Tissue plasminogen activator prevents white matter damage following stroke

• DOI: 10.1084/jem.20101880
• Publication Date: 2011-05-17T04:40:08Z
• Authors: Fernando Correa; Maxime Gauberti; Jérôme Parcq; Richard Macrez; Yannick Hommet; Pauline Obiang; Miriam Hernangómez; Axel Montagne; Géraldine Liot; Carmen Guaza; Eric Maubert; Carine Ali; Denis Vivien; Fabian Docagne
• Keywords: 0301 basic medicine; Aging; Apoptosis; Endothelium, Vascular -- cytology; Inbred C57BL; Article; Mice; 03 medical and health sciences; Vascular -- cytology; Stroke -- pathology; Brain -- pathology; Animals; Humans; Cell Lineage; Endothelium; Extracellular Signal-Regulated MAP Kinases; Brain Injuries -- pathology; Epidermal Growth Factor; Caspase 3; Caspase 3 -- metabolism; Brain; Sciences bio-médicales et agricoles; Extracellular Signal-Regulated MAP Kinases -- metabolism; Tissue Plasminogen Activator -- metabolism; Epidermal Growth Factor -- chemistry; 3. Good health; Cytokines -- metabolism; Mice, Inbred C57BL; Stroke; Oligodendroglia; Brain Injuries; Tissue Plasminogen Activator; Oligodendroglia -- cytology; Cytokines; Endothelium, Vascular

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.