Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via matrix metalloproteinase-9 inhibition.
Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via matrix metalloproteinase-9 inhibition.
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DOI：
10.1002/acn3.492
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发表时间：
2017-12
影响因子：
5.3
通讯作者：
Zipfel GJ
中科院分区：
文献类型：
--
作者：
Vellimana AK;Zhou ML;Singh I;Aum DJ;Nelson JW;Harris GR;Athiraman U;Han BH;Zipfel GJ
迟发性脑缺血（DCI）是动脉瘤性蛛网膜下腔出血（SAH）后预后不良的独立危险因素，其病因是多因素的。虽然先前的研究表明基质金属蛋白酶 9 (MMP-9) 在 SAH 后早期脑损伤中发挥作用，但其对 DCI 病理生理学的贡献尚不清楚。在第一个实验中，野生型 (WT) 和 MMP-9−/− 小鼠接受了假手术或血管内穿孔 SAH 手术。在单独的实验中，WT 和 MMP-9−/− 小鼠在 SAH 前或后给予载体或米诺环素。所有小鼠均接受 DCI 多种成分的评估，包括血管痉挛、神经行为功能和微血管血栓形成。在另一项实验中，对兔子进行假手术或小脑延髓池注射SAH手术，并给予载体或米诺环素，然后进行血管痉挛评估。 SAH 后 MMP-9 表达和活性增加。 MMP-9 的遗传（MMP-9−/− 小鼠）和药理学（SAH 前米诺环素给药）抑制导致血管痉挛和神经行为缺陷减少。 SAH 后给予米诺环素的治疗可行策略导致 DCI 的多种成分减弱。对 MMP-9−/− 小鼠施用米诺环素并没有产生额外的保护作用。与小鼠实验一致，蛛网膜下腔出血前和蛛网膜下腔出血后给予米诺环素均能减轻兔子蛛网膜下腔出血引起的血管痉挛。 MMP-9 是 DCI 发病机制中的关键角色。在不同物种和 SAH 实验模型中，SAH 前后给予米诺环素可一致减弱 DCI 的多种成分，再加上米诺环素在人体中出色的安全性，表明有必要在 SAH 患者中进行临床试验。
Delayed cerebral ischemia (DCI) is an independent risk factor for poor outcome after aneurysmal subarachnoid hemorrhage (SAH) and is multifactorial in etiology. While prior studies have suggested a role for matrix metalloproteinase‐9 (MMP‐9) in early brain injury after SAH, its contribution to the pathophysiology of DCI is unclear. In the first experiment, wild‐type (WT) and MMP‐9−/− mice were subjected to sham or endovascular perforation SAH surgery. In separate experiments, WT and MMP‐9−/−mice were administered vehicle or minocycline either pre‐ or post‐SAH. All mice underwent assessment of multiple components of DCI including vasospasm, neurobehavioral function, and microvessel thrombosis. In another experiment, rabbits were subjected to sham or cisterna magna injection SAH surgery, and administered vehicle or minocycline followed by vasospasm assessment. MMP‐9 expression and activity was increased after SAH. Genetic (MMP‐9−/− mice) and pharmacological (pre‐SAH minocycline administration) inhibition of MMP‐9 resulted in decreased vasospasm and neurobehavioral deficits. A therapeutically feasible strategy of post‐SAH administration of minocycline resulted in attenuation of multiple components of DCI. Minocycline administration to MMP‐9−/− mice did not yield additional protection. Consistent with experiments in mice, both pre‐ and post‐SAH administration of minocycline attenuated SAH‐induced vasospasm in rabbits. MMP‐9 is a key player in the pathogenesis of DCI. The consistent attenuation of multiple components of DCI with both pre‐ and post‐SAH administration of minocycline across different species and experimental models of SAH, combined with the excellent safety profile of minocycline in humans suggest that a clinical trial in SAH patients is warranted.
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影响因子：
8.3
作者：
Chou SH;Lee PS;Konigsberg RG;Gallacci D;Chiou T;Arai K;Simmons S;Bauer D;Feske SK;Lo EH;Ning M
通讯作者：
Ning M
影响因子：
1.9
作者：
Lago, Aida;Ignacio Tembl, Jose;Parkhutik, Vera
通讯作者：
Parkhutik, Vera
影响因子：
8.3
作者：
Claassen, J;Carhuapoma, JR;Mayer, SA
通讯作者：
Mayer, SA
影响因子：
5.3
作者：
Milner, Eric;Johnson, Andrew W.;Nelson, James W.;Harries, Michael D.;Gidday, Jeffrey M.;Han, Byung Hee;Zipfel, Gregory J.
通讯作者：
Zipfel, Gregory J.
影响因子：
8.3
作者：
Fagan SC;Waller JL;Nichols FT;Edwards DJ;Pettigrew LC;Clark WM;Hall CE;Switzer JA;Ergul A;Hess DC
通讯作者：
Hess DC