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

Anton Reiner,Lauren D'Surney,Yunping Deng,Scott Heldt,Chaela Presley,Wei Bu,Steven Gurley,Marcia Honig,Nobel Del Mar,Jessica Ferrell,Bob Ii,Andrea Elberger,Joshua Rogers,Natalie Guley

doi:10.3390/ijms16010758

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.

Highlights

Mild traumatic brain injury (TBI) is a common occurrence during military combat, sports, recreational activities, and vehicle use [1,2]
Four of the five cytokines whose expression by microglia was increased with LPS treatment showed significantly reduced expression when SMM-189 treatment was combined with LPS-treatment, and the remaining cytokine (TNF-α) trended in that direction
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, and increased intensity of ionized calcium-binding adapter molecule-1 (IBA1) immunolabeling (Figure 5A,B)

Summary

Introduction

Mild traumatic brain injury (TBI) is a common occurrence during military combat, sports, recreational activities, and vehicle use [1,2]. Mild TBI leads to a variety of adverse sensory, motor, cognitive and emotional outcomes [1,2,3]. The initial injury with mild TBI appears to stem from the brain tissue deformation that results from the shock wave transmitted through brain and CSF by the blast impact, or from the brain compression—expansion during rapid head acceleration—deceleration [5]. Many approaches have been tested in animal models and human clinical trials [6], effective therapies for mitigating the effects of mild TBI have not been developed. Since microglial activation is thought to play a role in the adverse outcome after mild TBI [7,8,9,10,11,12,13,14], we used our focal blast model of mild TBI in mice [15,16] to evaluate the benefits of a novel pharmacological approach for reducing the adverse actions of activated microglia after TBI

Methods

Results

Discussion

Conclusion