Neutralizing the neurotoxic effects of exogenous and endogenous tPA

Armstead, William M.; Nassar, Taher; Akkawi, Sa’ed; Smith, Douglas H.; Chen, Xiaohan; Cines, Douglas B.; Higazi, Abd Al‐Roof

doi:10.1038/nn1757

Cited by 69 publications

(90 citation statements)

References 29 publications

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“…8,11 However, as already mentioned, although the proexcitotoxic effect of endogenous and exogenous tPA is much documented, its mechanism of action remains debated, especially regarding the putative plasmin-independent cleavage of the NMDAR NR1 subunit. [7][8][9][10][11][12][13][14][15][16][17][18] A clear demonstration of the exact mechanism involved in the proneurotoxic effect of tPA is thus mandatory to define efficient adjunctive therapies for stroke. By using a protocol of vaccination followed by stroke-induced boost of the immune system, we aimed at proving that tPA leads to the cleavage of the ATD-NR1 to promote neurotoxicity in vivo after stroke.…”

Section: Discussionmentioning

confidence: 99%

Functional Occurrence of the Interaction of Tissue Plasminogen Activator With the NR1 Subunit of N -Methyl- d -Aspartate Receptors During Stroke

Macrez

Bezin

Mauff

et al. 2010

Stroke

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Background and Purpose-Despite its fibrinolytic effect, tissue-type plasminogen activator (tPA) displays deleterious effects in the brain, including proexcitotoxicity, that can reduce the overall benefit from thrombolysis during stroke. We have proposed that tPA potentiates excitotoxicity by interacting with and cleaving the aminoterminal end of the NR1 subunit of N-methyl-D-aspartate receptors, leading to an increased calcium influx, Erk1/2 activation, and neurotoxicity. Because this mechanism is debated, our aim was to demonstrate its in vivo occurrence and relevance. Because tPA is released under ischemic conditions, we hypothesized that if it indeed processes NR1, then the released fragment should reactivate the immune system in animals that had been immunized long before with recombinant aminoterminal end of the NR1. This effect should be exacerbated in ischemic animals thrombolysed with recombinant tPA. Methods-At a time when specific antibodies could not be detected any longer, mice previously vaccinated with recombinant aminoterminal end of the NR1 were subjected to thromboembolic stroke induced by injecting thrombin in the middle cerebral artery alone or with intravenous thrombolysis. Results-Stroke performed 1 year after active immunization induced the reappearance of antibodies against the aminoterminal end of the NR1 in the plasma, an effect significantly increased when ischemia was followed by recombinant tPA-induced reperfusion. Moreover, immunization preventing the interaction of tPA with aminoterminal end of the NR1 reduced ischemic brain damages and extended the therapeutic window of tPA-induced thrombolysis. Conclusion-We

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Section: Discussionmentioning

confidence: 99%

Functional Occurrence of the Interaction of Tissue Plasminogen Activator With the NR1 Subunit of N -Methyl- d -Aspartate Receptors During Stroke

Macrez

Bezin

Mauff

et al. 2010

Stroke

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“…22 Nowadays, this selection mainly rely on early CT findings such as the ASPECTS score or the 1/3 MCA hypodensity rule, [23][24][25][26] although new neuroimaging and biochemical predictors have been described. 8,27,28 High serum levels of c-Fn, a component of the basal lamina which plays an important role in maintaining microvascular integrity, have been associated with malignant brain edema 8 and hemorrhagic transformation.…”

Section: Discussionmentioning

confidence: 99%

High Serum Levels of Endothelin-1 Predict Severe Cerebral Edema in Patients With Acute Ischemic Stroke Treated With t-PA

Moldes

Sobrino

Millán

et al. 2008

Stroke

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Background and Purpose-Severe cerebral edema is associated with poor outcome in patients with acute stroke.Experimental studies suggest that astrocytic endothelin-1 (ET-1) has deleterious effects on water homeostasis, cerebral edema, and blood brain barrier (BBB) integrity, which contribute to more severe ischemic brain injury. In this study we analyze the association between high serum levels of ET-1 and the development of severe cerebral edema in patients treated with t-PA. Methods-One hundred thirty-four patients treated with t-PA according SITS-MOST (Safe Implementation of Thrombolysis in Stroke Monitoring Study) criteria were prospectively studied. Serum levels of ET-1, matrix metalloproteinase-9 (MMP-9), and cellular fibronectin (c-Fn) were determined by ELISA in serum samples obtained on admission, before t-PA bolus. Severe brain edema was diagnosed if extensive swelling caused any shifting of the structures of the midline was detected on the cranial CT performed at 24 to 36 hours. Stroke severity was evaluated before t-PA administration and at 24 hours by NIHSS. Functional outcome at 3 months was evaluated by the modified Rankin Scale (mRS). .6] mg/L, PϽ0.0001) serum levels were significantly higher in patients with severe cerebral edema. The best cut-off values for ET-1 and c-Fn serum levels for the prediction of severe brain edema were 5.5 fmol/mL (sensitivity 95% and specificity 94%) and 4.5 mg/L (sensitivity 73% and specificity 77%) respectively. ET-1 serum levels Ͼ5.5 fmol/mL before t-PA treatment were independently associated with development of severe brain edema (OR, 139.7; CI95%, 19.3 to 1012.2; PϽ0.0001), after adjustment for baseline stroke severity, early CT signs of infarction, serum levels of cFn Ͼ4.5 mg/L, and cardioembolic stroke subtype. Conclusions-ET-1 serum levels Ͼ5.5 fmol/mL are associated with severe brain edema in acute stroke patients treated with t-PA. These results suggest that ET-1 may be a new diagnostic marker for development of severe brain edema in patients with acute ischemic stroke treated with t-PA.

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“…APC may also have hemorrhagic risk by itself [40,41]. tPA + plasminogen activator inhibitor-1 attenuated tPA-mediated signal transduction without compromising its catalytic activity [88]. tPA + neuroserpin (an endogenous tPA inhibitor) [25,89,90].…”

Section: Fig 2 Blood Clot Formationmentioning

confidence: 99%

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

Adibhatla

Hatcher²

2008

CNSNDDT

170

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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Neutralizing the neurotoxic effects of exogenous and endogenous tPA

Cited by 69 publications

References 29 publications

Functional Occurrence of the Interaction of Tissue Plasminogen Activator With the NR1 Subunit of N -Methyl- d -Aspartate Receptors During Stroke

Functional Occurrence of the Interaction of Tissue Plasminogen Activator With the NR1 Subunit of N -Methyl- d -Aspartate Receptors During Stroke

High Serum Levels of Endothelin-1 Predict Severe Cerebral Edema in Patients With Acute Ischemic Stroke Treated With t-PA

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

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