Matrix Metalloproteinase Inhibition Facilitates Cell Death in Intracerebral Hemorrhage in Mouse

Grossetete, Mark; Rosenberg, Gary A.

doi:10.1038/sj.jcbfm.9600572

Cited by 58 publications

(50 citation statements)

References 40 publications

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“…4,22 MMP-3, -9, and -12 null mice have lesser degrees of damage resulting from ICH, 4,21,22 although the opposite result for MMP-9 has also been reported. 31,32 These data indicate that inhibition of MMPs represents a practical therapeutic strategy for patients with ICH, although therapy would need to be restricted to a short timeframe not to interfere with the delayed beneficial remodeling and repair mechanisms of MMPs. 15,16 The presence of thrombin within the CNS is of particular importance in ICH because its ability to convert fibrinogen to fibrin, trigger platelet aggregation, and cause vasoconstriction would all be of benefit in preventing further hemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Relative Importance of Proteinase-Activated Receptor-1 Versus Matrix Metalloproteinases in Intracerebral Hemorrhage-Mediated Neurotoxicity in Mice

Xue

Hollenberg

Demchuk

et al. 2009

Stroke

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Background and Purpose-To reduce bleeding and damage to central nervous system tissue in intracerebral hemorrhage, the coagulant effect of thrombin is essential. However, thrombin itself can kill neurons in intracerebral hemorrhage as can the matrix metalloproteinases (MMPs), which are also elevated in this condition, in part due to thrombin-mediated activation of MMPs. It is thus important to understand and block the neurotoxic effects of thrombin without inhibiting its therapeutic outcomes. In this study, we have investigated the relative roles of proteinase activated receptor-1, a thrombin receptor, and MMPs in brain injury induced by thrombin or blood. Methods-Mice were subjected to stereotactic intracerebral injections of saline, thrombin, and autologous blood, with or without hirudin, a thrombin inhibitor, or GM6001, an MMP inhibitor. Twenty-four hours later, tissue sections were obtained to evaluate the area of brain damage and extent of dying neurons. Data from wild-type mice were compared with results obtained with proteinase activated receptor-1 null mice. Results-In blood-induced damage to the brain parenchyma, both hirudin and GM6001 significantly reduced injury to a comparable extent (Ͼ40%) implicating both thrombin and MMPs in neurotoxicity. In proteinase activated receptor-1 null mice, blood-induced brain damage was reduced by 22.6% relative to wild-type animals; by comparison, the blood-induced brain damage was reduced by 48.3% using GM6001. Conclusions-The neurotoxicity of blood in intracerebral hemorrhage involves both proteinase activated receptor-1 and MMP activation, with the latter appearing more prominent in causing death. Key Words: intracerebral hemorrhage Ⅲ MMPs Ⅲ neurotoxicity Ⅲ PAR 1 Ⅲ thrombin I ntracerebral hemorrhage (ICH) accounts for approximately 15% to 20% of all strokes and has a poor prognosis. Many factors contribute to brain injury after ICH 1,2 including thrombin, 3,4 which comes either from resident neural cells or from prothrombin in blood. That thrombin is neurotoxic in vitro and in vivo is well recognized. 3,[5][6][7] In contrast with its deleterious effects, thrombin plays a key protective role in ICH, particularly in promoting coagulation, which is vital to prevent further bleeding. 8 Recombinant activated Factor VIIa, which reduces the size of hematomas in ICH, 8 acts largely by generating thrombin to facilitate clot formation.Given the competing beneficial and detrimental effects of thrombin, it would be advantageous to define and neutralize the mechanisms by which thrombin is neurotoxic so that the important effects of thrombin in regulating clot formation are maintained. At least 2 mechanisms account for thrombinmediated neurotoxicity. The first involves the interaction of thrombin with proteinase activated receptors (PARs), 3,9,10 which are G protein-coupled receptors that regulate the cellular response to extracellular serine proteinases. Of the 4 family members, PAR 1 , PAR 3 , and PAR 4 are targeted by thrombin, 9,11 whereas PAR 2 is activated by trypsin and ...

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Section: Discussionmentioning

confidence: 99%

Relative Importance of Proteinase-Activated Receptor-1 Versus Matrix Metalloproteinases in Intracerebral Hemorrhage-Mediated Neurotoxicity in Mice

Xue

Hollenberg

Demchuk

et al. 2009

Stroke

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“…BB-1101, a broad spectrum MMP inhibitor, attenuated BBB dysfunction during the early phase but did not have any effect on infarct volume at 2 days and had adverse effects on neurologic outcome in rats at 3 and 4 weeks after MCAO [55]. Another broad spectrum MMP inhibitor, BB94, increased apoptosis and hemorrhage size after collagenase-induced intracerebral hemorrhage in mouse [56]. Therefore, it is important to test both the short-term beneficial actions and the possible long-term detrimental actions of MMP inhibitors.…”

Section: Mmps In Stroke [See For Review 46]-expression Of Mmps In Thementioning

confidence: 99%

Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases in the Pathogenesis of Stroke: Therapeutic Strategies

Adibhatla

Hatcher²

2008

CNSNDDT

173

135

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Today there exists only one FDA-approved treatment for ischemic stroke; i.e., the serine protease tissue-type plasminogen activator (tPA). In the aftermath of the failed stroke clinical trials with the nitrone spin trap/radical scavenger, NXY-059, a number of articles raised the question: are we doing the right thing? Is the animal research truly translational in identifying new agents for stroke treatment? This review summarizes the current state of affairs with plasminogen activators in thrombolytic therapy. In addition to therapeutic value, potential side effects of tPA also exist that aggravate stroke injury and offset the benefits provided by reperfusion of the occluded artery. Thus, combinational options (ultrasound alone or with microspheres/nanobubbles, mechanical dissociation of clot, activated protein C (APC), plasminogen activator inhibitor-1 (PAI-1), neuroserpin and CDPcholine) that could offset tPA toxic side effects and improve efficacy are also discussed here. Desmoteplase, a plasminogen activator derived from the saliva of Desmodus rotundus vampire bat, antagonizes vascular tPA-induced neurotoxicity by competitively binding to low-density lipoprotein related-receptors (LPR) at the blood-brain barrier (BBB) interface, minimizing the tPA uptake into brain parenchyma. tPA can also activate matrix metalloproteinases (MMPs), a family of endopeptidases comprised of 24 mammalian enzymes that primarily catalyze the turnover and degradation of the extracellular matrix (ECM). MMPs have been implicated in BBB breakdown and neuronal injury in the early times after stroke, but also contribute to vascular remodeling, angiogenesis, neurogenesis and axonal regeneration during the later repair phase after stroke. tPA, directly or by activation of MMP-9, could have beneficial effects on recovery after stroke by promoting neurovascular repair through vascular endothelial growth factor (VEGF). However, any treatment regimen directed at MMPs must consider their pleiotropic nature and the likelihood of either beneficial or detrimental effects that might depend on the timing of the treatment in relation to the stage of brain injury.

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“…Similar findings relating to MMP-9 and hemorrhagic transformation have been reported after edaravone treatment in rats (Yagi et al, 2009). While there is little question that MMP-9 inhibition is cytoprotective after striatal autologous blood injection in rodents (Tejima et al, 2007;Xue et al, 2006), it has been argued that MMP-9 downregulation could lead to aggravation of brain injury after collagenase-induced ICH (Grossetete and Rosenberg, 2008;Tang et al, 2004). In fact, MMP-9-null mice experienced greater hemorrhagic volume, brain edema, and diminished neurological function than wild-type controls .…”

mentioning

confidence: 99%

Protective Effect of Melatonin upon Neuropathology, Striatal Function, and Memory Ability after Intracerebral Hemorrhage in Rats

Lekic

Hartman

Rojas

et al. 2010

Journal of Neurotrauma

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Since free radicals play a role in the mechanisms of brain injury after hemorrhagic stroke, the effect of melatonin (a potent antioxidant and free-radical scavenger) on outcomes was investigated after intracerebral hemorrhage (ICH) in rats. ICH was induced by clostridial collagenase infusion into the right caudate putamen, and several time points and doses of melatonin were studied. Brain edema and neurological function at 24 h were unchanged in comparison with vehicle-treated groups, in spite of oxidative stress reductions. Repeated treatment with the lower dose of melatonin (5 mg=kg) given at 1 h and every 24 h thereafter for 3 days after ICH, led to normalization of striatal function and memory ability over the course of 8 weeks, and less brain atrophy 2 weeks later. These results suggest that melatonin is safe for use after ICH, reduces oxidative stress, provides brain protection, and could be used for future investigations of free radical mechanisms after cerebral hemorrhage.

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Matrix Metalloproteinase Inhibition Facilitates Cell Death in Intracerebral Hemorrhage in Mouse

Cited by 58 publications

References 40 publications

Relative Importance of Proteinase-Activated Receptor-1 Versus Matrix Metalloproteinases in Intracerebral Hemorrhage-Mediated Neurotoxicity in Mice

Relative Importance of Proteinase-Activated Receptor-1 Versus Matrix Metalloproteinases in Intracerebral Hemorrhage-Mediated Neurotoxicity in Mice

Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases in the Pathogenesis of Stroke: Therapeutic Strategies

Protective Effect of Melatonin upon Neuropathology, Striatal Function, and Memory Ability after Intracerebral Hemorrhage in Rats

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