Kuroda S, Tsuchidate R, Smith M L, Maples K R, Siesjö B K
Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, Lund University, Sweden.
J Cereb Blood Flow Metab. 1999 Jul;19(7):778-87. doi: 10.1097/00004647-199907000-00008.
Recent results have demonstrated that the spin trapping agent alpha-phenyl-N-tert-butyl nitrone (PBN) reduces infarct volume in rats subjected to 2 hours of middle cerebral artery occlusion, even when given 1 to 3 hours after the start of recirculation. In the current study, the authors assessed the effect of NXY-059, a novel nitrone that is more soluble than PBN. Loading doses were given of 0.30, 3.0, or 30 mg x kg(-1) followed by 0.30, 3.0, or 30 mg x kg(-1) x h(-1) for 24 or 48 hours. Dose-response studies showed that when treatment was begun 1 hour after recirculation, 0.30 mg x kg(-1) had a small and 30 mg x kg(-1) a marked effect on infarct volume. At equimolar doses (3.0 mg x kg(-1) for NXY-059 and 1.4 mg x kg(-1) for PBN), NXY-059 was more efficacious than PBN. Similar results were obtained when a recovery period of 7 days was allowed. The window of therapeutic opportunity for NXY-059 was 3 to 6 hours after the start of recirculation. Studies of the transfer constant of [14C]NXY-059 showed that, in contrast to PBN, this more soluble nitrone penetrates the blood-brain barrier less extensively. This fact, and the pronounced antiischemic effect of NXY-059, suggest that the delayed events leading to infarction may be influenced by reactions occurring at the blood-endothelial interface.
近期研究结果表明，自旋捕捉剂α-苯基-N-叔丁基硝酮（PBN）可减少大脑中动脉闭塞2小时的大鼠梗死体积，即便在再灌注开始1至3小时后给药亦是如此。在本研究中，作者评估了一种新型硝酮NXY-059的作用，该硝酮比PBN更易溶解。分别给予0.30、3.0或30 mg·kg⁻¹的负荷剂量，随后以0.30、3.0或30 mg·kg⁻¹·h⁻¹的剂量持续给药24或48小时。剂量反应研究表明，再灌注1小时后开始治疗时，0.30 mg·kg⁻¹对梗死体积有轻微影响，30 mg·kg⁻¹则有显著影响。在等摩尔剂量下（NXY-059为3.0 mg·kg⁻¹，PBN为1.4 mg·kg⁻¹），NXY-059比PBN更有效。给予7天恢复期时也得到了类似结果。NXY-059的治疗机会窗为再灌注开始后的3至6小时。对[¹⁴C]NXY-059转运常数的研究表明，与PBN不同，这种更易溶解的硝酮穿透血脑屏障的程度较低。这一事实以及NXY-059显著的抗缺血作用表明，导致梗死的延迟事件可能受血-内皮界面发生的反应影响。
