Hall E D, Andrus P K, Smith S L, Oostveen J A, Scherch H M, Lutzke B S, Raub T J, Sawada G A, Palmer J R, Banitt L S, Tustin J S, Belonga K L, Ayer D E, Bundy G L
CNS Diseases Research, Upjohn Company, Kalamazoo, MI, USA.
Acta Neurochir Suppl. 1996;66:107-13. doi: 10.1007/978-3-7091-9465-2_19.
The 21-aminosteroid (lazaroid) tirilazad mesylate has been demonstrated to be a potent inhibitor of lipid peroxidation and to reduce traumatic and ischemic damage in a number of experimental models. Currently, tirilazad is being actively investigated in phase III clinical trials in head and spinal cord injury, ischemic stroke and subarachnoid hemorrhage. This compound acts in large part to protect the microvascular endothelium and consequently to maintain normal blood-brain barrier (BBB) permeability and cerebral blood flow autoregulatory mechanisms. However, due to its limited penetration into brain parenchyma, tirilazad has generally failed to affect delayed neuronal damage to the selectively vulnerable hippocampal CA1 and striatal regions. Recently, we have discovered a new group of antioxidant compounds, the pyrrolopyrimidines, which possess significantly improved ability to penetrate the BBB and gain direct access to neural tissue. Several compounds in the series, such as U-101033E, have demonstrated greater ability to protect the CA1 region in the gerbil transient forebrain ischemia model with a post-ischemic therapeutic window of at least four hours. In addition, U-101033E has been found to reduce infarct size in the mouse permanent middle cerebral artery occlusion model in contrast to tirilazad which is minimally effective. These results suggest that antioxidant compounds with improved brain parenchymal penetration are better able to limit certain types of ischemic brain damage compared to those which are localized in the cerebral microvasculature. On the other hand, microvascularly-localized agents like tirilazad appear to have better ability to limit BBB damage.
21-氨基类固醇（拉扎罗类化合物）甲磺替拉扎特已被证明是脂质过氧化的有效抑制剂，并能在多种实验模型中减轻创伤性和缺血性损伤。目前，甲磺替拉扎特正在进行头部和脊髓损伤、缺血性中风及蛛网膜下腔出血的III期临床试验。该化合物在很大程度上通过保护微血管内皮来维持正常的血脑屏障（BBB）通透性和脑血流自动调节机制。然而，由于其对脑实质的穿透有限，甲磺替拉扎特通常无法影响对选择性易损的海马CA1区和纹状体区域的迟发性神经元损伤。最近，我们发现了一组新的抗氧化化合物——吡咯并嘧啶，它们穿透血脑屏障并直接进入神经组织的能力有显著提高。该系列中的几种化合物，如U-101033E，在沙鼠短暂性前脑缺血模型中已证明具有更强的保护CA1区的能力，缺血后治疗窗至少为4小时。此外，与效果甚微的甲磺替拉扎特相比，已发现U-101033E可减小小鼠永久性大脑中动脉闭塞模型中的梗死体积。这些结果表明，与那些定位于脑微血管的抗氧化化合物相比，具有更好脑实质穿透性的抗氧化化合物能更好地限制某些类型的缺血性脑损伤。另一方面，像甲磺替拉扎特这类定位于微血管的药物似乎在限制血脑屏障损伤方面能力更强。
