reproducable-paraplegia-thoracic-aortic-occlusion-murine-model-spinal

Reproducable Paraplegia by Thoracic Aortic Occlusion in a Murine Model of Spinal Cord Ischemia-reperfusion

Background
Lower extremity paralysis continues to complicate aortic interventions. The lack of understanding of the underlying pathology has hindered ...

University of Colorado

Despite surgical adjuncts, paralysis remains a devastating complication after thoracoabdominal aortic interventions. Dexmedetomidine, a selective α-2a agonist commonly used for sedation in the critical care setting, has been shown to have protective effects against ischemia-reperfusion injuries in multiple organ systems. We hypothesized that treatment with dexmedetomidine would attenuate spinal cord ischemia-reperfusion injury via α-2a receptor activation.

Attenuation of spinal cord ischemia-reperfusion injury by specific α-2a receptor activation with dexmedetomidine.

Paraplegia remains a devastating complication of thoracoabdominal aortic procedures resulting from spinal cord ischemia and reperfusion injury (SCIR). Pharmacologic interventions have not proven efficacious in attenuating this injury, with poor understanding of the underlying mechanisms. The resident macrophages, or microglia in the spinal cord, may play a significant role in SCIR. The macrolide antibiotic, minocycline, has been shown in stroke models to inhibit microglial activation. This study hypothesized that microglial inhibition by minocycline after SCIR will attenuate injury with preservation of motor function.

Preservation of motor function after spinal cord ischemia and reperfusion injury through microglial inhibition.

Despite investigation into preventable pharmacologic adjuncts, paraplegia continues to complicate thoracoabdominal aortic interventions. 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 postischemic inflammation in vivo following thoracic aortic occlusion with in vitro demonstration of microglial inhibition following lipopolysaccharide (LPS) stimulation.

Interruption of spinal cord microglial signaling by alpha-2 agonist dexmedetomidine in a murine model of delayed paraplegia.

Paraplegia continues to complicate thoracoabdominal aortic interventions. The elusive mechanism of spinal cord ischemia-reperfusion injury has delayed the development of pharmacological adjuncts. Microglia, the resident macrophages of the central nervous system, can have pathological responses after a variety of insults. This can occur through toll-like receptor 4 (TLR-4) in stroke models. We hypothesize that spinal cord ischemia-reperfusion injury after aortic occlusion results from TLR-4-mediated microglial activation in mice.

Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury.

Dexmedetomidine, an α-2a adrenergic agonist, given pre- and postoperatively was previously shown to attenuate neuronal injury in a murine model of spinal cord ischemia-reperfusion. In the brain, α-2 agonists have been shown to induce the phosphorylation of cyclic AMP response-element binding protein (CREB), a transcription factor necessary for neuron survival. We hypothesized that the α-2a adrenergic agonist given preoperatively increases CREB-mediated neuroprotective proteins, attenuating neuronal injury and cytoarchitectural decay.

Article	Year
Attenuation of spinal cord ischemia-reperfusion injury by specific α-2a receptor activation with dexmedetomidine. Journal of vascular surgery\| PubMed ID: 22832266	2012
Preservation of motor function after spinal cord ischemia and reperfusion injury through microglial inhibition. The Annals of thoracic surgery\| PubMed ID: 23541432	2013
Interruption of spinal cord microglial signaling by alpha-2 agonist dexmedetomidine in a murine model of delayed paraplegia. Journal of vascular surgery\| PubMed ID: 23850057	2013
Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury. Circulation\| PubMed ID: 24030400	2013
Dexmedetomidine, an α-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 24035379	2014

Marshall T. Bell

Biography

JoVE Journal Publications

Other Publications