title: HMGB-1 promotes fibrinolysis and reduces neurotoxicity mediated by tissue plasminogen activator.
abstract: Owing to its ability to generate the clot-dissolving protease plasmin, tissue plasminogen activator (tPA) is the only approved drug for the acute treatment of ischemic stroke. However, tPA also promotes hemorrhagic transformation and excitotoxic events. High mobility group box-1 protein (HMGB-1) is a non-histone transcription factor and a pro-inflammatory cytokine, which has also been shown to bind to both tPA and plasminogen. We thus investigated the cellular and molecular effects through which HMGB-1 could influence the vascular and parenchymal effects of tPA during ischemia. We demonstrate that HMGB-1 not only increases clot lysis by tPA, but also reduces the passage of vascular tPA across the blood-brain barrier, as well as tPA-driven leakage of the blood-brain barrier. In addition, HMGB-1 prevents the pro-neurotoxic effect of tPA, by blocking its interaction with N-methyl-D-aspartate (NMDA) receptors and the attendant potentiation of NMDA-induced neuronal Ca²⁺ influx. In conclusion, we show in vitro that HMGB-1 can promote the beneficial effects of tPA while counteracting its deleterious properties. We suggest that derivatives of HMGB-1, devoid of pro-inflammatory properties, could be used as adjunctive therapies to improve the overall benefit of tPA-mediated thrombolysis following stroke.
authors: INSERM U919 'serine proteases and pathophysiology of the neurovascular unit', UMR CNRS 6232 Cinaps, GIP Cyceron, University of Caen, 14032 Caen, France. bdr24@cam.ac.uk
authors: Benoit D
authors: BD
authors: Roussel
authors: Caroline
authors: C
authors: Mysiorek
authors: Ari
authors: A
authors: Rouhiainen
authors: Amandine
authors: A
authors: Jullienne
authors: Jerome
authors: J
authors: Parcq
authors: Yannick
authors: Y
authors: Hommet
authors: Maxime
authors: M
authors: Culot
authors: Vincent
authors: V
authors: Berezowski
authors: Romeo
authors: R
authors: Cecchelli
authors: Heikki
authors: H
authors: Rauvala
authors: Denis
authors: D
authors: Vivien
authors: Carine
authors: C
authors: Ali