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J Thorac Cardiovasc Surg 2004;127:1033-1040
© 2004 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

Blockade of the extracellular signal-regulated kinase pathway by U0126 attenuates neuronal damage following circulatory arrest

Deog-Gon Cho, MDa, Matthew R. Mulloy, MDa, Paul A. Chang, BSa, Mahlon D. Johnson, MD, PhDa, Alon S. Aharon, MDb, Trevor A. Robison, BSa, Tamara L. Buckles, BSa, Daniel W. Byrne, MSa, Davis C. Drinkwater, Jr, MDa,*

a Vanderbilt University Medical Center, Nashville, Tenn, USA
b St Louis University Health Sciences Center, St Louis, Mo, USA

Read at the Eighty-third Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 4-7, 2003.

Received for publication May 2, 2003; revisions received August 29, 2003; accepted for publication September 29, 2003.

* Address for reprints: Davis C. Drinkwater, Jr, MD, William S. Stoney Professor and Chairman, Department of Cardiac and Thoracic Surgery, Vanderbilt University Medical Center, 1161 21st Ave South 2986 TVC, Nashville, TN, USA, 37232-5734
davis.drinkwater{at}vanderbilt.edu

OBJECTIVES: The extracellular signal-regulated kinase pathway of the mitogen-activated protein kinase signal transduction cascade has been implicated in the neuronal and endothelial dysfunction witnessed following cerebral ischemia-reperfusion injury. Extracellular signal-regulated kinase is activated by mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2. We evaluated the ability of a mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2–specific inhibitor (U0126) to block extracellular signal-regulated kinase activation and mitigate ischemic neuronal damage in a model of deep hypothermic circulatory arrest.

METHODS: Piglets underwent normal flow cardiopulmonary bypass (control, n = 4), deep hypothermic circulatory arrest (n = 6), and deep hypothermic circulatory arrest with U0126 (n = 5) at 20°C for 60 minutes. The deep hypothermic circulatory arrest with U0126 group was given 200 µg/kg of U0126 45 minutes prior to initiation of bypass followed by 100 µg/kg at reperfusion. Following 24 hours of post–cardiopulmonary bypass recovery, brains were harvested. Eleven distinct cortical regions were evaluated for neuronal damage using hematoxylin and eosin staining. A section of ischemic cortex was further evaluated by immunohistochemistry with rabbit polyclonal antibody against phosphorylated extracellular signal-regulated kinase 1/2.

RESULTS: The deep hypothermic circulatory arrest and deep hypothermic circulatory arrest with U0126 groups displayed diffuse ischemic changes. However, the deep hypothermic circulatory arrest with U0126 group possessed significantly lower neuronal damage scores in the right frontal watershed zone of cerebral cortex, basal ganglia, and thalamus (P <= .05) and an overall trend toward neuroprotection versus the deep hypothermic circulatory arrest group. This neuroprotection was accompanied by nearly complete blockade of phosphorylated extracellular signal-regulated kinase in the cerebral vascular endothelium.

CONCLUSIONS: In this experimental model of deep hypothermic circulatory arrest, U0126 blocked extracellular signal-regulated kinase activation and provided a significant neuroprotective effect. These results support targeting of the extracellular signal-regulated kinase pathway for inhibition as a novel therapeutic approach to mitigate neuronal damage following deep hypothermic circulatory arrest.




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K. Lu, C.-L. Cho, C.-L. Liang, S.-D. Chen, P.-C. Liliang, S.-Y. Wang, and H.-J. Chen
Inhibition of the MEK/ERK pathway reduces microglial activation and interleukin-1-beta expression in spinal cord ischemia/reperfusion injury in rats
J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 934 - 941.
[Abstract] [Full Text] [PDF]


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