Single- and two- chain tissue type plasminogen activator treatments differentially influence cerebral recovery after stroke

Anfray, Antoine; Brodin, Camille; Drieu, Antoine; Potzeha, Fanny; Dalarun, Basile; Agin, Véronique; Vivien, Denis; Orset, Cyrille

doi:10.1016/j.expneurol.2021.113606

Cited by 8 publications

(7 citation statements)

References 32 publications

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“…Furthermore, it was discovered that at concentrations found in the ischemic brain, tPA attenuated NMDA-induced neuronal death by a mechanism that did not entail plasmin generation but required the co-receptor function of a member of the low-density lipoprotein receptor (LDLR) family, most likely LRP1. In an attempt to explain these discrepancies, it was proposed that selective activation of NMDA receptors by single-chain but not two-chain tPA is responsible for the neurotoxic effect of tPA [ 118 ], and therefore that treatment with two-chain tPA is more efficient than single-chain tPA to reduce the volume of the ischemic lesion and promote functional recovery after the experimental induction of an ischemic stroke [ 119 ]. Together, these results show that a causal link between tPA and cerebral ischemia- and excitotoxin-induced neuronal death was difficult to establish, as it seemed to depend on the chemical structure and dose of rtPA as well as the specific experimental paradigm used in each report.…”

Section: Plasminogen Activators In the Neurovascular Unit (Nvu) Under Ischemic Conditionsmentioning

confidence: 99%

Plasminogen Activators in Neurovascular and Neurodegenerative Disorders

Yepes

Woo²,

Martin-Jimenez³

2021

IJMS

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The neurovascular unit (NVU) is a dynamic structure assembled by endothelial cells surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons. A carefully coordinated interplay between these cellular and non-cellular components is required to maintain normal neuronal function, and in line with these observations, a growing body of evidence has linked NVU dysfunction to neurodegeneration. Plasminogen activators catalyze the conversion of the zymogen plasminogen into the two-chain protease plasmin, which in turn triggers a plethora of physiological events including wound healing, angiogenesis, cell migration and inflammation. The last four decades of research have revealed that the two mammalian plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), are pivotal regulators of NVU function during physiological and pathological conditions. Here, we will review the most relevant data on their expression and function in the NVU and their role in neurovascular and neurodegenerative disorders.

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Section: Plasminogen Activators In the Neurovascular Unit (Nvu) Under Ischemic Conditionsmentioning

confidence: 99%

Plasminogen Activators in Neurovascular and Neurodegenerative Disorders

Yepes

Woo²,

Martin-Jimenez³

2021

IJMS

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“…Alteplase is a recombinant tissue plasminogen activator (rt-PA) and only approved to treat cerebral ischemia stroke by the United States Food and Drug Administration. However, its therapeutic potential is limited by the hemolytic risk and short treatment window (4.5 h), with only a few patients benefitting from its use (Ishiguro et al, 2012;Bruch et al, 2019;Anfray et al, 2021). Therefore, finding a new therapeutic strategy against ischemic stroke is crucial.…”

Section: Introductionmentioning

confidence: 99%

Exosomes in pathogenesis, diagnosis, and therapy of ischemic stroke

Jin

Zhang

Wang

et al. 2022

Front. Bioeng. Biotechnol.

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Ischemic stroke is one of the major contributors to death and disability worldwide. Thus, there is an urgent need to develop early brain tissue perfusion therapies following acute stroke and to enhance functional recovery in stroke survivors. The morbidity, therapy, and recovery processes are highly orchestrated interactions involving the brain with other tissues. Exosomes are natural and ideal mediators of intercellular information transfer and recognized as biomarkers for disease diagnosis and prognosis. Changes in exosome contents express throughout the physiological process. Accumulating evidence demonstrates the use of exosomes in exploring unknown cellular and molecular mechanisms of intercellular communication and organ homeostasis and indicates their potential role in ischemic stroke. Inspired by the unique properties of exosomes, this review focuses on the communication, diagnosis, and therapeutic role of various derived exosomes, and their development and challenges for the treatment of cerebral ischemic stroke.

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“…24,27 In addition to these direct effects on brain vasculature, tPA can also exit the bloodstream 28,29 and contribute to tPA within the brain parenchyma, leading to increased neuronal activity and potential neuronal loss. 17,30 Preclinical studies investigating the role and effect of tPA during ischemic stroke have yielded controversial findings, with some reporting beneficial outcomes [31][32][33] and others indicating deleterious effects. [34][35][36][37][38] However, this literature can be criticized because the results are primarily obtained from mice in which tPA is invalidated throughout the organism, or by increasing tPA expression to irrelevant levels (such as in genetically modified mice, through hydrodynamic transfection, or via intravenous injection of alteplase, etc).…”

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confidence: 99%

mentioning

confidence: 99%

Parabiosis Discriminates the Circulating, Endothelial, and Parenchymal Contributions of Endogenous Tissue-Type Plasminogen Activator to Stroke

Furon,

Lebrun,

Yétim

et al. 2024

Stroke

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BACKGROUND: Intravenous injection of alteplase, a recombinant tPA (tissue-type plasminogen activator) as a thrombolytic agent has revolutionized ischemic stroke management. However, tPA is a more complex enzyme than expected, being for instance able to promote thrombolysis, but at the same time, also able to influence neuronal survival and to affect the integrity of the blood-brain barrier. Accordingly, the respective impact of endogenous tPA expressed/present in the brain parenchyma versus in the circulation during stroke remains debated. METHODS: To address this issue, we used mice with constitutive deletion of tPA (tPA Null [tPA-deficient mice]) or conditional deletion of endothelial tPA (VECad [vascular endothelial-Cadherin-Cre-recombinase]-Cre ∆tPA ). We also developed parabioses between tPA Null and wild-type mice (tPA WT ), anticipating that a tPA WT donor would restore levels of tPA to normal ones, in the circulation but not in the brain parenchyma of a tPA Null recipient. Stroke outcomes were investigated by magnetic resonance imaging in a thrombo-embolic or a thrombotic stroke model, induced by local thrombin injection or FeCl 3 application on the endothelium, respectively. RESULTS: First, our data show that endothelial tPA, released into the circulation after stroke onset, plays an overall beneficial role following thrombo-embolic stroke. Accordingly, after 24 hours, tPA Null /tPA Null parabionts displayed less spontaneous recanalization and reperfusion and larger infarcts compared with tPA WT /tPA WT littermates. However, when associated to tPA WT littermates, tPA Null mice had similar perfusion deficits, but less severe brain infarcts. In the thrombotic stroke model, homo- and hetero-typic parabionts did not differ in the extent of brain damages and did not differentially recanalize and reperfuse. CONCLUSIONS: Together, our data reveal that during thromboembolic stroke, endogenous circulating tPA from endothelial cells sustains a spontaneous recanalization and reperfusion of the tissue, thus, limiting the extension of ischemic lesions. In this context, the impact of endogenous parenchymal tPA is limited.

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Single- and two- chain tissue type plasminogen activator treatments differentially influence cerebral recovery after stroke

Cited by 8 publications

References 32 publications

Plasminogen Activators in Neurovascular and Neurodegenerative Disorders

Plasminogen Activators in Neurovascular and Neurodegenerative Disorders

Exosomes in pathogenesis, diagnosis, and therapy of ischemic stroke

Parabiosis Discriminates the Circulating, Endothelial, and Parenchymal Contributions of Endogenous Tissue-Type Plasminogen Activator to Stroke

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