Publications
THR-18, a 18-mer peptide derived from PAI-1, is neuroprotective and improves thrombolysis by tPA in rat stroke models.
Krakovsky M, Polianski V, Nimrod A, Higazi A, Leker RR, Lamensdorf I.
Neurol Res. 2011 Nov;33(9):983-90.
Published online November 2011
The thrombolytic treatment of stroke is limited by a narrow therapeutic time window and is associated with significant adverse side effects. To improve this situation, the modulation of tissue-type plasminogen activator (tPA) activity by a synthetic plasminogen activator inhibitor-1-derived 18-mer peptide (THR-18) was examined in two models of stroke in rats.
http://www.ncbi.nlm.nih.gov/pubmed/22081002
Blood-brain barrier permeability and tPA-mediated neurotoxicity.
Abu Fanne R, Nassar T, Yarovoi S, Rayan A, Lamensdorf I, Karakoveski M, Vadim P, Jammal M, Cines DB, Higazi AA.
Neuropharmacology. 2010 Jun;58(7):972-80. Epub 2010 Jan 6.
Published online June 2010
Tissue type plasminogen activator (tPA) can induce neuronal apoptosis, disrupt the blood-brain barrier (BBB), and promote dilation of the cerebral vasculature. The timing, sequence and contributions of these and other deleterious effects of tPA and their contribution to post-ischemic brain damage after stroke, have not been fully elucidated. To dissociate the effects of tPA on BBB permeability, cerebral vasodilation and protease-dependent pathways, we developed several tPA mutants and PAI-1 derived peptides constructed by computerized homology modeling of tPA. Our data show that intravenous administration of human tPA to rats increases BBB permeability through a non-catalytic process that is associated with reversible neurotoxicity, brain damage, mortality and contributes significantly to its brief therapeutic window. Furthermore, our data show that inhibiting the effect of tPA on BBB function without affecting its catalytic activity, improves outcome and significantly extends its therapeutic window in mechanical as well as in thromboembolic models of stroke.
http://www.ncbi.nlm.nih.gov/pubmed/20060006
Novel plasminogen activator inhibitor-1-derived peptide protects against impairment of cerebrovasodilation after
Armstead WM, Riley J, Kiessling JW, Cines DB, Higazi AA.
Am J Physiol Regul Integr Comp Physiol. 2010 Aug;299(2):R480-5. Epub 2010 Jun 10.
Published online August 2010
The sole FDA-approved treatment for acute stroke is recombinant tissue-type plasminogen activator (rtPA). However, rtPA aggravates the impairment of cerebrovasodilation induced by global hypoxia/ischemia; this impairment is attenuated by the preinjury treatment with the plasminogen activator inhibitor derivative EEIIMD. MAPK (a family of kinases, p38, and JNK) is upregulated after cerebral ischemia. In this study, we determined whether the novel plasminogen activator inhibitor-derived peptide, Ac-RMAPEEIIMDRPFLYVVR-amide, (PAI-1-DP) given 30 min before or 2 h after, focal central nervous system injury induced by photothrombosis would preserve responses to cerebrovasodilators and the role of p38 and JNK MAPK in such effects
http://www.ncbi.nlm.nih.gov/pubmed/20538898
Marrying Activase with Gleevec
Tim Fulmer
SciBX 1(23); doi:10.1038/scibx.2008.542
Published online July 10 2008
A Nature Medicine report suggests that repurposing Novartis' Gleevec cancer drug as an adjunct therapy in the stoke setting could
reduce the risk associated with Genentech's clot buster Activase and thus widen the tPA's therapeutic window. The article includes an interview with Thrombotech Chief Scientist Abd Al-Roof Higazi and discussion of THR-18’s method and results.
http://www.nature.com/scibx/journal/v1/n23/full/scibx.2008.542.html
Taming the clot-buster tPA
Ted M Dawson & Valina L Dawson
Nature Medicine 2006;12(9):993-4
Studies have found that strokes treated with tissue plasminogen activator (tPA) can help dissolve blood clots and improve outcome, buttPA can also increase the risk of hemorrhage and cause other deleterious effects. Scientists have developed a new approach that reduces the risk of intracranial bleeding and minimizes other deleterious effects of tPA on animal models by administering a hexapeptide (EEIIMD) that spans a region of plasminogen activator inhibitor type (PAI-1) which interferes with a part of tPA signaling that is not involved in clot-busting activity.
http://www.nature.com/nm/journal/v12/n9/full/nm0906-993.html
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
Design By
Nature Neuroscience 9, 1150 - 1155 (2006); doi: 10.1038/nn1757
Published online August 27 2006
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.
http://www.nature.com/neuro/journal/v9/n9/abs/nn1757.html |
