Neutralizing the neurotoxic effects of exogenous and endogenous tPA

William M. Armstead, Taher Nassar, Saed Akkawi, Douglas H. Smith, Xiao Han Chen, Douglas B. Cines, Abd Al Roof Higazi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)1150-1155
Number of pages6
JournalNature Neuroscience
Volume9
Issue number9
DOIs
StatePublished - Sep 2006
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the US National Institutes of Health (grants HL06831, HL076406, HL076206, HL82545 and HL67381), the University of Pennsylvania Research Foundation and the Israeli Science Foundation (grant 930/04).

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