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Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases
Christopher Power1, Scot Henry, Marc R Del Bigio
1Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. power@ucalgary.ca
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.
Insights
Intracerebral hemorrhage (ICH) increases matrix metalloproteinases (MMPs), particularly MMP-12. Minocycline treatment reduced MMP-12, glial activation, and apoptosis, improving neurobehavioral outcomes in ICH rats.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Intracerebral hemorrhage (ICH) involves brain tissue damage and inflammation.
- Matrix metalloproteinases (MMPs) are linked to inflammation and cell death in neurological disorders.
Purpose of the Study:
- To investigate MMP expression and roles in ICH pathogenesis.
- To evaluate minocycline's neuroprotective effects in an ICH model.
Main Methods:
- A collagenase-induced rat model of ICH was used.
- MMP expression (mRNA and protein) was analyzed via RT-PCR and immunohistochemistry.
- In vitro studies assessed thrombin's effect on MMP-12 in monocytoid cells.
- Minocycline's impact on MMP-12, glial activation, apoptosis, and neurobehavior was evaluated.
Main Results:
- ICH significantly upregulated MMP-2, -3, -7, and -9 mRNA levels.
- MMP-12 (macrophage metalloelastase) showed the highest induction (>80-fold) and localized to activated monocytoid cells.
- Thrombin induced MMP-12 in vitro, an effect reduced by minocycline.
- Minocycline treatment in vivo reduced MMP-12 levels, glial activation, apoptosis, and improved neurobehavioral outcomes.
Conclusions:
- ICH elevates the expression of specific MMPs, with MMP-12 being significantly upregulated.
- Minocycline demonstrates neuroprotective effects in ICH by inhibiting monocytoid cell activation and downregulating MMP-12.
- Minocycline treatment mitigates ICH-induced neuropathology and improves functional recovery.