Acute Tissue Damage After Injections of Thrombin and Plasmin into Rat Striatum

Xue, Mengzhou; Bigio, Marc R. Del

doi:10.1161/hs0901.095408

Cited by 117 publications

(86 citation statements)

References 57 publications

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“…Moreover, while having blood-clotting, woundhealing and, at low dose, neuroprotective properties (40), thrombin was also reported to have a profound neurotoxic potential (1,5). Several studies revealed impairment of neuronal populations upon thrombin exposure (10,13,19,35,40). Cytokines could play a critical role in these in vivo scenarios.…”

Section: Thrombin As An Assumed Activator Of Microglial Releasementioning

confidence: 99%

“…Most serum proteins are normally denied CNS entry (5,14). However, when the BBB integrity is compromised due to trauma, stroke, viral and bacterial infection, autoimmune diseases, or neurodegenerative processes, blood content can more or less inundate the tissue (1,5,12,13,15). Proteases, protease inhibitors or their complexes, lipid-loaded albumin, complement factors, immunoglobulins, or cytokines may then gain access to neurons and glial cells (1, 3, 5, 14, 16 -22).…”

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confidence: 99%

“…Blood-borne proteases seem to have a tremendous impact on the tissue. Brain cell injury associated with hemorrhage differs from pure ischemia, and the extent of CNS damage, for example upon stroke, is drastically reduced when certain protease activities are eliminated (13,23,24).…”

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confidence: 99%

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The Microglia-activating Potential of Thrombin

Hanisch

Rossum

Xie

et al. 2004

Journal of Biological Chemistry

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The serine protease thrombin is known as a blood coagulation factor. Through limited cleavage of proteinase-activated receptors it can also control growth and functions in various cell types, including neurons, astrocytes, and microglia (brain macrophages). A number of previous studies indicated that thrombin induces the release of proinflammatory cytokines and chemokines from microglial cells, suggesting another important role for the protease beyond hemostasis. In the present report, we provide evidence that this effect is not mediated by any proteolytic or non-proteolytic mechanism involving thrombin proper. Inhibition of the enzymatic thrombin activity did not affect the microglial release response. Instead the cyto-/chemokine-inducing activity solely resided in a high molecular weight protein fraction that could be isolated in trace amounts even from apparently homogenous ␣-and ␥-thrombin preparations. High molecular weight material contained thrombin-derived peptides as revealed by mass spectrometry but was devoid of thrombin-like enzymatic activity. Separated from the high molecular weight fraction by fast protein liquid chromatography, enzymatically intact ␣-and ␥-thrombin failed to trigger any release. Our findings may force a revision of the notion that thrombin itself is a direct proinflammatory release signal for microglia. In addition, they could be relevant for the study of other cellular activities and their assignment to this protease.

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Section: Thrombin As An Assumed Activator Of Microglial Releasementioning

confidence: 99%

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confidence: 99%

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The Microglia-activating Potential of Thrombin

Hanisch

Rossum

Xie

et al. 2004

Journal of Biological Chemistry

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“…Angewandte Communications 326 www.angewandte.org uncleaved probe, in which FRET was intact (Figure 2, blue), from cleaved probe, in which FRET was disrupted (Figure 2, red). Images confirmed that RACPP PPRSFL (10) and RACPP DPRSFL (5) are cleaved by thrombin in a time-dependent manner and that RACPP PPRSFL (10) is selective for thrombin. An MMP cleavable RACPP PLGC(Me)AG (20) was also shown, as a control that was not cleaved by any of the procoagulation enzymes.…”

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confidence: 76%

“…[3][4][5] Thrombin is a major therapeutic target for thrombosis and stroke intervention/prevention through indirect inhibitors such as heparin or warfarin, and direct inhibitors hirudin (divalent), and argatroban (monovalent). [6,7] In addition to its role in thrombosis and stroke, [8][9][10][11] thrombin is reported as a relevant player in cardiovascular disease, [12,13] renal injury, [14] and cancer. [15] Activatable cell-penetrating peptides (ACPPs) target various cargos, including fluorescent imaging agents, to sites of protease activity in vivo.…”

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Ratiometric Activatable Cell‐Penetrating Peptides Provide Rapid In Vivo Readout of Thrombin Activation

et al. 2012

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Extracellular proteases including thrombin are involved in numerous biological processes and play major roles in a variety of human diseases. The spatial and temporal patterns of activation of proteases in vivo control their biological role in diseases and amenability to therapeutic targeting. Previously we developed activatable cell-penetrating peptides (ACPPs) to monitor matrix metalloproteinase (MMP) and elastase activity in tumors. Later ACPPs detect thrombin activation in atherosclerosis and brain injury. We have now modified the thrombin ACPP in two independent ways, 1) to provide a FRET-dependent emission ratiometric readout and 2) to accelerate the kinetics of cleavage by thrombin. Emission ratioing improves kinetic detection of enzyme activity, because it reflects the ratio of cleaved versus uncleaved probe but cancels out total probe concentration, illumination intensity, detection sensitivity, and tissue thickness. Because pharmacokinetic washout of the uncleaved probe is not necessary, yet the cleavage converts a diffusible substrate into an immobilized product, thrombin activity can be imaged in real time with good spatial resolution. Meanwhile, placement of norleucine-threonine (Nle-Thr) at the P4-P3 substrate positions accelerates the kinetics of thrombin cleavage by 1-2 orders of magnitude, while preserving selectivity against related proteases. The new ratiometric ACPPs detect localized thrombin activation in rapidly forming blood clots minutes after probe injection, and the signal is inhibited by thrombin specific inhibitors.Thrombin is a serine protease and a key regulator of blood coagulation. It is responsible for the proteolytic cleavage and activation of multiple coagulation factors including Factor V,

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Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases

Power¹,

Henry²,

Bigio³

et al. 2003

Annals of Neurology

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327

264

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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.

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Acute Tissue Damage After Injections of Thrombin and Plasmin into Rat Striatum

Cited by 117 publications

References 57 publications

The Microglia-activating Potential of Thrombin

The Microglia-activating Potential of Thrombin

Ratiometric Activatable Cell‐Penetrating Peptides Provide Rapid In Vivo Readout of Thrombin Activation

Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases

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