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Alpha 2a Agonist Dexmedetomidine Interrupts Macrophage Toll-Like Receptor 4 Signaling in Murine Model of Spinal Cord Iscehmia Repferfusion.
Marshall T Bell, Viktor A Agoston, Ferenc Puskas, Joseph C Cleveland, Jr., David A Fullerton, Kristen Freeman, Fabia Gamboni, Paco Herson, Joshua Mares, Michael J Weyant, T Brett Reece
University of Colorado, Aurora, CO

INTRODUCTION:
Paraplegia persists following thoracoabdominal aortic interventions despite investigation into preventative pharmacological adjuncts. The alpha 2a adrenergic receptor agonist, dexmedetomidine, has been shown to preserve neurologic function and neuronal viability in a murine model of spinal cord ischemia reperfusion, although the mechanism remains elusive. We hypothesize that dexmedetomidine will blunt the inflammation of reperfusion effects in vivo following thoracic aortic occlusion with in vitro demonstration of microglial inhibition via blunted TLR-4 signaling
METHODS:
Adult male C57BL/6 mice underwent 4 minutes of aortic occlusion. Treatment groups received 25 μg/kg dexmedetomidine at reperfusion and 12 hour intervals post procedurally. Functional scoring was done at 6 hours following surgery and 12 hour intervals until 60 hours when spinal cords were removed and examined for neuronal viability and cytokine production. Identical mice had spinal cord removed for microglial isolation culture. Cells were grown to confluence and stimulated with TLR-4 agonist LPS 10ng/ml in presence of dexmedetomidine or vehicle control. Media was then removed for cytokine analysis. All treatment groups were compared to ischemic controls and significance determined by p<0.05.
RESULTS:
Dexmedetomidine treatment significantly preserved neurologic function, cytoarchitecture and neuronal viability in the murine spinal cord. Treatment was associated with significantly reduced IL-6 production at 6 and 60 hours. Microglial cells stimulated with LPS had production of proinflammatory cytokines TNF-α and IL-6 which was significantly attenuated with treatment of dexmedetomidine
CONCLUSIONS:
Alpha 2a agonist, dexmedetomidine, preserved neurologic function and attenuated pro-inflammatory cytokine production both in vivo and in vitro murine models. Furthermore this relationship, appears occurs through interruption of TLR-4 mediated microglial activation and cytokine production. This involvement of TLR-4 signaling in dexmedetomidine protection provides an insight into the mechanism of paralysis following thoracic aortic interventions to guide future pharmacological targets for attenuating spinal cord ischemia and reperfusion injury.


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