-189-treated 50-psi mice (p = 0.454). Similarly, post blast mean turn radius was significantly less in vehicle-treated 50-psi mice than in vehicle-treated 0-psi mice (p = 0.028) across test sessions by ANOVA, but SMM-189-treated 50-psi mice did not differ from sham mice (p = 0.944), but did differ significantly from vehicle-treated 50-psi mice (p = 0.038).

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