title: Combination treatment with N-acetyl-seryl-aspartyl-lysyl-proline and tissue plasminogen activator provides potent neuroprotection in rats after stroke.
abstract: OBJECTIVE
  N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), an endogenously produced circulating peptide in humans and rodents, exerts anti-inflammatory and cardioprotective activities in various cardiovascular diseases.
  
  
  METHODS
  The present study evaluated the neuroprotective effect of AcSDKP alone and in combination with thrombolytic therapy in a rat model of embolic focal cerebral ischemia.
  
  
  RESULTS
  We found that treatment with AcSDKP alone at 1 hour or the combination treatment with AcSDKP and tissue plasminogen activator (tPA) at 4 hours after stroke onset substantially increased AcSDKP levels in plasma and cerebrospinal fluid and robustly reduced infarct volume and neurological deficits, without increasing the incidence of brain hemorrhage compared with ischemic rats treated with saline, AcSDKP alone at 4 hours, and tPA alone at 4 hours. Moreover, the combination treatment considerably reduced the density of nuclear transcription factor-κB (NF-κB), transforming growth factor β (TGF-β), and plasminogen activator inhibitor-1 (PAI-1) positive cerebral blood vessels in the ischemic brain, all of which were associated with reduced microvascular fibrin extravasation and platelet accumulation compared with tPA monotherapy. In vitro, AcSDKP blocked fibrin-elevated TGF-β1, PAI-1, and NF-κB proteins in primary human brain microvascular endothelial cells.
  
  
  CONCLUSIONS
  Our data indicate that AcSDKP passes the blood-brain barrier, and that treatment of acute stroke with AcSDKP either alone at 1 hour or in combination with tPA at 4 hours of the onset of stroke is effective to reduce ischemic cell damage in a rat model of embolic stroke. Inactivation of TGF-β and NF-κB signaling by AcSDKP in the neurovascular unit may underlie the neuroprotective effect of AcSDKP.
authors.affiliation: From the Department of Neurology (L.Z., M.C., H.T., G.D., Q.J., Z.G.Z.), Hypertension and Vascular Research Division (X.P.Y., N.E.R.), Henry Ford Health Sciences Center, Detroit, MI; and Department of Physics (M.C.), Oakland University, Rochester, MI.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: Hua
authors.initials: H
authors.lastname: Teng
authors.forename: Guangliang
authors.initials: G
authors.lastname: Ding
authors.forename: Quan
authors.initials: Q
authors.lastname: Jiang
authors.forename: Xiao Ping
authors.initials: XP
authors.lastname: Yang
authors.forename: Nour Eddine
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D020766:Intracranial Embolism / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D005343:Fibrinolytic Agents; D006131:Growth Inhibitors; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009842:Oligopeptides; D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1; D010959:Tissue Plasminogen Activator; C058504:goralatide
keywords: capillary permeability; ischemia; stroke