Tissue-type plasminogen activator has a neuroprotective effect in the ischemic brain mediated by neuronal TNF-α

• Type of Material: Article
• Authors: Woldeab B Haile, Emory University; Jialing Wu, Emory University; Ramiro Echeverry, Emory University; Fang Wu, Emory University; Jie An, Shandong University; Manuel Yepes, Emory University
• Language: English
• Date: 2012-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 International Society for Cerebral Blood Flow & Metabolism, Inc.
• Final Published Version (URL): http://www.nature.com/jcbfm/journal/v32/n1/full/jcbfm2011106a.html
• Title of Journal or Parent Work: Journal of Cerebral Blood Flow and Metabolism
• Volume: 32
• Issue: 1
• Start Page: 57
• End Page: 69
• Grant/Funding Information: This work was supported in part by National Institutes of Health Grants NS-062073 and HL-095063, and VA MERIT award BX000474 (M Yepes), and National Natural Science Foundation of China 30900458 (J An).
• Keywords: cerebral ischemia; tumor necrosis factor-α; tissue-type plasminogen activator
• Research Categories: Biology, Physiology; Biology, Neuroscience

Abstract

Cerebral cortical neurons have a heightened sensitivity to hypoxia and their survival depends on their ability to accommodate to changes in the concentration of oxygen in their environment. Tissue-type plasminogen activator (tPA) is a serine proteinase that activates the zymogen plasminogen into plasmin. Hypoxia induces the release of tPA from cerebral cortical neurons, and it has been proposed that tPA mediates hypoxic and ischemic neuronal death. Here, we show that tPA is devoid of neurotoxic effects and instead is an endogenous neuroprotectant that renders neurons resistant to the effects of lethal hypoxia and ischemia. We present in vitro and in vivo evidence indicating that endogenous tPA and recombinant tPA induce the expression of neuronal tumor necrosis factor-α. This effect, mediated by plasmin and the N-methyl--aspartate receptor, leads to increased expression of the cyclin-dependent kinase inhibitor p21 and p21-mediated development of early hypoxic and ischemic tolerance.