Plasma and Brain Matrix Metalloproteinase-9 After Acute Focal Cerebral Ischemia in Rats

Park, Kyung-Pil; Rosell, Anna; Foerch, Christian; Xing, Chao; Kim, Woo Jean; Lee, Seoul; Opdenakker, Ghislain; Furie, Karen L.; Lo, Eng H.

doi:10.1161/strokeaha.109.554824

Cited by 124 publications

(90 citation statements)

References 32 publications

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“…3). In consistent with the previous report (Park et al 2009), the proMMP9 level was increased 24 h after HI injury as compared to the sham level (data not shown). Future study is required to investigate the pro-MMPs and their transcriptional levels after HI injury.…”

Section: Discussionsupporting

confidence: 93%

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Chen

Hartman

Ayer

et al. 2009

Journal of Neurochemistry

109

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Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which are capable of degrading many types of extracellular matrix proteins and involved in the process of tissue remodeling in various pathologic conditions, including inflammatory diseases, tumor cell invasion, and angiogenesis. Previous studies suggest that MMPs, in particular MMP-2 and MMP-9, are deleterious in the brain after stroke (Power et al. 2003;Svedin et al. 2007). In acute stage after ischemic stroke, the effect of MMP activity is correlated to degradation of neurovascular matrix and opening of blood-brain barrier (BBB), which promotes vasogenic edema and results in neurological deficits. However, recent studies suggest that MMPs were also indicated to be involved in the repairing phase in the delayed stage after cerebral ischemia, including neuroblasts migration and neuronal plasticity (Lee et al. 2006;Zhao et al. 2006 AbstractThe present study was designed to investigate the role of matrix metalloproteinases (MMPs) in the immature brain and the long term effects of early MMPs inhibition after hypoxicischemic (HI) injury. HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O 2 for 2 h) in P7 rat pups. GM6001, a broad spectrum MMPs inhibitor, was injected (50 mg/kg or 100 mg/kg) intraperitoneally at 2 h and 24 h after HI injury. Blood-brain barrier (BBB) integrity, brain edema, MMP-2/-9 activity, TIMP-1/-2 and tight junction protein (TJP) level were evaluated using IgG staining, Evan's blue extravasation, brain water content, zymography and western blot. Doxycycline, another MMPs inhibitor, was injected (10 mg/kg or 30 mg/kg) intraperitoneally at 2 h after HI, then BBB integrity and brain edema were measured at 48 h post-HI using brain water content measurement and IgG staining. The long-term effects of early MMPs inhibition (GM6001, 100 mg/ kg) were evaluated by neurobehavioral tests, body weight, and brain atrophy measurement. GM6001 attenuated brain edema and BBB disruption at the dosage of 100 mg/kg. MMP-2 activity increased at 24 h and peaked at 48 h after HI, whereas MMP-9 activity peaked at 24 h and tapered by 48 h after HI. MMP-9/-2 activities were significantly attenuated by GM6001 at 24 h and 48 h after HI. The degradation of TJPs (ZO-1 and occludin) at 48 h after HI was reversed by GM6001 treatment. Early MMPs inhibition had long-term effects that attenuated ipsilateral brain tissue loss, and improved neurobehavioral outcomes after HI. These results suggest that early MMPs inhibition with a broad-spectrum inhibitor provides both acute and long-term neuroprotection in the developing brain by reducing TJPs degradation, preserving BBB integrity, and ameliorating brain edema after neonatal HI injury. Keywords: blood-brain barrier, hypoxic/ischemic, matrix metalloproteinase, neonatal.

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Section: Discussionsupporting

confidence: 93%

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Chen

Hartman

Ayer

et al. 2009

Journal of Neurochemistry

109

View full text Add to dashboard Cite

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“…31 For in vivo studies, using the same ischemic mouse models, we previously observed during the course of experiments that MMP-9 levels were dramatically unregulated and activated while MMP-2 levels remained similar in the ischemic cortex and the non-lesioned cortex, suggesting that MMP-9 is the predominant gelatinase involved, at least under our experimental conditions. 8,20,21,32 Our observations are consistent with the studies of Lo and others, [33][34][35] suggesting that there is only low level induction of MMP-2 after cerebral ischemia in rodent models; moreover, these levels of MMP-2 are much lower than those of MMP-9. Similar results were found in brain tissues and blood from human stroke patients showing increased MMP-9 levels.…”

Section: Discussionsupporting

confidence: 91%

Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke

Chen

Cui

Jiang

et al. 2016

J Cereb Blood Flow Metab

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Matrix metalloproteinases (MMPs), particularly gelatinases (MMP-2/-9), are involved in neurovascular impairment after stroke. Detection of gelatinase activity in vivo can provide insight into blood-brain barrier disruption, hemorrhage, and nerve cell injury or death. We applied gelatinase-activatable cell-penetrating peptides (ACPP) with a cleavable L-amino acid linker to examine gelatinase activity in primary neurons in culture and ischemic mouse brain in vivo. We found uptake of Cy5-conjugated ACPP (ACPP-Cy5) due to gelatinase activation both in cultured neurons exposed to N-methyl-D-aspartate and in mice after cerebral ischemia. Fluorescence intensity was significantly reduced when cells or mice were treated with MMP inhibitors or when a cleavage-resistant ACPP-Cy5 was substituted. We also applied an ACPP dendrimer (ACPPD) conjugated with multiple Cy5 and/or gadolinium moieties for fluorescence and magnetic resonance imaging (MRI) in intact animals. Fluorescence analysis showed that ACPPD was detected in subfemtomole range in ischemic tissues. Moreover, MRI and inductively coupled plasma mass spectrometry revealed that ACPPD produced quantitative measures of gelatinase activity in the ischemic region. The resulting spatial pattern of gelatinase activity and neurodegeneration were very similar. We conclude that ACPPs are capable of tracing spatiotemporal gelatinase activity in vivo, and will therefore be useful in elucidating mechanisms of gelatinase-mediated neurodegeneration after stroke.

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“…MMPs also play a crucial role in brain inflammation by increasing blood-brain barrier permeability through the destruction of extracellular matrix (Park et al, 2009). Neutrophil infiltration contributes to the increase in MMP-9 in the ischemic brain (Justicia et al, 2003) of stroke patients (Lo et al, 2003).…”

Section: /Ach3mentioning

confidence: 99%

Myeloperoxidase Inhibition Increases Neurogenesis after Ischemic Stroke

Kim

Wei

Lee

et al. 2016

J Pharmacol Exp Ther

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The relationship between inflammation and neurogenesis in stroke is currently not well understood. Focal ischemia enhances cell proliferation and neurogenesis in the neurogenic regions, including the subventricular zone (SVZ), dentate gyrus, as well as the non-neurogenic striatum, and cortex in the ischemic hemisphere. Myeloperoxidase (MPO) is a potent oxidizing enzyme secreted during inflammation by activated leukocytes, and its enzymatic activity is highly elevated after stroke. In this study, we investigated whether the inhibition of MPO activity by a specific irreversible inhibitor, 4-aminobenzoic acid hydrazide (ABAH) (MPO 2/2 mice) can increase neurogenesis after transient middle cerebral artery occlusion in mice. ABAH administration increased the number of proliferating bromodeoxyuridine (BrdU)-positive cells expressing markers for neural stems cells, astrocytes, neuroprogenitor cells (Nestin), and neuroblasts (doublecortin) in the ischemic SVZ, anterior SVZ, striatum, and cortex. MPO inhibition also increased levels of brain-derived neurotrophic factor, phosphorylation of cAMP response element-binding protein (Ser133), acetylated H3, and NeuN to promote neurogenesis in the ischemic SVZ. ABAH treatment also increased chemokine CXC receptor 4 expression in the ischemic SVZ. MPO-deficient mice treated with vehicle or ABAH both showed similar effects on the number of BrdU 1 cells in the ischemic hemisphere, demonstrating that ABAH is specific to MPO. Taken together, our results underscore a detrimental role of MPO activity to postischemia neurogenesis and that a strategy to inhibit MPO activity can increase cell proliferation and improve neurogenesis after ischemic stroke.

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Plasma and Brain Matrix Metalloproteinase-9 After Acute Focal Cerebral Ischemia in Rats

Cited by 124 publications

References 32 publications

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Matrix metalloproteinases inhibition provides neuroprotection against hypoxia‐ischemia in the developing brain

Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke

Myeloperoxidase Inhibition Increases Neurogenesis after Ischemic Stroke

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