title: A radical scavenger edaravone inhibits matrix metalloproteinase-9 upregulation and blood-brain barrier breakdown in a mouse model of prolonged cerebral hypoperfusion.
abstract: 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 (3mg/kg, i.p. at days 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 (10μM 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.
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, USA.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Miyamoto
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, USA.
authors.forename: Loc-Duyen D
authors.initials: LD
authors.lastname: Pham
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, USA.
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Liang
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D017536:Carotid Artery, Common; D016893:Carotid Stenosis / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D016923:Cell Death; D002470:Cell Survival; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology*; D002534:Hypoxia, Brain / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D066127:White Matter / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D061965:Matrix Metalloproteinase Inhibitors; D020780:Matrix Metalloproteinase 9; D000077553:Edaravone; D000983:Antipyrine
keywords: Blood–brain barrier; Edaravone; Matrix metalloproteinase-9; Prolonged cerebral hypoperfusion; White matter injury