title: Neuroprotection by freezing ischemic penumbra evolution without cerebral blood flow augmentation with a postsynaptic density-95 protein inhibitor.
abstract: OBJECTIVE
  The purpose of this study was to determine whether neuroprotection is feasible without cerebral blood flow augmentation in experimental permanent middle cerebral artery occlusion.
  
  
  METHODS
  Rats were subjected to permanent middle cerebral artery occlusion by the suture occlusion method and were treated 1 hour thereafter with a single 5-minute intravenous infusion of the postsynaptic density-95 protein inhibitor Tat-NR2B9c (7.5 mg/kg) or saline (n=8/group). Arterial spin-labeled perfusion-weighted MRI and diffusion weighted MRI were obtained with a 4.7-T Bruker system at 30, 45, 70, 90, 120, 150, and 180 minutes postmiddle cerebral artery occlusion to determine cerebral blood flow and apparent diffusion coefficient maps, respectively. At 24 hours, animals were neurologically scored (0 to 5), euthanized, and the brains stained with 2-3-5-triphenyl tetrazolium chloride to ascertain infarct volumes corrected for edema. Additionally, the effects of Tat-NR2B9c on adenosine 5'-triphosphate levels were measured in vitro in neurons subjected to oxygen-glucose deprivation.
  
  
  RESULTS
  Final infarct volume was decreased by 30.3% in the Tat-NR2B9c-treated animals compared with controls (P=0.028). There was a significant improvement in 24 hours neurological scores in the Tat-NR2B9c group compared with controls, 1.8±0.5 and 2.8±1.0, respectively (P=0.021). Relative to controls, Tat-NR2B9c significantly attenuated diffusion-weighted imaging lesion growth and preserved the diffusion-weighted imaging/perfusion-weighted imaging mismatch (ischemic penumbra) without affecting cerebral blood flow in the ischemic core or penumbra. Tat-NR2B9c treatment of primary neuronal cultures resulted in 26% increase in cell viability and 34% greater adenosine 5'-triphosphate levels after oxygen-glucose deprivation.
  
  
  CONCLUSIONS
  Preservation of adenosine 5'-triphosphate levels in vitro and neuroprotection in permanent middle cerebral artery occlusion in rats is achievable without cerebral blood flow augmentation using a postsynaptic density-95 protein inhibitor.
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA. Bernt.Bratane@umassmed.edu
authors: Bernt T
authors: BT
authors: Bråtane
authors: Hong
authors: H
authors: Cui
authors: Douglas J
authors: DJ
authors: Cook
authors: James
authors: J
authors: Bouley
authors: Michael
authors: M
authors: Tymianski
authors: Marc
authors: M
authors: Fisher
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D000076122:Disks Large Homolog 4 Protein; D005615:Freezing; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D010455:Peptides; C542597:Tat-NR2B9c