A radical scavenger edaravone inhibits matrix metalloproteinase-9 upregulation and blood-brain barrier breakdown in a mouse model of prolonged cerebral hypoperfusion.
A radical scavenger edaravone inhibits matrix metalloproteinase-9 upregulation and blood-brain barrier breakdown in a mouse model of prolonged cerebral hypoperfusion.
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DOI：
10.1016/j.neulet.2014.05.005
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发表时间：
2014-06-24
影响因子：
2.5
通讯作者：
Arai K
中科院分区：
文献类型：
--
作者：
Miyamoto N;Pham LD;Maki T;Liang AC;Arai K
Matrix metalloproteinase-9 (MMP-9) plays key roles in the brain pathophysiology, especially in blood-brain barrier (BBB) breakdown. Therefore, inhibiting MMP-9 activity may be a promising therapy for protecting brains in cerebrovascular diseases. Here we show that in a mouse prolonged cerebral hypoperfusion model, a clinically proven radical scavenger edaravone suppressed MMP-9 and reduced BBB damage in cerebral white matter. Prolonged cerebral hypoperfusion was induced by bilateral common carotid artery stenosis in male adult C57BL/6J mice (10 weeks old). After 7 days of cerebral hypoperfusion, white matter region (e.g. corpus callosum) exhibited significant BBB leakage, assessed by IgG staining. Correspondingly, immunostaining and western blotting showed that MMP-9 was upregulated in the white matter. Edaravone treatment (3 mg/kg, i.p. at day 0 and 3) inhibited both BBB leakage and MMP-9 increase. Under the early phase of cerebral hypoperfusion conditions, oligodendrocyte precursor cells (OPCs) mainly contribute to the MMP-9 increase, but our immunostaining data showed that very little OPCs expressed MMP-9 in the edaravone-treated animals at day 7. Therefore, in vitro studies with primary rat OPCs were conducted to examine whether edaravone would directly suppressed MMP-9 expressions in OPCs. OPC cultures were exposed to sub-lethal CoCl2 for 7 days to induce prolonged chemical hypoxic stress. Prolonged chemical hypoxic stress increased MMP-9 expression in OPCs, and radical scavenging with edaravone (10 μM for 7 days) ameliorated the increase. Taken together, our proof-of-concept study demonstrates that radical scavengers may provide a potential therapeutic approach for white matter injury by suppressing BBB damage.
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影响因子：
5.3
作者：
Arai, Ken;Lo, Eng H.
通讯作者：
Lo, Eng H.
影响因子：
5
作者：
Amemiya, S;Kamiya, T;Katayama, Y
通讯作者：
Katayama, Y
影响因子：
6.2
作者：
Kawasaki, Toshiyuki;Kitao, Tatsuya;Matsuda, Toshio
通讯作者：
Matsuda, Toshio
氧化应激会在小鼠长期脑部灌注延长后干扰白质的更新。
影响因子：
8.3
作者：
Miyamoto N;Maki T;Pham LD;Hayakawa K;Seo JH;Mandeville ET;Mandeville JB;Kim KW;Lo EH;Arai K
通讯作者：
Arai K
影响因子：
4.2
作者：
French, Heather Morein;Reid, Mary;Mamontov, Polina;Simmons, Rebecca A.;Grinspan, Judith B.
通讯作者：
Grinspan, Judith B.