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: Jeong Eun Han, Eun-Jung Lee, Eunjung Moon, Jong Hoon Ryu, Ji Woong Choi, Hee-Sun Kim
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 53 Issue 1 Pg. 231-239 (Jan 2016) ISSN: 1559-1182 [Electronic] United States
• PMID: 25421209 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Claudin-5
• RNA, Small Interfering
• Matrix Metalloproteinase 8

Topics

• Animals
• Blood-Brain Barrier (drug effects, pathology)
• Brain (drug effects, enzymology, pathology)
• Brain Ischemia (complications, enzymology, pathology)
• Claudin-5 (metabolism)
• Down-Regulation (drug effects)
• Infarction, Middle Cerebral Artery (complications, pathology)
• Inflammation (pathology)
• Lentivirus (metabolism)
• Male
• Matrix Metalloproteinase 8 (metabolism)
• Mice, Inbred ICR
• RNA, Small Interfering (metabolism)
• Reperfusion
• Up-Regulation (drug effects)