Doğan A, Rao A M, Başkaya M K, Rao V L, Rastl J, Donaldson D, Dempsey R J
Department of Neurological Surgery, University of Wisconsin, and Veterans Administration Hospital, Madison 53792, USA.
J Neurosurg. 1997 Dec;87(6):921-6. doi: 10.3171/jns.1997.87.6.0921.
Polyamines and N-methyl-D-aspartate (NMDA) receptors are both thought to play an important role in secondary neuronal injury after cerebral ischemia. Ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, was studied after transient focal cerebral ischemia occurred. Spontaneously hypertensive male rats, each weighing between 250 and 350 g, underwent 3 hours of tandem middle cerebral artery (MCA) and common carotid artery occlusion followed by reperfusion for a period of 3 hours or 21 hours. Intravenous ifenprodil (10 microg/kg/minute) or saline infusion was started immediately after the onset of MCA occlusion and continued throughout the ischemic period. Physiological parameters including blood pressure, blood gas levels, blood glucose, hemoglobin, and rectal and temporal muscle temperatures were monitored. Six rats from each group were evaluated at 6 hours postocclusion for brain water content, an indicator of brain edema, and Evans blue dye extravasation for blood-brain barrier breakdown. Infarct volume was also measured in six rats from each group at 6 and 24 hours postocclusion. Ifenprodil treatment significantly reduced brain edema (82.5 +/- 0.4% vs. 83.5 +/- 0.4%, p < 0.05) and infarct volume (132 +/- 14 mm3 vs. 168 +/- 25 mm3, p < 0.05) compared with saline treatment, with no alterations in temporal muscle (brain) or rectal (body) temperature (35.9 +/- 0.4 degrees C vs. 36.2 +/- 0.2 degrees C; 37.7 +/- 0.4 degrees C vs. 37.6 +/- 0.6 degrees C; not significant). These results demonstrate that ifenprodil has neuroprotective properties after ischemia/reperfusion injury in the absence of hypothermia. This indicates that antagonists selective for the polyamine site of the NMDA receptors may be a viable treatment option and helps to explain some of the pathophysiological mechanisms involved in secondary injury after transient focal cerebral ischemia has occurred.
多胺和N-甲基-D-天冬氨酸（NMDA）受体均被认为在脑缺血后的继发性神经元损伤中起重要作用。在短暂性局灶性脑缺血发生后，对已知为NMDA受体多胺位点非竞争性抑制剂的艾芬地尔进行了研究。体重在250至350克之间的自发性高血压雄性大鼠，经历了3小时的大脑中动脉（MCA）和颈总动脉串联闭塞，随后再灌注3小时或21小时。在MCA闭塞开始后立即开始静脉输注艾芬地尔（10微克/千克/分钟）或生理盐水，并在整个缺血期持续输注。监测包括血压、血气水平、血糖、血红蛋白以及直肠和颞肌温度在内的生理参数。在闭塞后6小时对每组6只大鼠进行评估，测定脑水肿指标脑含水量以及血脑屏障破坏指标伊文思蓝染料外渗情况。在闭塞后6小时和24小时对每组6只大鼠也测量了梗死体积。与生理盐水治疗相比，艾芬地尔治疗显著减轻了脑水肿（82.5±0.4%对83.5±0.4%，p<0.05）和梗死体积（132±14立方毫米对168±25立方毫米，p<0.05），颞肌（脑）或直肠（身体）温度无变化（35.9±0.4℃对36.2±0.2℃；37.7±0.4℃对37.6±0.6℃；无显著性差异）。这些结果表明，在无低温的情况下，艾芬地尔在缺血/再灌注损伤后具有神经保护特性。这表明对NMDA受体多胺位点具有选择性的拮抗剂可能是一种可行的治疗选择，并有助于解释短暂性局灶性脑缺血发生后继发性损伤所涉及的一些病理生理机制。
