title: THR-18, a 18-mer peptide derived from PAI-1, is neuroprotective and improves thrombolysis by tPA in rat stroke models.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  In the first model (thromboembolic), stroke was induced by intra-carotid injection of micro-clots to rats, and tPA (6 mg/kg) was intravenously infused for 30 minutes with or without THR-18 (1 mg/kg) at 4 hours post-induction. In the second model [transient middle cerebral artery occlusion (tMCAO)], stroke was induced for 2 hours by a transient mechanical occlusion. tPA and/or THR-18 (0.02, 0.1, and 1 mg/kg) were intravenously infused for 60 minutes at the time of reperfusion.
  
  
  RESULTS
  In the thromboembolic model, cerebral blood flow, measured before and up to 5.5 hours post-induction, revealed that tPA administration caused reperfusion of flow at 30 minutes post-infusion. Later on, an additional increase in reperfusion was seen in the tPA+THR-18 group, and not with tPA alone. In both models, the frequency of intracranial hemorrhage in the tPA-treated group was found to be significantly higher than the control, and this tPA effect was attenuated by THR-18. In the thromboembolic study, infarct size and brain edema were similar in the control and tPA-treated rats. However, the combination of tPA and THR-18 caused a statistically significant reduction in both parameters (infarct size 17.8 versus 25.0%, brain edema 5 versus 8%, tPA+THR-18 versus control, respectively). In the tMCAO mechanical model, infarct size and brain edema were both increased by tPA treatment as compared to the control group, and this increase was markedly diminished by THR-18 co-administration. Neurobehavioral assessment of the tMCAO animals performed at 72 hours post-stroke induction revealed significant improvements (P<0.05-0.01) in neuroscores in all groups of animals treated with peptide-tPA, as compared to the tPA monotherapy group. A significant (P<0.05) improvement in the neurological outcome was also seen in the THR-18 monoterapy group, as compared to the control animals, thus demonstrating a clear neuroprotective effect by the peptide on its own.
  
  
  CONCLUSIONS
  The results support the use of THR-18 together with tPA in the thrombolytic therapy of stroke, in order to achieve better patency, less tPA-induced damage, and possibly a widening of tPA therapeutic time window.
authors.affiliation: Pharmaseed Ltd, Nes Ziona, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Krakovsky
authors.forename: V
authors.initials: V
authors.lastname: Polianski
authors.forename: A
authors.initials: A
authors.lastname: Nimrod
authors.forename: A
authors.initials: A
authors.lastname: Higazi
authors.forename: R R
authors.initials: RR
authors.lastname: Leker
authors.forename: I
authors.initials: I
authors.lastname: Lamensdorf
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D020300:Intracranial Hemorrhages / Q000517:prevention & control; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage; D017395:Plasminogen Activator Inhibitor 1 / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy*; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
chemical_list: D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D010455:Peptides; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator