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  • 1
    Online Resource
    Online Resource
    Antibodies Preventing the Interaction of Tissue-Type Plasminogen Activator With N-Methyl- d -Aspartate Receptors Reduce Stroke Damages and Extend the Therapeutic Window of Thrombolysis
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Stroke Vol. 42, No. 8 ( 2011-08), p. 2315-2322
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. 8 ( 2011-08), p. 2315-2322
    Abstract: Tissue-type plasminogen activator (tPA) is the only drug approved for the acute treatment of ischemic stroke but with two faces in the disease: beneficial fibrinolysis in the vasculature and damaging effects on the neurovascular unit and brain parenchyma. To improve this profile, we developed a novel strategy, relying on antibodies targeting the proneurotoxic effects of tPA. Methods— After production and characterization of antibodies (αATD-NR1) that specifically prevent the interaction of tPA with the ATD-NR1 of N-methyl- d -aspartate receptors, we have evaluated their efficacy in a model of murine thromboembolic stroke with or without recombinant tPA-induced reperfusion, coupled to MRI, near-infrared fluorescence imaging, and behavior assessments. Results— In vitro, αATD-NR1 prevented the proexcitotoxic effect of tPA without altering N-methyl- d -aspartate-induced neurotransmission. In vivo, after a single administration alone or with late recombinant tPA-induced thrombolysis, antibodies dramatically reduced brain injuries and blood–brain barrier leakage, thus improving long-term neurological outcome. Conclusions— Our strategy limits ischemic damages and extends the therapeutic window of tPA-driven thrombolysis. Thus, the prospect of this immunotherapy is an extension of the range of treatable patients.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.110.606293
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1467823-8
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  • 2
    Online Resource
    Online Resource
    Tissue plasminogen activator prevents white matter damage following stroke
    Rockefeller University Press ; 2011
    In:  Journal of Experimental Medicine Vol. 208, No. 6 ( 2011-06-06), p. 1229-1242
    Details
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 208, No. 6 ( 2011-06-06), p. 1229-1242
    Abstract: Tissue plasminogen activator (tPA) is the only available treatment for acute stroke. In addition to its vascular fibrinolytic action, tPA exerts various effects within the brain, ranging from synaptic plasticity to control of cell fate. To date, the influence of tPA in the ischemic brain has only been investigated on neuronal, microglial, and endothelial fate. We addressed the mechanism of action of tPA on oligodendrocyte (OL) survival and on the extent of white matter lesions in stroke. We also investigated the impact of aging on these processes. We observed that, in parallel to reduced levels of tPA in OLs, white matter gets more susceptible to ischemia in old mice. Interestingly, tPA protects murine and human OLs from apoptosis through an unexpected cytokine-like effect by the virtue of its epidermal growth factor–like domain. When injected into aged animals, tPA, although toxic to the gray matter, rescues white matter from ischemia independently of its proteolytic activity. These studies reveal a novel mechanism of action of tPA and unveil OL as a target cell for cytokine effects of tPA in brain diseases. They show overall that tPA protects white matter from stroke-induced lesions, an effect which may contribute to the global benefit of tPA-based stroke treatment.
    Type of Medium: Online Resource
    ISSN: 1540-9538 , 0022-1007
    URL: Article
    DOI: 10.1084/jem.20101880
    RVK:
    XA 10000
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2011
    detail.hit.zdb_id: 1477240-1
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  • 3
    Online Resource
    Online Resource
    O2L-001, an innovative thrombolytic to evacuate intracerebral haematoma
    Oxford University Press (OUP) ; 2023
    In:  Brain ( 2023-07-14)
    Details
    In: Brain, Oxford University Press (OUP), ( 2023-07-14)
    Abstract: Intracerebral haemorrhage is an unmet medical need affecting more than 3 million people worldwide every year and leading to the formation of an intracerebral haematoma. Updated guidelines (2022) for the management of intracerebral haemorrhage patients recognize that minimally invasive approaches for the evacuation of supratentorial intracerebral haemorrhage have demonstrated reductions in mortality compared with medical management alone. However, improvement of functional outcome with a procedure involving thrombolytic therapy was neutral in the last large phase 3 clinical trial and requires a more effective and safer thrombolytic agent than those currently available. Here, we demonstrate that O2L-001 allows for the extended release of W253R/R275S recombinant tissue-type plasminogen activator (rtPA). A new rtPA variant, called optimized tPA (OptPA), offers improved efficacy for haematoma evacuation as well as improved safety. OptPA was produced in a Chinese hamster ovary cell line before purification, nanoprecipitation using the NANOp2Lysis® technological platform followed by suspension in a solution of 17% poloxamer 407 to obtain O2L-001. Plasmin generation assays were performed to demonstrate O2L-001 safety. Ex vivo haematoma models using human blood were used to demonstrate O2L-001 thrombolysis properties and efficacy. For the best translational significance, a clinical sized haematoma was used to ensure catheter placement and to allow administration of the thrombolytic agent into the core of the haematoma via a minimally invasive procedure. The capacity of OptPA to convert plasminogen into plasmin is strongly decreased compared to rtPA, thereby reducing potential bleeding events. However, a clot lysis assay showed that OptPA had the same fibrinolytic activity as rtPA. We demonstrated that long-term exposure to a thrombolytic agent was essential to achieve high thrombolysis efficacy. Indeed, 24 h continuous exposure to 0.1 µg/ml rtPA had similar efficacy than repeated short exposure to 30 µg/ml rtPA. This finding led to the development of O2L-001, allowing the extended release of OptPA in the first 6 h following injection. An ex vivo model using human blood was used to demonstrate O2L-001 efficacy. Interestingly, unlike rtPA, O2L-001 was able to induce the complete lysis of the 5 ml haematoma. In clinical sized haematomas (obtained from 30 ml of human blood), a single injection of O2L-001 at 1 mg/ml into the core of the haematoma led to a 44% increase in thrombolysis compared to rtPA. Taken together, these results demonstrate that O2L-001 provides new hope for haematoma evacuation and the treatment of patients with intracerebral haemorrhage.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad237
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Understanding the Functions of Endogenous and Exogenous Tissue-Type Plasminogen Activator During Stroke
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Stroke Vol. 46, No. 1 ( 2015-01), p. 314-320
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. 1 ( 2015-01), p. 314-320
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.114.006698
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467823-8
    Location Call Number Limitation Availability
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