Abstract | BACKGROUND: METHODS: Adult male C57BL/6 mice underwent 4 minutes of aortic occlusion. Mice received 25 μg/kg intraperitoneal dexmedetomidine (n = 8) or 0.9% normal saline (n = 7) at reperfusion and 12-hour intervals postoperatively until 48 hours. Additionally, sham mice (n = 3), which had aortic arch exposed with no occlusion, were included for comparison. 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. Additional analysis of microglia activation was done in 12 hours following surgery. Age- and sex-matched mice had spinal cord removed for microglial isolation culture. Cells were grown to confluence and stimulated with toll-like receptor-4 agonist LPS 100 ng/mL in presence of dexmedetomidine or vehicle control for 24 hours. Microglia and media were then removed for analysis of protein expression. RESULTS:
Dexmedetomidine treatment at reperfusion significantly preserved neurologic function with mice in treatment group having a Basso Score of 6.3 in comparison to 2.3 in ischemic control group. Treatment was associated with a significant reduction in microglia activation and in interleukin-6 production. Microglial cells in isolation when stimulated with LPS had an increased production of proinflammatory cytokines and markers of activation. Treatment with dexmedetomidine significantly attenuated microglial activation and proinflammatory cytokine production in vitro with a greater than twofold reduction in tumor necrosis factor-α. CONCLUSIONS: Alpha 2a agonist, dexmedetomidine treatment at reperfusion preserved neurologic function and neuronal viability. Furthermore, dexmedetomidine treatment resulted in an attenuation of microglial activation and proinflammatory cytokine production both in vivo and in vitro following LPS stimulation. This finding lends insight into the mechanism of paralysis following thoracic aortic interventions and may guide future pharmacologic targets for attenuating spinal cord ischemia and reperfusion.
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Authors | Marshall T Bell, Viktor A Agoston, Kirsten A Freeman, Ferenc Puskas, Paco S Herson, Joshua Mares, David A Fullerton, T Brett Reece |
Journal | Journal of vascular surgery
(J Vasc Surg)
Vol. 59
Issue 4
Pg. 1090-7
(Apr 2014)
ISSN: 1097-6809 [Electronic] United States |
PMID | 23850057
(Publication Type: Journal Article)
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Copyright | Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved. |
Chemical References |
- Adrenergic alpha-2 Receptor Agonists
- Anti-Inflammatory Agents
- Cytokines
- Inflammation Mediators
- Lipopolysaccharides
- Neuroprotective Agents
- Receptors, Adrenergic, alpha-2
- Tlr4 protein, mouse
- Toll-Like Receptor 4
- Dexmedetomidine
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Topics |
- Adrenergic alpha-2 Receptor Agonists
(pharmacology)
- Animals
- Anti-Inflammatory Agents
(pharmacology)
- Aorta, Thoracic
(surgery)
- Cell Survival
(drug effects)
- Cells, Cultured
- Cytokines
(metabolism)
- Dexmedetomidine
(pharmacology)
- Disease Models, Animal
- Inflammation Mediators
(metabolism)
- Ligation
- Lipopolysaccharides
(pharmacology)
- Male
- Mice
- Mice, Inbred C57BL
- Microglia
(drug effects, metabolism, pathology)
- Neuroprotective Agents
(pharmacology)
- Paraplegia
(drug therapy, metabolism, physiopathology)
- Receptors, Adrenergic, alpha-2
(drug effects, metabolism)
- Signal Transduction
(drug effects)
- Spinal Cord
(drug effects, metabolism, pathology, physiopathology)
- Time Factors
- Toll-Like Receptor 4
(agonists, metabolism)
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