PMID- 24549864
OWN - NLM
STAT- MEDLINE
DCOM- 20140610
LR  - 20211021
IS  - 1524-4628 (Electronic)
IS  - 0039-2499 (Print)
IS  - 0039-2499 (Linking)
VI  - 45
IP  - 4
DP  - 2014 Apr
TI  - Combination treatment with N-acetyl-seryl-aspartyl-lysyl-proline and tissue 
      plasminogen activator provides potent neuroprotection in rats after stroke.
PG  - 1108-14
LID - 10.1161/STROKEAHA.113.004399 [doi]
AB  - BACKGROUND AND PURPOSE: 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-kappaB (NF-kappaB), transforming growth factor beta 
      (TGF-beta), 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-beta1, PAI-1, and NF-kappaB 
      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-beta and NF-kappaB signaling by AcSDKP in 
      the neurovascular unit may underlie the neuroprotective effect of AcSDKP.
FAU - Zhang, Li
AU  - Zhang L
AD  - 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.
FAU - Chopp, Michael
AU  - Chopp M
FAU - Teng, Hua
AU  - Teng H
FAU - Ding, Guangliang
AU  - Ding G
FAU - Jiang, Quan
AU  - Jiang Q
FAU - Yang, Xiao Ping
AU  - Yang XP
FAU - Rhaleb, Nour Eddine
AU  - Rhaleb NE
FAU - Zhang, Zheng Gang
AU  - Zhang ZG
LA  - eng
GR  - R01 NS62832/NS/NINDS NIH HHS/United States
GR  - R01 NS079612/NS/NINDS NIH HHS/United States
GR  - R01 NS 079612/NS/NINDS NIH HHS/United States
GR  - R01 AG037506/AG/NIA NIH HHS/United States
GR  - R01 NS062832/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140218
PL  - United States
TA  - Stroke
JT  - Stroke
JID - 0235266
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Growth Inhibitors)
RN  - 0 (NF-kappa B)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Oligopeptides)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (Transforming Growth Factor beta1)
RN  - EC 3.4.21.68 (Tissue Plasminogen Activator)
RN  - H041538E9P (goralatide)
SB  - IM
MH  - Animals
MH  - Blood-Brain Barrier/drug effects
MH  - Disease Models, Animal
MH  - Drug Therapy, Combination
MH  - Endothelial Cells/cytology/*drug effects/metabolism
MH  - Fibrinolytic Agents/pharmacology
MH  - Growth Inhibitors/pharmacology
MH  - Humans
MH  - Intracranial Embolism/*drug therapy/metabolism/pathology
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - NF-kappa B/metabolism
MH  - Neuroprotective Agents/*pharmacology
MH  - Oligopeptides/*pharmacology
MH  - Plasminogen Activator Inhibitor 1/metabolism
MH  - Primary Cell Culture
MH  - Rats
MH  - Rats, Wistar
MH  - Stroke/*drug therapy/metabolism/pathology
MH  - Tissue Plasminogen Activator/*pharmacology
MH  - Transforming Growth Factor beta1/metabolism
PMC - PMC3966939
MID - NIHMS561226
OTO - NOTNLM
OT  - capillary permeability
OT  - ischemia
OT  - stroke
EDAT- 2014/02/20 06:00
MHDA- 2014/06/11 06:00
PMCR- 2015/04/01
CRDT- 2014/02/20 06:00
PHST- 2014/02/20 06:00 [entrez]
PHST- 2014/02/20 06:00 [pubmed]
PHST- 2014/06/11 06:00 [medline]
PHST- 2015/04/01 00:00 [pmc-release]
AID - STROKEAHA.113.004399 [pii]
AID - 10.1161/STROKEAHA.113.004399 [doi]
PST - ppublish
SO  - Stroke. 2014 Apr;45(4):1108-14. doi: 10.1161/STROKEAHA.113.004399. Epub 2014 Feb 
      18.