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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

Effect of SMM-189 on chemokines secreted from primary human microglial cells in vitro. Primary human microglia were treated with LPS or vehicle, and then SMM-189 or vehicle was added one hour later. Chemokines were then assayed 17 h subsequently. LPS significantly increased chemokine levels above that in control for all chemokines shown. SMM-189 treatment alone had no significant effect on chemokine secretion, other than a slight reducing effect on MCP-1 (monocyte chemoattractant protein-1). SMM-189 significantly reduced the LPS-induced increase in the levels of IL-8 (interleukin-8), MCP-1, TARC (thymus and activation-regulated chemokine, also called chemokine ligand 17, or CCL17), MDC (macrophage-derived chemokine, also called C–C motif chemokine 22, or CCL22), and eotaxin-3 (also called C–C motif chemokine 11, or CCL11), and trended toward doing so for MIP-1β (macrophage inflammatory protein-1-beta, also called chemokine C–C motif ligand 3, or CCL3). Asterisks above bars spanning the LPS-alone and LPS + SMM-189 columns, or the SMM-189-alone and LPS + SMM-189 columns indicate significance levels for the comparison between these two conditions. Asterisks on a column indicate a significant difference from the control condition. *p < 0.05, **p < 0.005, ***p < 0.0005.
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ijms-16-00758-f002: Effect of SMM-189 on chemokines secreted from primary human microglial cells in vitro. Primary human microglia were treated with LPS or vehicle, and then SMM-189 or vehicle was added one hour later. Chemokines were then assayed 17 h subsequently. LPS significantly increased chemokine levels above that in control for all chemokines shown. SMM-189 treatment alone had no significant effect on chemokine secretion, other than a slight reducing effect on MCP-1 (monocyte chemoattractant protein-1). SMM-189 significantly reduced the LPS-induced increase in the levels of IL-8 (interleukin-8), MCP-1, TARC (thymus and activation-regulated chemokine, also called chemokine ligand 17, or CCL17), MDC (macrophage-derived chemokine, also called C–C motif chemokine 22, or CCL22), and eotaxin-3 (also called C–C motif chemokine 11, or CCL11), and trended toward doing so for MIP-1β (macrophage inflammatory protein-1-beta, also called chemokine C–C motif ligand 3, or CCL3). Asterisks above bars spanning the LPS-alone and LPS + SMM-189 columns, or the SMM-189-alone and LPS + SMM-189 columns indicate significance levels for the comparison between these two conditions. Asterisks on a column indicate a significant difference from the control condition. *p < 0.05, **p < 0.005, ***p < 0.0005.

Mentions: LPS treatment also significantly increased the levels of eight of the nine pro-inflammatory chemokines we tested: IL-8 (interleukin-8), MCP-1 (monocyte chemoattractant protein-1), MIP-1β (macrophage inflammatory protein-1-beta, also called chemokine C–C motif ligand 3, or CCL3), TARC (thymus and activation-regulated chemokine, also called chemokine ligand 17, or CCL17), MDC (macrophage-derived chemokine, also called C–C motif chemokine 22, or CCL22), eotaxin-3, eotaxin-1 (also called C–C motif chemokine 11, or CCL11), and IP-10 (interferon gamma-induced protein-10, also called C–X–C motif chemokine 10 or CXCL10) (Figure 2). LPS treatment did not significantly increase monocyte chemotactic protein-4 (MCP-4). Addition of SMM-189 significantly reduced the LPS-induced elevation in IL-8 (p = 0.000053), MCP-1 (p = 1.1331 × 10−10), MIP-1β (p = 0.0308), TARC (p = 0.0409), MDC (p = 0.000001), and eotaxin-3 (p = 4.3072 × 10−7). No effect of SMM-189 treatment on the LPS-induced elevation was seen for eotaxin-1 or IP-10. Thus, six of the eight chemokines with increased expression after LPS treatment, showed reduced expression when SMM-189 treatment was combined with LPS-treatment. By itself, SMM-189 did not affect expression of any of the chemokines examined, except for a slight depressing effect on TARC (p = 0.04744).


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)

Effect of SMM-189 on chemokines secreted from primary human microglial cells in vitro. Primary human microglia were treated with LPS or vehicle, and then SMM-189 or vehicle was added one hour later. Chemokines were then assayed 17 h subsequently. LPS significantly increased chemokine levels above that in control for all chemokines shown. SMM-189 treatment alone had no significant effect on chemokine secretion, other than a slight reducing effect on MCP-1 (monocyte chemoattractant protein-1). SMM-189 significantly reduced the LPS-induced increase in the levels of IL-8 (interleukin-8), MCP-1, TARC (thymus and activation-regulated chemokine, also called chemokine ligand 17, or CCL17), MDC (macrophage-derived chemokine, also called C–C motif chemokine 22, or CCL22), and eotaxin-3 (also called C–C motif chemokine 11, or CCL11), and trended toward doing so for MIP-1β (macrophage inflammatory protein-1-beta, also called chemokine C–C motif ligand 3, or CCL3). Asterisks above bars spanning the LPS-alone and LPS + SMM-189 columns, or the SMM-189-alone and LPS + SMM-189 columns indicate significance levels for the comparison between these two conditions. Asterisks on a column indicate a significant difference from the control condition. *p < 0.05, **p < 0.005, ***p < 0.0005.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-00758-f002: Effect of SMM-189 on chemokines secreted from primary human microglial cells in vitro. Primary human microglia were treated with LPS or vehicle, and then SMM-189 or vehicle was added one hour later. Chemokines were then assayed 17 h subsequently. LPS significantly increased chemokine levels above that in control for all chemokines shown. SMM-189 treatment alone had no significant effect on chemokine secretion, other than a slight reducing effect on MCP-1 (monocyte chemoattractant protein-1). SMM-189 significantly reduced the LPS-induced increase in the levels of IL-8 (interleukin-8), MCP-1, TARC (thymus and activation-regulated chemokine, also called chemokine ligand 17, or CCL17), MDC (macrophage-derived chemokine, also called C–C motif chemokine 22, or CCL22), and eotaxin-3 (also called C–C motif chemokine 11, or CCL11), and trended toward doing so for MIP-1β (macrophage inflammatory protein-1-beta, also called chemokine C–C motif ligand 3, or CCL3). Asterisks above bars spanning the LPS-alone and LPS + SMM-189 columns, or the SMM-189-alone and LPS + SMM-189 columns indicate significance levels for the comparison between these two conditions. Asterisks on a column indicate a significant difference from the control condition. *p < 0.05, **p < 0.005, ***p < 0.0005.
Mentions: LPS treatment also significantly increased the levels of eight of the nine pro-inflammatory chemokines we tested: IL-8 (interleukin-8), MCP-1 (monocyte chemoattractant protein-1), MIP-1β (macrophage inflammatory protein-1-beta, also called chemokine C–C motif ligand 3, or CCL3), TARC (thymus and activation-regulated chemokine, also called chemokine ligand 17, or CCL17), MDC (macrophage-derived chemokine, also called C–C motif chemokine 22, or CCL22), eotaxin-3, eotaxin-1 (also called C–C motif chemokine 11, or CCL11), and IP-10 (interferon gamma-induced protein-10, also called C–X–C motif chemokine 10 or CXCL10) (Figure 2). LPS treatment did not significantly increase monocyte chemotactic protein-4 (MCP-4). Addition of SMM-189 significantly reduced the LPS-induced elevation in IL-8 (p = 0.000053), MCP-1 (p = 1.1331 × 10−10), MIP-1β (p = 0.0308), TARC (p = 0.0409), MDC (p = 0.000001), and eotaxin-3 (p = 4.3072 × 10−7). No effect of SMM-189 treatment on the LPS-induced elevation was seen for eotaxin-1 or IP-10. Thus, six of the eight chemokines with increased expression after LPS treatment, showed reduced expression when SMM-189 treatment was combined with LPS-treatment. By itself, SMM-189 did not affect expression of any of the chemokines examined, except for a slight depressing effect on TARC (p = 0.04744).

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