Neutralizing the neurotoxic effects of exogenous and endogenous tPA.
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.
Armstead
William M
WM
Department of Anesthesiology, University of Pennsylvania, 3620 Hamilton Walk, JM3, Philadelphia, Pennsylvania 19104, USA.
Nassar
Taher
T
Akkawi
Saed
S
Smith
Douglas H
DH
Chen
Xiao-Han
XH
Cines
Douglas B
DB
Higazi
Abd Al-Roof
AA
D000595:Amino Acid Sequence; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000139:chemically induced / Q000517:prevention & control; D020520:Brain Infarction / Q000139:chemically induced / Q000517:prevention & control; D002545:Brain Ischemia / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000493:pharmacokinetics; D014664:Vasodilation / Q000187:drug effects
D009842:Oligopeptides; D010959:Tissue Plasminogen Activator