title: Matrix Metalloproteinase-8 is a Novel Pathogenetic Factor in Focal Cerebral Ischemia.
abstract: The neutrophil collagenase matrix metalloproteinase-8 (MMP8) is a recently identified member of MMPs that have important roles in various inflammation-related disorders. Previously, we identified MMP8 as a new neuroinflammatory mediator in activated microglia by regulating TNF-α productivity. Here, we present evidence that MMP8 is a critical factor for brain damage in transient focal cerebral ischemia by modulating neuroinflammation likely microglial activation and TNF-α production. Biochemical analyses showed upregulation of MMP8 expression at mRNA and protein levels in transient middle cerebral artery occlusion/reperfusion (M/R)-challenged brains. Furthermore, double immunolabeling showed that MMP8 expression was upregulated in the activated microglia of M/R-challenged brains. Assessment of infarct volume, neurological score, and survival/death of neural cells revealed that administration of an MMP8 inhibitor (M8I) immediately after reperfusion reduced brain damage. Histological analyses showed that microglial activation and TNF-α expression in ischemic conditions was abrogated by exposure to M8I, as demonstrated in our previous study using cultured microglia. These outcomes from a pharmacological approach were reaffirmed by a genetic approach using a lentiviral system. Intracerebroventricular microinjection of MMP8-specific shRNA lentivirus reduced the extent of ischemia-induced brain damage, as assessed by infarct volume, neurological score, microglial activation, and TNF-α expression. These results suggest a novel pathogenetic role of MMP8 and implicate modulation of its activity as a tractable strategy for therapies against cerebral ischemia.
authors.affiliation: Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 406-799, South Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Han
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Mok-6-dong 911-1, Yangchun-Ku, Seoul, 158-710, South Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 406-799, South Korea.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Moon
authors.affiliation: Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, South Korea.
authors.forename: Jong Hoon
authors.initials: JH
authors.lastname: Ryu
authors.affiliation: Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 406-799, South Korea. pharmchoi@gachon.ac.kr.
authors.forename: Ji Woong
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Mok-6-dong 911-1, Yangchun-Ku, Seoul, 158-710, South Korea. hskimp@ewha.ac.kr.
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D062507:Claudin-5 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D016086:Lentivirus / Q000378:metabolism; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism*; D008813:Mice, Inbred ICR; D034741:RNA, Small Interfering / Q000378:metabolism; D015424:Reperfusion; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D062507:Claudin-5; D034741:RNA, Small Interfering; D020784:Matrix Metalloproteinase 8
keywords: MMP8; MMP8 inhibitor; MMP8 shRNA; Microglia; Middle cerebral artery occlusion/reperfusion; TNF-α