Motor, Visual and Emotional Deficits in Mice after Closed-Head Mild Traumatic Brain Injury Are Alleviated by the Novel CB2 Inverse Agonist SMM-189

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.

A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice

“…We have, in fact, shown that targeting microglia via their type-2 cannabinoid receptors (CB2) with a CB2 receptor inverse agonist can reduce the motor, visual, and behavioral deficits and the brain, spinal cord, and retinal injury seen after 50-psi blast injury. 110 Comparison with open-skull rodent models Many studies have used lateral fluid percussion, weight drop, or controlled piston impact to the exposed dura in rats or mice, which causes necrotic brain destruction at the site of impact, thereby modeling severe TBI. 8,10,11,[13][14][15][16][17][18] In addition to the neuron loss at the impact site, these approaches commonly yield subdural hemorrhage, brain vascular damage, microglial activation, and axonal injury.…”

“…For example, we recently described the benefits of reducing neuroinflammation in our TBI model. 110 Finally, the injury produced with our focal blast model can be compared with that resulting from focal mechanical impact to the same head location. The forces associated with blast and with mechanical impact are similar in duration and could readily be adjusted to be similar in magnitude and in the minimal amount of head movement that occurs.…”

Synthesis and biological evaluation of (3′,5′-dichloro-2,6-dihydroxy-biphenyl-4-yl)-aryl/alkyl-methanone selective CB2 inverse agonist

“…44 Based on the potential of CB2 inverse agonist in treating CNS diseases, we demonstrated that SMM-189 beneficially down-regulates cytokine and chemokine production in LPS stimulated primary human microglia. 25,44 Subsequent testing of SMM-189 in the murine model of mild traumatic brain injury (mTBI), and pre-clinical evaluation of biopharmaceutical properties, demonstrated the protective effects of SMM-189 in mTBI and indicated that the 2,6-dihydroxy-biphenyl-aryl-methanone scaffold has acceptable drug-like properties to warrant further investigation. 25 The potential of the scaffold for developing selective CB2 inverse agonist prompted us to investigate the functional group requirements required for activity.…”

“…25,44 Subsequent testing of SMM-189 in the murine model of mild traumatic brain injury (mTBI), and pre-clinical evaluation of biopharmaceutical properties, demonstrated the protective effects of SMM-189 in mTBI and indicated that the 2,6-dihydroxy-biphenyl-aryl-methanone scaffold has acceptable drug-like properties to warrant further investigation. 25 The potential of the scaffold for developing selective CB2 inverse agonist prompted us to investigate the functional group requirements required for activity. A set of compounds were synthesized and evaluated for CB1 and CB2 receptor binding in ACTOne membrane preparations and functional activity using the ACTOne cAMP assay.…”

“…[21][22][23] The apparent selective up-regulation of CB2 on microglia in response to insult indicates that CB2 ligands would provide selective effects in only the damaged CNS tissue. In fact, both agonists and inverse agonists of CB2 have been evaluated for efficacy in ameliorating disease progression in in vivo models of traumatic brain injury, 24,25 Alzheimer's 17,18,[26][27][28][29][30] and Parkinson's disease, 19,31,32 amyotrophic lateral sclerosis, 6,20 and multiple sclerosis. 5,[33][34][35][36][37][38][39] The comparable efficacy of agonists and inverse agonists highlights one of the major unanswered questions in this field, what is the optimum functional activity of CB2 ligands?…”