Storini Claudio, Bergamaschini Luigi, Gesuete Raffaella, Rossi Emanuela, Maiocchi Diana, De Simoni Maria Grazia
Department of Neuroscience, Mario Negri Institute, Milan, Italy.
J Pharmacol Exp Ther. 2006 Aug;318(2):849-54. doi: 10.1124/jpet.106.105064. Epub 2006 May 16.
We have studied the effect of DX-88, a selective recombinant inhibitor of human plasma kallikrein, in transient or permanent focal brain ischemia (with or without reperfusion, respectively) induced in C57BL/6 mice. Twenty-four hours after transient ischemia, DX-88 administered at the beginning of ischemia (pre) induced a dose-dependent reduction of ischemic volume that, at the dose of 30 microg/mouse, reached 49% of the volume of saline-treated mice. At the same dose, DX-88 was also able to reduce brain swelling to 32%. Mice treated with DX-88 pre had significantly lower general and focal deficit score. Fluoro-Jade staining, a marker for neuronal degeneration, showed that DX-88-treated mice had a reduction in the number of degenerating cells, compared with saline-treated mice. Seven days after transient ischemia, the DX-88 protective effect was still present. When the inhibitor was injected at the end of ischemia (post), it was still able to reduce ischemic volume, brain swelling, and neurological deficits. DX-88 efficacy was lost when the inhibitor was given 30 min after the beginning of reperfusion (1 h post) or when reperfusion was not present (permanent occlusion model). This study shows that DX-88 has a strong neuroprotective effect in the early phases of brain ischemia preventing reperfusion injury and indicates that inhibition of plasma kallikrein may be a useful tool in the strategy aimed at reducing the detrimental effects linked to reperfusion.
我们研究了人血浆激肽释放酶的选择性重组抑制剂DX-88对C57BL/6小鼠诱导的短暂性或永久性局灶性脑缺血（分别伴有或不伴有再灌注）的影响。短暂性缺血后24小时，在缺血开始时（预先）给予DX-88可导致缺血体积呈剂量依赖性减少，在30微克/小鼠的剂量下，缺血体积减少至生理盐水处理小鼠的49%。在相同剂量下，DX-88还能将脑肿胀减少至32%。预先用DX-88处理的小鼠总体和局灶性缺陷评分显著更低。Fluoro-Jade染色是神经元变性的标志物，结果显示与生理盐水处理的小鼠相比，DX-88处理的小鼠变性细胞数量减少。短暂性缺血7天后，DX-88的保护作用仍然存在。当在缺血结束时（事后）注射该抑制剂时，它仍然能够减少缺血体积、脑肿胀和神经功能缺损。当在再灌注开始后30分钟（1小时后）给予该抑制剂或不存在再灌注（永久性闭塞模型）时，DX-88的疗效消失。这项研究表明，DX-88在脑缺血早期具有强大的神经保护作用，可预防再灌注损伤，并表明抑制血浆激肽释放酶可能是旨在减少与再灌注相关的有害影响的策略中的一种有用工具。
