Glutamate Excitotoxicity Mediates Neuronal Apoptosis After Hypothermic Circulatory Arrest

Elaine E. Tseng, Malcolm V. Brock, Mary S. Lange, Juan C. Troncoso, Mary E. Blue, Charles J. Lowenstein, Michael V. Johnston, William A. Baumgartner

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Prolonged hypothermic circulatory arrest results in neuronal cell death and neurologic injury. We have previously shown that hypothermic circulatory arrest causes both neuronal apoptosis and necrosis in a canine model. Inhibition of neuronal nitric oxide synthase reduced neuronal apoptosis, while glutamate receptor antagonism reduced necrosis in our model. This study was undertaken to determine whether glutamate receptor antagonism reduces nitric oxide formation and neuronal apoptosis after hypothermic circulatory arrest. Methods: Sixteen hound dogs underwent 2 hours of circulatory arrest at 18°C and were sacrificed after 8 hours. Group 1 (n = 8) was treated with MK-801, 0.75 mg/kg intravenously prior to arrest followed by 75 μg/kg/hour infusion. Group 2 dogs (n = 8) received vehicle only. Intracerebral levels of excitatory amino acids and citrulline, an equal coproduct of nitric oxide, were measured. Apoptosis, identified by hematoxylin and eosin staining and confirmed by electron microscopy, was blindly scored from 0 (normal) to 100 (severe injury), while nick-end labeling demonstrated DNA fragmentation. Results: Dogs in groups 1 and 2 had similar intracerebral levels of glutamate. However, MK-801 significantly reduced intracerebral glycine and citrulline levels compared with hypothermic circulatory arrest controls. The MK-801 significantly inhibited apoptosis (7.92 ± 7.85 vs 62.08 ± 6.28, group 1 vs group 2, p < 0.001). Conclusions: Our results showed that glutamate receptor antagonism significantly reduced nitric oxide formation and neuronal apoptosis. We provide evidence that glutamate excitotoxicity mediates neuronal apoptosis in addition to necrosis after hypothermic circulatory arrest. Clinical glutamate receptor antagonists may have therapeutic benefits in ameliorating both types of neurologic injury after hypothermic circulatory arrest.

Original languageEnglish (US)
Pages (from-to)440-445
Number of pages6
JournalAnnals of Thoracic Surgery
Volume89
Issue number2
DOIs
StatePublished - Feb 2010

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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