title: Tissue plasminogen activator prevents white matter damage following stroke.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM-U919, Caen Cedex, F-14074 France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Correa
authors.forename: Maxime
authors.initials: M
authors.lastname: Gauberti
authors.forename: Jérôme
authors.initials: J
authors.lastname: Parcq
authors.forename: Richard
authors.initials: R
authors.lastname: Macrez
authors.forename: Yannick
authors.initials: Y
authors.lastname: Hommet
authors.forename: Pauline
authors.initials: P
authors.lastname: Obiang
authors.forename: Miriam
authors.initials: M
authors.lastname: Hernangómez
authors.forename: Axel
authors.initials: A
authors.lastname: Montagne
authors.forename: Géraldine
authors.initials: G
authors.lastname: Liot
authors.forename: Carmen
authors.initials: C
authors.lastname: Guaza
authors.forename: Eric
authors.initials: E
authors.lastname: Maubert
authors.forename: Carine
authors.initials: C
authors.lastname: Ali
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.forename: Fabian
authors.initials: F
authors.lastname: Docagne
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology*; D001930:Brain Injuries / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D019070:Cell Lineage; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004815:Epidermal Growth Factor / Q000737:chemistry; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009836:Oligodendroglia / Q000166:cytology; D020521:Stroke / Q000473:pathology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D010959:Tissue Plasminogen Activator; D053148:Caspase 3