Limits...
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.

Show MeSH

Related in: MedlinePlus

Double immunostaining for the activated microglial marker OX6 (major histocompatibility complex (MHC) class II antigen, red) and phosphorylated-CREB (the cyclic adenosine monophosphate (cAMP) response element binding protein, green) in the right optic tract of a 60-psi blasted mouse treated with SMM-189 (C,F,I) three days after blast compared to a sham blasted mouse not treated with SMM-189 (A,D,G) seven days after sham, and a 60-psi mouse not treated with SMM-189 (B,E,H) five days after blast. The first row (A–C) shows merged images, while the second (D–F) and third (G–I) rows show the red and green channels, respectively. Note that OX-6 immunostaining is more intense and found in more microglia after 60-psi blast (red arrows) compared to sham blast regardless of SMM-189 treatment (second and third columns). Phosphorylated-CREB, however, is evident in microglial nuclei (green arrows) only after SMM-189 treatment (last column).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4307274&req=5

ijms-16-00758-f006: Double immunostaining for the activated microglial marker OX6 (major histocompatibility complex (MHC) class II antigen, red) and phosphorylated-CREB (the cyclic adenosine monophosphate (cAMP) response element binding protein, green) in the right optic tract of a 60-psi blasted mouse treated with SMM-189 (C,F,I) three days after blast compared to a sham blasted mouse not treated with SMM-189 (A,D,G) seven days after sham, and a 60-psi mouse not treated with SMM-189 (B,E,H) five days after blast. The first row (A–C) shows merged images, while the second (D–F) and third (G–I) rows show the red and green channels, respectively. Note that OX-6 immunostaining is more intense and found in more microglia after 60-psi blast (red arrows) compared to sham blast regardless of SMM-189 treatment (second and third columns). Phosphorylated-CREB, however, is evident in microglial nuclei (green arrows) only after SMM-189 treatment (last column).

Mentions: We have found that axonal pathology is evident in the left optic nerve and right optic tract shortly after left cranial 50–60 psi blasts [16] and is accompanied by microglial activation, as revealed by the change in microglial morphology (shorter processes, larger cell bodies, rod-like appearance), and increased intensity of ionized calcium-binding adapter molecule-1 (IBA1) immunolabeling (Figure 5A,B). The activation was also seen in right optic tract target areas, such as the right dorsal lateral geniculate nucleus (Figure 5C,D) and the upper layers of the right superior colliculus (Figure 5F). In the case of the right optic tract and its target areas, the microglial activation was evident by the third day after blast, more prominent at one week, and no longer prominent by two to eight weeks. We also observed microglial activation in other brain regions where we detected axonal pathology, for example, in the medial lemniscus (Figure 5E), lateral lemniscus, cerebellar peduncles and deep cerebellar white matter (Figure 5G), and pyramidal tract (Figure 5H). Heightened immunolabeling with OX6 confirms microglia are activated after 50–60 psi blast (Figure 6A,B,D,E). Axonal pathology in the right optic nerve was, by contrast, minimal, although some axonal pathology was seen in the left optic tract (possibly representing injured uncrossed left optic nerve axons).


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)

Double immunostaining for the activated microglial marker OX6 (major histocompatibility complex (MHC) class II antigen, red) and phosphorylated-CREB (the cyclic adenosine monophosphate (cAMP) response element binding protein, green) in the right optic tract of a 60-psi blasted mouse treated with SMM-189 (C,F,I) three days after blast compared to a sham blasted mouse not treated with SMM-189 (A,D,G) seven days after sham, and a 60-psi mouse not treated with SMM-189 (B,E,H) five days after blast. The first row (A–C) shows merged images, while the second (D–F) and third (G–I) rows show the red and green channels, respectively. Note that OX-6 immunostaining is more intense and found in more microglia after 60-psi blast (red arrows) compared to sham blast regardless of SMM-189 treatment (second and third columns). Phosphorylated-CREB, however, is evident in microglial nuclei (green arrows) only after SMM-189 treatment (last column).
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-00758-f006: Double immunostaining for the activated microglial marker OX6 (major histocompatibility complex (MHC) class II antigen, red) and phosphorylated-CREB (the cyclic adenosine monophosphate (cAMP) response element binding protein, green) in the right optic tract of a 60-psi blasted mouse treated with SMM-189 (C,F,I) three days after blast compared to a sham blasted mouse not treated with SMM-189 (A,D,G) seven days after sham, and a 60-psi mouse not treated with SMM-189 (B,E,H) five days after blast. The first row (A–C) shows merged images, while the second (D–F) and third (G–I) rows show the red and green channels, respectively. Note that OX-6 immunostaining is more intense and found in more microglia after 60-psi blast (red arrows) compared to sham blast regardless of SMM-189 treatment (second and third columns). Phosphorylated-CREB, however, is evident in microglial nuclei (green arrows) only after SMM-189 treatment (last column).
Mentions: We have found that axonal pathology is evident in the left optic nerve and right optic tract shortly after left cranial 50–60 psi blasts [16] and is accompanied by microglial activation, as revealed by the change in microglial morphology (shorter processes, larger cell bodies, rod-like appearance), and increased intensity of ionized calcium-binding adapter molecule-1 (IBA1) immunolabeling (Figure 5A,B). The activation was also seen in right optic tract target areas, such as the right dorsal lateral geniculate nucleus (Figure 5C,D) and the upper layers of the right superior colliculus (Figure 5F). In the case of the right optic tract and its target areas, the microglial activation was evident by the third day after blast, more prominent at one week, and no longer prominent by two to eight weeks. We also observed microglial activation in other brain regions where we detected axonal pathology, for example, in the medial lemniscus (Figure 5E), lateral lemniscus, cerebellar peduncles and deep cerebellar white matter (Figure 5G), and pyramidal tract (Figure 5H). Heightened immunolabeling with OX6 confirms microglia are activated after 50–60 psi blast (Figure 6A,B,D,E). Axonal pathology in the right optic nerve was, by contrast, minimal, although some axonal pathology was seen in the left optic tract (possibly representing injured uncrossed left optic nerve axons).

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