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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

Cell surface receptor expression of the M2 phenotype-associated markers CD206 and CD209 24 h after treatment with interleukin-4 (IL-4), or IL-4 + SMM-189. Note that IL-4 significantly increased expression of both CD206 and CD209, and that SMM-189 significantly increased expression of CD206 beyond that seen with IL-4 alone. Asterisks above bars spanning the LPS-alone and LPS + SMM-189 columns indicate significance levels for the comparison between these two conditions. Asterisks above a column indicate a significant difference from the control condition. *p < 0.05, ****p < 0.0005.
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ijms-16-00758-f004: Cell surface receptor expression of the M2 phenotype-associated markers CD206 and CD209 24 h after treatment with interleukin-4 (IL-4), or IL-4 + SMM-189. Note that IL-4 significantly increased expression of both CD206 and CD209, and that SMM-189 significantly increased expression of CD206 beyond that seen with IL-4 alone. Asterisks above bars spanning the LPS-alone and LPS + SMM-189 columns indicate significance levels for the comparison between these two conditions. Asterisks above a column indicate a significant difference from the control condition. *p < 0.05, ****p < 0.0005.

Mentions: We next examined the effects of the M2-polarizing stimulant, interleukin-4 (IL-4), on the immortalized human microglia. Treatment with IL-4 led to significant increases in the levels of the M2 markers CD206 (p = 0.000006) and CD209 (p = 0.000002) on immortalized human microglia (Figure 4). Combined treatment with SMM-189 and IL-4 yielded a statistically significant increase in CD206 above that seen with IL-4 alone (p = 0.00734), while no significant change from IL-4 alone was seen in CD209 expression with SMM-189 co-treatment.


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)

Cell surface receptor expression of the M2 phenotype-associated markers CD206 and CD209 24 h after treatment with interleukin-4 (IL-4), or IL-4 + SMM-189. Note that IL-4 significantly increased expression of both CD206 and CD209, and that SMM-189 significantly increased expression of CD206 beyond that seen with IL-4 alone. Asterisks above bars spanning the LPS-alone and LPS + SMM-189 columns indicate significance levels for the comparison between these two conditions. Asterisks above a column indicate a significant difference from the control condition. *p < 0.05, ****p < 0.0005.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-00758-f004: Cell surface receptor expression of the M2 phenotype-associated markers CD206 and CD209 24 h after treatment with interleukin-4 (IL-4), or IL-4 + SMM-189. Note that IL-4 significantly increased expression of both CD206 and CD209, and that SMM-189 significantly increased expression of CD206 beyond that seen with IL-4 alone. Asterisks above bars spanning the LPS-alone and LPS + SMM-189 columns indicate significance levels for the comparison between these two conditions. Asterisks above a column indicate a significant difference from the control condition. *p < 0.05, ****p < 0.0005.
Mentions: We next examined the effects of the M2-polarizing stimulant, interleukin-4 (IL-4), on the immortalized human microglia. Treatment with IL-4 led to significant increases in the levels of the M2 markers CD206 (p = 0.000006) and CD209 (p = 0.000002) on immortalized human microglia (Figure 4). Combined treatment with SMM-189 and IL-4 yielded a statistically significant increase in CD206 above that seen with IL-4 alone (p = 0.00734), while no significant change from IL-4 alone was seen in CD209 expression with SMM-189 co-treatment.

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