Matrix Metalloproteinase-8 is a Novel Pathogenetic Factor in Focal Cerebral Ischemia

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• 作者：Jeong Eun Han ; Eun-Jung Lee ; Eunjung Moon ; Jong Hoon Ryu…
• 关键词：MMP8 ; MMP8 inhibitor ; MMP8 shRNA ; Microglia ; TNF ; α ; Middle cerebral artery occlusion/reperfusion
• 刊名：Molecular Neurobiology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：53
• 期：1
• 页码：231-239
• 全文大小：4,940 KB
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• 作者单位：Jeong Eun Han (1)
  Eun-Jung Lee (2)
  Eunjung Moon (1)
  Jong Hoon Ryu (3)
  Ji Woong Choi (1)
  Hee-Sun Kim (2)
  
  1. Laboratory of Neuropharmacology, College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, 406-799, Republic of Korea
  2. 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, Republic of Korea
  3. Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
  
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182

文摘

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.