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Neutralizing the neurotoxic effects of exogenous and endogenous tPA

Nature Neuroscience volume 9, pages 1150–1155 (2006)Cite this article

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.

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Figure 1: Neuroprotective effect of the PAI-1–derived peptide EEIIMD.
Figure 2: The PAI-1–derived peptide does not accelerate tPA clearance.
Figure 3: EEIIMD reduces infarct size in rats treated with tPA after embolic stroke.
Figure 4: EEIIMD decreases histopathologic changes associated with FPI.
Figure 5: Decreasing the degenerating neurons in the cortex by EEIIMD treatment.
Figure 6: EEIIMD decreased the effect of FPI on cortical swelling.
Figure 7: EEIIMD decreases post-FPI brain water content.

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Acknowledgements

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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Author notes

  1. William M Armstead and Taher Nassar: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Anesthesiology and Critical Care, and Department of Pharmacology, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, 19104, Pennsylvania, USA

    William M Armstead

  2. Department of Clinical Biochemistry, Hadassah University Hospital and Hebrew University–Hadassah Medical School, Jerusalem, 91120, Israel

    Taher Nassar, Saed Akkawi & Abd Al-Roof Higazi

  3. Department of Neurosurgery, University of Pennsylvania, 513A Stellar-Chance Pavilion, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Douglas H Smith & Xiao-Han Chen

  4. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 513A Stellar-Chance Pavilion, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Douglas B Cines & Abd Al-Roof Higazi

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Correspondence to Abd Al-Roof Higazi.

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Armstead, W., Nassar, T., Akkawi, S. et al. Neutralizing the neurotoxic effects of exogenous and endogenous tPA. Nat Neurosci 9, 1150–1155 (2006). https://doi.org/10.1038/nn1757

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