Addition of intravenous N-methyl-D-aspartate receptor antagonists to local fibrinolytic therapy for the optimal treatment of experimental intracerebral hemorrhages
Addition of intravenous N-methyl-D-aspartate receptor antagonists to local fibrinolytic therapy for the optimal treatment of experimental intracerebral hemorrhages
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DOI：
10.3171/jns.2007.106.2.314
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发表时间：
2007-02-01
影响因子：
4.1
通讯作者：
Rohde, Veit
中科院分区：
文献类型：
--
作者：
Thiex, Ruth;Weis, Joachim;Rohde, Veit
Object.重组组织型纤溶酶原激活剂（rtPA）的纤溶治疗被认为是深部脑出血（ICH）患者的一种治疗选择。然而，动物实验的结果表明，tPA在脑中发挥多效性作用，包括调节血管活性、通过切割N-甲基-D-天冬氨酸（NMDA）受体亚单位放大钙电导、激活金属蛋白酶，这会增加兴奋性毒性、损害血脑屏障并加重水肿。作者研究了非竞争性NMDA受体拮抗剂MK 801是否可以作为辅助治疗与rtPA联合使用，以减轻在实验性猪ICH模型中观察到的rdPA治疗后不利的延迟水肿形成和炎症。本研究中使用了20头猪;在血肿诱导后立即以及在血肿诱导后第1天和第3天，对每头猪静脉给予MK 801（0.3 mg/kg）。20头猪中的10头被随机分配接受rtPA纤维蛋白溶解治疗（MK 801-tPA组），而在其余10头对照动物（MK 801组）中，允许血肿遵循其自然的再吸收过程。在血肿诱导后第0、4和10天使用磁共振（MR）成像体积测定法评价水肿形成的程度，并与尸检时发现的组织病理学变化进行比较。还将这两组中的平均水肿体积与在先前实验系列中检查的9只猪的组中的平均水肿体积进行比较，其中动物的血肿仅用rtPA处理在MK 801-tPA组的10只动物中，在血肿诱导后第4天（p < 0.08）或第10天（p < 0.35），MR图像上的平均血肿周围水肿体积没有显著增加。在MK 801组的10只动物中，平均病灶周围水肿尺寸在4天后显著增加（p < 0.001），在10天后不显著（p < 0.09）。在tPA组的9只动物中，平均水肿体积在第4天（p < 0.002）和第10天（p < 0.03）显著增加。正如延迟水肿体积和炎症反应的减少所表明的那样，MK 801改变了rtPA的神经毒性特性，但不改变血液降解产物的神经毒性特性。如果与MK 801等药物联合使用，ICH的纤溶治疗可能更有益。
Object. Fibrinolytic therapy with recombinant tissue plasminogen activator (rtPA) is considered a treatment option in patients with deep-seated intracerebral hemorrhage (ICH). Nevertheless, the results of animal experiments have shown that tPA exerts pleiotropic actions in the brain, including regulation of vasoactivity, amplification of calcium conductance by cleavage of the N-methyl-D-aspartate (NMDA) receptor subunit, and activation of metalloproteinases, which increase excitotoxicity, damage the blood-brain barrier, and worsen edema. The authors investigated whether the noncompetitive NMDA receptor antagonist MK801 can be used as an adjuvant therapy in combination with rtPA to attenuate the unfavorable delayed edema formation and inflammation observed following rdPA therapy in an experimental porcine model of ICH.Methods. Twenty pigs were used in this study; MK801 (0.3 mg/kg) was administered to each pig intravenously immediately after hematoma induction and on the 1st and 3rd day after hematoma induction. Ten of the 20 pigs were randomly assigned to fibrinolytic therapy with rtPA (MK801-tPA group), whereas in the remaining 10 control animals (MK801 group) the hematomas were allowed to follow their natural courses of resorption. The extent of edema formation was evaluated using magnetic resonance (MR) imaging volumetry on Days 0, 4, and 10 after hematoma induction and was compared with histopathological changes found at necropsy. The mean edema volumes in these two groups were also compared with that in the group of nine pigs examined in a preceding experimental series, in which the animals' hematomas were only treated with rtPA (tPA group).In the 10 animals in the MK801-tPA group, the mean perihematoma edema volume on MR images had not significantly increased by Day 4 (p < 0.08) or Day 10 (p < 0.35) after hematoma induction. In the 10 animals in the MK801 group, the increase in mean perifocal edema size was significant after 4 days (p < 0.001) and nonsignificant after 10 days (p < 0.09). In the nine animals in the tPA group, the mean edema volume significantly increased by Days 4 (p < 0.002) and 10 (p < 0.03).Conclusions. As suggested by the reduction in delayed edema volume and the inflammatory response, MK801 modifies the neurotoxic properties of rtPA but not those of blood degradation products. Possibly, fibrinolytic therapy of ICH is more beneficial if combined with agents such as MK801.