Monosialoganglioside GM1 inhibits neurotoxicity after hypothermic circulatory arrest

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 GM(1) inhibits NO synthase. The purpose of this study was to determine whether GM(1) 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 degrees C and were sacrificed 8 hours after HCA. Group 1 (n = 6) was pretreated with GM(1), 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. GM(1) pretreatment did not appreciably alter levels of glutamate, aspartate, and glycine; however, it substantially decreased citrulline and there fore NO production throughout the experiment. GM(1) 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 GM(1) inhibits NO synthase to reduce NO production and HCA-induced neuronal apoptosis. GM(1) did not affect excitatory glutamate or aspartate level. GM(1) has been used in clinical trials of spinal cord injury and may be efficacious in reducing neurologic injury after HCA.