Marshall Jonathan W B, Cummings Rosalyn M, Bowes Laura J, Ridley Rosalind M, Green A Richard
Medical Research Council Comparative Cognition Team, Department of Experimental Psychology, University of Cambridge, UK.
Stroke. 2003 Sep;34(9):2228-33. doi: 10.1161/01.STR.0000087790.79851.A8. Epub 2003 Aug 14.
NXY-059 has substantial protective effects when administered immediately after the onset of ischemia in a primate model of stroke. This study examined the efficacy of this drug when administered 4 hours after onset, a more clinically relevant time point.
Before surgery, marmosets were trained and tested on a number of neurological tests, which assessed general neurological function, motor ability, and spatial awareness. Four hours after permanent middle cerebral artery occlusion (pMCAO), marmosets received a bolus of saline (n=13) or NXY-059 (n=13), and osmotic minipumps were implanted, providing 48-hour saline or drug (85 micromol/kg per hour) infusion. The monkeys were retested 3 and 10 weeks after surgery. Finally, infarct size was evaluated with histological analysis.
The unbound plasma NXY-059 concentration was 200+/-9 micromol/L after 24-hour infusion, a concentration well tolerated in stroke patients. Drug treatment ameliorated the long-term motor impairment produced by pMCAO; the marmosets were better at using their contralesional, stroke-affected arm than controls at both 3 and 10 weeks. Saline-treated animals had a debilitating spatial neglect at 3 weeks with residual signs evident at 10 weeks. NXY-059 treatment substantially attenuated neglect at 3 weeks, with no deficit being seen at 10 weeks. NXY-059 reduced the overall infarct size by 28% (saline, 324+/-46 mm3; NXY-059, 234+/-30 mm3) with protection to the cortex, white matter, and subcortical structures.
NXY-059 is an effective neuroprotective agent when administered 4 hours after pMCAO in a primate species, attenuating both motor and spatial neglect. The compound also substantially lessened the volume of cerebral damage.
在灵长类动物中风模型中，NXY - 059在缺血发作后立即给药具有显著的保护作用。本研究考察了在发作后4小时给药时该药物的疗效，这是一个更具临床相关性的时间点。
手术前，对狨猴进行多项神经学测试的训练和测试，这些测试评估一般神经功能、运动能力和空间意识。在永久性大脑中动脉闭塞（pMCAO）4小时后，狨猴接受一次生理盐水推注（n = 13）或NXY - 059（n = 13），并植入渗透微型泵，以提供48小时的生理盐水或药物（每小时85微摩尔/千克）输注。术后3周和10周对猴子进行重新测试。最后，通过组织学分析评估梗死体积。
24小时输注后，未结合的血浆NXY - 059浓度为200±9微摩尔/升，这一浓度在中风患者中耐受性良好。药物治疗改善了pMCAO引起的长期运动障碍；在3周和10周时，狨猴使用对侧受中风影响手臂的能力比对照组更好。接受生理盐水治疗的动物在3周时出现严重的空间忽视，在10周时仍有残留迹象。NXY - 059治疗在3周时显著减轻了忽视，在10周时未观察到缺陷。NXY - 059使总体梗死体积减少了28%（生理盐水组，324±46立方毫米；NXY - 059组，234±30立方毫米），对皮质、白质和皮质下结构均有保护作用。
在灵长类动物中，pMCAO后4小时给予NXY - 059是一种有效的神经保护剂，可减轻运动和空间忽视。该化合物还显著减少了脑损伤的体积。
