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

Images of sections through the basolateral amygdala on the blasted side from mice engineered to express enhanced yellow fluorescent protein (EYFP) in Thy1-enriched telencephalic neurons. Note that the basolateral amygdala (BLA) in the vehicle-treated 0-psi mouse (A) contains numerous Thy1-EYFP+ neurons, while the BLA in the vehicle-treated 50-psi mouse (B) contains fewer. Thy1+ neurons in BLA are increased in SMM-189-treated 50-psi mice (C) above that seen in the vehicle-treated 50-psi mouse.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-00758-f012: Images of sections through the basolateral amygdala on the blasted side from mice engineered to express enhanced yellow fluorescent protein (EYFP) in Thy1-enriched telencephalic neurons. Note that the basolateral amygdala (BLA) in the vehicle-treated 0-psi mouse (A) contains numerous Thy1-EYFP+ neurons, while the BLA in the vehicle-treated 50-psi mouse (B) contains fewer. Thy1+ neurons in BLA are increased in SMM-189-treated 50-psi mice (C) above that seen in the vehicle-treated 50-psi mouse.

Mentions: We have also previously shown that three to eight weeks after 50–60 psi left cranial blast, mice show increased contextual fear, and heightened retention of learned fear [15]. In the present study, we found that SMM-189 treatment diminished both forms of learned fear (Figure 11). For example, vehicle-treated 50-psi mice showed a significant increase in learned contextual fear compared to vehicle-treated sham mice when re-introduced into their training context over the first minute of the first fear extinction session (p = 0.012). SMM-189 treatment reduced this significant increase in contextual fear, so that it was statistically indistinguishable from that shown by sham-blasted mice receiving vehicle (p = 0.904), and significantly less than that shown by the vehicle-treated 50-psi mice (p = 0.018). Secondly, vehicle-treated 50-psi mice also showed a large and significant overall increase across trials in learned fear responses to the conditioned stimulus (CS) during the three extinction sessions compared to vehicle-treated sham mice (p = 0.000147), with significant specific elevations evident during CS presentations 4–6 (p = 0.023) and 7–9 (p = 0.028). Although responses to the CS in the SMM-189-treated mice remained greater than in the vehicle-treated sham mice across trials overall (p = 0.049), they reached sham levels by the 10th–12th CS presentations, and were not significantly greater than in sham for any of the four grouped CS presentations. Moreover, they trended overall toward being significantly different than in the 50-psi vehicle treated mice (p = 0.051). The morphological basis of the SMM-189 benefit is uncertain, but we have previously noted that the Thy1+ fear-suppressing neurons in the basolateral amygdala are reduced by about 25% in their abundance by 50–60 psi blasts [15]. In the present study, we confirmed a 20% reduction in Thy1+ neurons in BLA in six vehicle-treated mice two months after 60-psi blast. SMM-189 treatment in ten 60-psi blast mice rescued this loss of Thy1+ fear suppressing neurons in the basolateral amygdala, so that their abundance in BLA was indistinguishable from that seen in vehicle-treated mice receiving 0–30 psi blasts (Figure 12).


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)

Images of sections through the basolateral amygdala on the blasted side from mice engineered to express enhanced yellow fluorescent protein (EYFP) in Thy1-enriched telencephalic neurons. Note that the basolateral amygdala (BLA) in the vehicle-treated 0-psi mouse (A) contains numerous Thy1-EYFP+ neurons, while the BLA in the vehicle-treated 50-psi mouse (B) contains fewer. Thy1+ neurons in BLA are increased in SMM-189-treated 50-psi mice (C) above that seen in the vehicle-treated 50-psi mouse.
© Copyright Policy
Related In: Results  -  Collection

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

ijms-16-00758-f012: Images of sections through the basolateral amygdala on the blasted side from mice engineered to express enhanced yellow fluorescent protein (EYFP) in Thy1-enriched telencephalic neurons. Note that the basolateral amygdala (BLA) in the vehicle-treated 0-psi mouse (A) contains numerous Thy1-EYFP+ neurons, while the BLA in the vehicle-treated 50-psi mouse (B) contains fewer. Thy1+ neurons in BLA are increased in SMM-189-treated 50-psi mice (C) above that seen in the vehicle-treated 50-psi mouse.
Mentions: We have also previously shown that three to eight weeks after 50–60 psi left cranial blast, mice show increased contextual fear, and heightened retention of learned fear [15]. In the present study, we found that SMM-189 treatment diminished both forms of learned fear (Figure 11). For example, vehicle-treated 50-psi mice showed a significant increase in learned contextual fear compared to vehicle-treated sham mice when re-introduced into their training context over the first minute of the first fear extinction session (p = 0.012). SMM-189 treatment reduced this significant increase in contextual fear, so that it was statistically indistinguishable from that shown by sham-blasted mice receiving vehicle (p = 0.904), and significantly less than that shown by the vehicle-treated 50-psi mice (p = 0.018). Secondly, vehicle-treated 50-psi mice also showed a large and significant overall increase across trials in learned fear responses to the conditioned stimulus (CS) during the three extinction sessions compared to vehicle-treated sham mice (p = 0.000147), with significant specific elevations evident during CS presentations 4–6 (p = 0.023) and 7–9 (p = 0.028). Although responses to the CS in the SMM-189-treated mice remained greater than in the vehicle-treated sham mice across trials overall (p = 0.049), they reached sham levels by the 10th–12th CS presentations, and were not significantly greater than in sham for any of the four grouped CS presentations. Moreover, they trended overall toward being significantly different than in the 50-psi vehicle treated mice (p = 0.051). The morphological basis of the SMM-189 benefit is uncertain, but we have previously noted that the Thy1+ fear-suppressing neurons in the basolateral amygdala are reduced by about 25% in their abundance by 50–60 psi blasts [15]. In the present study, we confirmed a 20% reduction in Thy1+ neurons in BLA in six vehicle-treated mice two months after 60-psi blast. SMM-189 treatment in ten 60-psi blast mice rescued this loss of Thy1+ fear suppressing neurons in the basolateral amygdala, so that their abundance in BLA was indistinguishable from that seen in vehicle-treated mice receiving 0–30 psi blasts (Figure 12).

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