Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases.
Intracerebral hemorrhage (ICH) is characterized by parenchymal hematoma formation with surrounding inflammation. Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of neurological diseases defined by inflammation and cell death. To investigate the expression profile and pathogenic aspects of MMPs in ICH, we examined MMP expression in vivo using a collagenase-induced rat model of ICH. ICH increased brain MMP-2, -3, -7, and -9 mRNA levels relative to sham-injected (control) animals in the vicinity of the hematoma, but MMP-12 (macrophage metalloelastase) was the most highly induced MMP (>80-fold). Immunohistochemistry showed MMP-12 to be localized in activated monocytoid cells surrounding the hematoma. In vitro studies showed that thrombin, released during ICH, induced MMP-12 expression in monocytoid cells, which was reduced by minocycline application. Similarly, in vivo minocycline treatment significantly reduced MMP-12 levels in brain. Neuropathological studies disclosed marked glial activation and apoptosis after ICH that was reduced by minocycline treatment. Neurobehavioral outcomes also were improved with minocycline treatment compared with untreated ICH controls. Thus, select MMPs exhibit increased expression after ICH, whereas minocycline is neuroprotective after ICH by suppressing monocytoid cell activation and downregulating MMP-12 expression.
Power
Christopher
C
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. power@ucalgary.ca
Henry
Scot
S
Del Bigio
Marc R
MR
Larsen
Peter H
PH
Corbett
Dale
D
Imai
Yumi
Y
Yong
Voon Wee
VW
Peeling
James
J
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology; D015153:Blotting, Western; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008264:Macrophages / Q000187:drug effects*; D008279:Magnetic Resonance Imaging; D008297:Male; D053508:Matrix Metalloproteinase 12; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008911:Minocycline / Q000008:administration & dosage / Q000494:pharmacology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000906:Antibodies; D012333:RNA, Messenger; D013917:Thrombin; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12; D008911:Minocycline