Nature Neuroscience
- 9, 1150 - 1155 (2006)
Published online: 27 August 2006; | doi:10.1038/nn1757
Neutralizing the neurotoxic effects of exogenous and endogenous tPAWilliam M Armstead1, 5, Taher Nassar2, 5, Saed Akkawi2, Douglas H Smith3, Xiao-Han Chen3, Douglas B Cines4 & Abd Al-Roof Higazi2, 41
Departments of Anesthesiology and Critical Care, and Department of Pharmacology, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia 19104, Pennsylvania, USA. 2
Department of Clinical Biochemistry, Hadassah University Hospital and Hebrew University–Hadassah Medical School, Jerusalem, 91120, Israel. 3
Department of Neurosurgery, University of Pennsylvania, 513A Stellar-Chance Pavilion, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. 4
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 513A Stellar-Chance Pavilion, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA. 5
These authors contributed equally to this work.
Correspondence should be addressed to higazi@mail.med.upenn.edu The clinical use of tissue-type plasminogen activator (tPA) in the treatment of stroke is profoundly constrained by its serious side effects. We report that the deleterious effects of tPA on cerebral edema and intracranial bleeding are separable from its fibrinolytic activity and can be neutralized. A hexapeptide (EEIIMD) corresponding to amino acids 350–355 of plasminogen activator inhibitor type 1 (PAI-1) abolished the tPA-induced increase in infarct size and intracranial bleeding in both mechanical and embolic models of stroke in rats, and reduced brain edema and neuronal loss after traumatic brain injury in pigs. These experiments suggest mechanisms to reduce the neurotoxic effects of tPA without compromising its fibrinolytic activity, through the use of selective antagonists and new tPA formulations.
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