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Anton Reiner, Natalie Guley, Nobel Del Mar, Bob M Moore, Marcia G Honig; Amelioration of Visual Deficits and Pathology after Mild TBI with the CB2 Inverse Agonist SMM189. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5893.
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© ARVO (1962-2015); The Authors (2016-present)
Mild TBI is often accompanied by visual system dysfunction and injury, which is at least in part caused by the microglial neuroinflammatory process initiated by the injury. Using our focal cranial blast mouse model of closed-skull mild TBI, we evaluated the ability of the CB2 inverse agonist SMM189, which biases microglia from the harmful M1 state to the beneficial M2 state, to mitigate visual system dysfunction and injury after TBI.
Male C57BL/6 or Thy1-EYFP reporter mice received closed-head blast of 0-psi (sham) or 50-psi to the left side of the cranium, as previously described (Guley et al., JNeurotrauma 2016). Blast mice received daily vehicle (50V) or 6 mg/kg SMM189 (50SMM) for two weeks beginning 2 hours after blast. Sham mice received vehicle (0V). Mice were functionally assessed by their scotopic ERG and by Optomotry 30 days after blast, and then by OCT. Retina and optic nerve/tract were assessed morphologically 3-7 days or 30-80 days after blast.
Contrast sensitivity in 50V mice was significantly reduced in both eyes at 30 days post-blast, but rescued in 50SMM mice. The left eye (LE) ERG B-wave peak was also abnormal in 50V mice, and SMM189 treatment restored it to control levels. OCT at 30 days post-blast revealed outer retinal thinning in the LE of 50V mice, but not in 50SMM mice. Immunolabeling showed a significant increase in microglia in the LE of 50V mice at 3 days post-blast, and a lesser elevation in both eyes at 30 days post-blast. SMM189 decreased the microglial elevation at both 3 and 30 days. GFAP immunolabeling of Müller cells was also elevated in the LE of 50V animals at 30 days, which was normalized by SMM189. Analysis of optic tract microglia for the M1 versus M2 markers CD16/32 and CD206 revealed that SMM189 biased microglia toward the M2 state. Analysis of left optic nerve 11 weeks post-blast revealed axon loss in 50V animals and rescue in 50SMM mice. At 3 days post-blast, axon damage was seen in the continuation of the left optic nerve (i.e. the right optic tract) in the form of swollen axon bulbs in 50V mice, but SMM189 treatment significantly reduced their abundance.
The novel drug SMM189 significantly mitigated visual system dysfunction and pathology caused by mild TBI. Our findings suggest the value of combatting visual system injury after TBI by using CB2 inverse agonists to target microglia and bias them toward the M2 state.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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