Monosialoganglioside GM1 inhibits neurotoxicity after hypothermic circulatory arrest

E. E. Tseng, M. V. Brock, M. S. Lange, J. C. Troncoso, M. E. Blue, C. J. Lowenstein, M. V. Johnston, W. A. Baumgartner, T. R. Billiar, F. W. Selke

Research output: Contribution to journalArticlepeer-review

Abstract

Background. Prolonged hypothermic circulatory arrest (HCA) causes clinical neurologic injury. This injury involves neuronal apoptosis, or programmed cell death. We have previously demonstrated that HCA causes glutamate excitotoxicity, increased nitric oxide (NO) production, and NO- mediated apoptosis. We hypothesized that monosialoganglioside GM1 inhibits NO synthase. The purpose of this study was to determine whether GM1 inhibits NO production and neuronal apoptosis after HCA. Methods. Fourteen dogs underwent intracerebral microdialysis to measure excitatory amino acids, glutamate, aspartate, and citrulline, an equal coproduct of NO. They underwent 2 hours of HCA at 18°C and were sacrificed 8 hours after HCA. Group 1 (n = 6) was pretreated with GM1, 30 mg/kg intravenously every day for 3 days, as well as before and after HCA. Group 2 control dogs (n = 8) received vehicle only. Apoptosis was scored from 0 (normal) to 100 (severe injury). Results. Excitatory amino acids, aspartate and glutamate, coagonist glycine, and citrulline levels increased significantly over baseline during HCA and after HCA. GM1 pretreatment did not appreciably alter levels of glutamate, aspartate, and glycine; however, it substantially decreased citrulline and therefore NO production throughout the experiment. GM1 significantly inhibited apoptosis (group 1 vs group 2: 15.56 ± 13.60 vs 62.92 ± 6.17;P< .001). Conclusions. Our results provide the first direct evidence that GM1 inhibits NO synthase to reduce NO production and HCA- induced neuronal apoptosis. GM1 did not affect excitatory glutamate or aspartate levels. GM1 has been used in clinical trials of spinal cord injury and may be efficacious in reducing neurologic injury after HCA.

Original languageEnglish (US)
Pages (from-to)298-306
Number of pages9
JournalSurgery
Volume124
Issue number2
DOIs
StatePublished - 1998

ASJC Scopus subject areas

  • Surgery

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