Attenuation of brain edema, blood-brain barrier breakdown, and injury volume by ifenprodil, a polyamine-site N-methyl-D-aspartate receptor antagonist, after experimental traumatic brain injury in rats
Attenuation of brain edema, blood-brain barrier breakdown, and injury volume by ifenprodil, a polyamine-site N-methyl-D-aspartate receptor antagonist, after experimental traumatic brain injury in rats
复制标题
DOI：
10.1097/00006123-200008000-00024
复制
发表时间：
2000-08-01
期刊：
影响因子：
4.8
通讯作者：
Dogan, A
中科院分区：
文献类型：
--
作者：
Dempsey, RJ;Baskaya, MK;Dogan, A
目的：创伤性脑损伤（TBI）已被证明会引起多胺代谢的显著变化。多胺和多胺依赖性钙内流在介导兴奋性毒性氨基酸对N -甲基 - D -天冬氨酸（NMDA）受体位点的作用中起重要作用。我们研究了艾芬地尔（一种已知的NMDA受体多胺位点的非竞争性抑制剂）对创伤性脑损伤后脑水肿形成、血脑屏障破坏和损伤体积的影响。
方法：采用可控皮质撞击装置以3米/秒的速度撞击造成2毫米变形，在Sprague - Dawley大鼠中诱导实验性创伤性脑损伤。在皮质撞击损伤后立即腹腔注射艾芬地尔或生理盐水（10毫克/千克），然后每90分钟注射一次，直至创伤性脑损伤后6小时。损伤后6小时通过伊文思蓝渗出的荧光测定法定量评估血脑屏障破坏情况。创伤性脑损伤后24小时用干湿法测量脑含水量（脑水肿的一个指标）。创伤性脑损伤后7天从用2%甲酚紫溶液染色的脑切片中定量损伤体积。
结果：艾芬地尔治疗组创伤皮质的血脑屏障破坏明显低于生理盐水治疗组（分别为84.4±26.8微克/克对161.8±27微克/克，P < 0.05）。与生理盐水治疗组相比，艾芬地尔治疗组皮质的脑水肿明显减轻（分别为80.9±0.5%对82.4±0.6%，P < 0.05）。艾芬地尔治疗显著减少了损伤体积（14.9±8.1立方毫米对24.4±6.7立方毫米，P < 0.05）。
结论：多胺位点的NMDA受体拮抗剂艾芬地尔在可控皮质撞击脑损伤模型中提供了显著的神经保护作用，可能对创伤性脑损伤后迟发性神经功能缺损机制的发现和治疗有希望。
OBJECTIVE: Traumatic brain injury (TBI) has been shown to induce a significant change in polyamine metabolism. Polyamines and polyamine-dependent calcium influx play an important role in mediating the effects of excitotoxic amino acids at the N-methyl-D-aspartate (NMDA) receptor site. We studied the effects of ifenprodil, known as a noncompetitive inhibitor of polyamine sites at the NMDA receptor, on brain edema formation, blood-brain barrier breakdown, and volume of injury after TBI.METHODS: Experimental TBI was induced in Sprague-Dawley rats by a controlled cortical impact device, functioning at a velocity of 3 m/s to produce a 2-mm deformation. Ifenprodil or saline (10 mg/kg) was injected intraperitoneally immediately after the cortical impact injury and then every 90 minutes until 6 hours after TBI. Blood-brain barrier breakdown was evaluated quantitatively 6 hours after injury by fluorometric assay of Evans blue extravasation. Brain water content, an indicator of brain edema, was measured with the wet-dry method 24 hours after TBI. Injury volume was quantitated from the brain slices stained with 2% cresyl violet solution 7 days after TBI.RESULTS: Blood-brain barrier breakdown was significantly lower in the traumatic cortex of the ifenprodil-treated group than in the saline-treated group (84.4 +/- 26.8 mu g/g versus 161.8 +/- 27 mu g/g, respectively, P < 0.05). Brain edema was significantly reduced in the cortex of the ifenprodil-treated group relative to that in the saline-treated group (80.9 +/- 0.5% versus 82.4 +/- 0.6% respectively, P < 0.05). Ifenprodil treatment reduced injury volume significantly (14.9 +/- 8.1 mm(3) versus 24.4 +/- 6.7 mm(3), P < 0.05).CONCLUSION: The polyamine-site NMDA receptor antagonist ifenprodil affords significant neuroprotection in a controlled cortical impact brain injury model and may hold promise for the discovery and treatment of the mechanism of delayed neurological deficits after TBI.