Inhibition of the MEK/ERK pathway reduces microglial activation and interleukin-1-beta expression in spinal cord ischemia/reperfusion injury in rats.

Abstract

Ischemic spinal cord injury is a serious complication of aortic surgery. Although the extracellular signal-regulated kinases 1 and 2 are generally regarded as related to cell proliferation and survival, increasing evidence suggests that the role of the extracellular signal-regulated kinase pathway in ischemia/reperfusion injury is much more sophisticated. Spinal cord ischemia in rats was induced by occluding the thoracic descending aorta with a balloon catheter introduced through a femoral artery, accompanied by concomitant exsanguination. Rats in the control group were given dimethyl sulfoxide (vehicle) before undergoing spinal cord ischemia/reperfusion injury. In the U0126-treated group, rats were pretreated with a specific inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinases 1 and 2, U0126, to inhibit extracellular signal-regulated kinases 1 and 2 phosphorylation. The sham-operated rats underwent aortic catheterization without occlusion. Parameters, including neurologic performance, neuronal survival, inflammatory cell infiltration, and interleukin-1beta production in the spinal cords, were compared between groups. Early extracellular signal-regulated kinases 1 and 2 phosphorylation was observed after injury in the control group, followed by abundant microglial accumulation in the infarct area and increased interleukin-1beta expression. In the U0126 group, U0126 treatment completely blocked extracellular signal-regulated kinases 1 and 2 phosphorylation. Microglial activation and spinal cord interleukin-1beta levels were significantly reduced. Neuronal survival and functional performance were improved. The mitogen-activated protein kinase/extracellular signal-regulated kinase pathway may play a noxious role in spinal cord ischemia/reperfusion injury by participating in inflammatory reactions and cytokine production. Targeting this pathway may be of potential value in terms of therapeutic intervention.