Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases

Abstract

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.

CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

“…Moreover, we analyzed CM352's effect on MMPs that had been reported to be upregulated after ICH in humans and experimental models 14, 25. We previously reported that CM352 efficiently inhibited MMP‐3 and MMP‐10,20 and in this study we describe that it also inhibits MMP‐2, MMP‐9, and MMP‐12 in the nanomolar range.…”

“…Rapid MMP upregulation after ICH has been proposed to cause neurovascular matrix degradation, proteolyzing the basal lamina around blood vessels and disrupting endothelial tight junctions, leading to edema, hemorrhage, and cell death 13. Based on this rationale, early treatment with broad‐range MMP inhibitors has been used in experimental models to reduce brain damage after ICH 13, 14…”

Inflammation after Intracerebral Hemorrhage

“…In 1997, Rosenberg and Navratil (1997) first demonstrated that MMP2 and 9 activation increased 16 to 24 h after collagenase-induced ICH in rats. Extending this work, a study by Power et al (2003) indicated that collagenase-induced hemorrhage in rat increased brain MMP2, 3, 7, and 9 mRNA levels at 24 h, but MMP12 (macrophage metalloelastase) was the most highly induced ( > 80-fold) at day 7. Immunohistochemistry showed MMP12 to be localized in activated microglia/macrophages surrounding the hematoma.…”

Detrimental Effects of Leptin on Intracerebral Hemorrhage via the STAT3 Signal Pathway

“…11,12 Inflammation after ICH can cause disruption of the blood-brain barrier, 13 elicit brain edema, 14 and contribute to cell death after hemorrhage via cytotoxic mediators. 15,16 In this context, we have focused on leptin and inflammation after ICH, and brain edema is used as an important marker of brain injury related to inflammation. We sought to investigate whether leptin has a detrimental effect on ICH in terms of post-ICH inflammation.…”