title: Cerebral activation of mitogen-activated protein kinases after circulatory arrest and low flow cardiopulmonary bypass.
abstract: OBJECTIVE
  Mitogen-activated protein kinases (MAPK) are important intermediates in the signal transduction pathways involved in neuronal dysfunction following cerebral ischemia-reperfusion injury. One subfamily, extracellular regulated kinase 1/2, has been heavily implicated in the pathogenesis of post-ischemic neuronal damage. However, the contribution of extracellular regulated kinase 1/2 to neuronal damage following deep hypothermic circulatory arrest and low flow cardiopulmonary bypass is unknown. We attempted to correlate the extent of neuronal damage present following deep hypothermic circulatory arrest and low flow cardiopulmonary bypass with phosphorylated extracellular regulated kinase 1/2 expression in the cerebral vascular endothelium.
  
  
  METHODS
  Piglets underwent normal flow cardiopulmonary bypass (n=4) deep hypothermic circulatory arrest (n=6) and low flow cardiopulmonary bypass (n=5). Brains were harvested following 24 h of post-cardiopulmonary bypass recovery. Cerebral cortical watershed zones, hippocampus, basal ganglia, thalamus, cerebellum, mesencephalon, pons and medulla were evaluated using hematoxylin and eosin staining. A section of ischemic cortex was evaluated by immunohistochemistry with rabbit polyclonal antibodies against phosphorylated extracellular regulated kinase 1/2.
  
  
  RESULTS
  Compared to cardiopulmonary bypass controls, the deep hypothermic circulatory arrest and low flow cardiopulmonary bypass piglets exhibited diffuse ischemic changes with overlapping severity and distribution. Significant neuronal damage occurred in the frontal watershed zones and basal ganglia of the deep hypothermic circulatory arrest group (P<0.05). No detectable phosphorylated extracellular regulated kinase 1/2 immunoreactivity was found in the cardiopulmonary bypass controls; however, ERK 1/2 immunoreactivity was present in the cerebral vascular endothelium of the deep hypothermic circulatory arrest and low flow cardiopulmonary bypass groups.
  
  
  CONCLUSIONS
  Our results indicate that phosphorylated extracellular regulated kinase 1/2 may play a prominent role in early cerebral ischemia-reperfusion injury and endothelial dysfunction. The pharmacologic inhibition of extracellular regulated kinase 1/2 represents a new and exciting opportunity for the modulation of cerebral tolerance to low flow cardiopulmonary bypass and deep hypothermic circulatory arrest.
authors.affiliation: Division of Cardiothoracic Surgery, St Louis University Health Sciences Center, 3635 Vista Avenue at Grand Boulevard, St Louis, MO 63110-0250, USA.
authors.forename: Alon S
authors.initials: AS
authors.lastname: Aharon
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Mulloy
authors.forename: Davis C
authors.initials: DC
authors.lastname: Drinkwater
authors.forename: Oliver B
authors.initials: OB
authors.lastname: Lao
authors.forename: Mahlon D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Megan
authors.initials: M
authors.lastname: Thunder
authors.forename: Chang
authors.initials: C
authors.lastname: Yu
authors.forename: Paul
authors.initials: P
authors.lastname: Chang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D002315:Cardiopulmonary Bypass / Q000009:adverse effects / Q000379:methods*; D004730:Endothelium, Vascular / Q000503:physiopathology; D004789:Enzyme Activation; D006324:Heart Arrest, Induced / Q000009:adverse effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000473:pathology; D015427:Reperfusion Injury / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D015398:Signal Transduction; D013552:Swine
chemical_list: D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases