Objective: 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.
Methods: Mice (ie, C57BL/6 mice) underwent 5 minutes of aortic occlusion via median sternotomy. Mice received 25 μg/kg dexmedetomidine or equivalent normal saline at 24 hours, 12 hours, and 30 minutes preoperatively. Functional outcomes were recorded at 6 to 48 hours postoperatively when spinal cords were removed for histologic analysis. Spinal cords were examined for protein kinase B, CREB, B-cell lymphoma 2, and brain-derived neurotrophic factor following treatment alone or ischemia-reperfusion surgery.
Results: Following aortic occlusion, mice in the treatment group had preserved neurologic function at all time points (P < .05). Histologic analysis showed preserved cytoarchitecture and decreased neuronal injury in the treatment group when compared with ischemic controls. Additionally, analysis of spinal cord homogenate following surgery and pretreatment revealed a significant (P < .05) increase in B-cell lymphoma 2 and brain-derived neurotrophic factor expression and protein kinase B and CREB phosphorylation with α-2a adrenergic agonist pretreatment.
Conclusions: Pretreatment with the α-2a agonist dexmedetomidine preserved neurologic function and attenuated neuronal injury following thoracic aortic occlusion in mice. This relationship was associated with an increased phosphorylation of protein kinase B and CREB and subsequent up-regulation of antiapoptotic factor B-cell lymphoma 2 and brain-derived neurotrophic factor. Thus, α-2a receptor agonism-induced CREB phosphorylation and contributes to dexmedetomidine's protective mechanism in the spinal cord following ischemia.
Keywords: 26.1; 38; 38.1; B-cell lymphoma 2; BCL-2; BDNF; CREB; IR; PBS; brain-derived neurotrophic factor; cyclic AMP response-element binding protein; ischemia-reperfusion; phosphate buffered saline.
Copyright © 2014. Published by Mosby, Inc.