title: Brain distribution and elimination of recombinant human TIMP-1 after cerebral ischemia and reperfusion in rats.
abstract: OBJECTIVE
  To investigate recombinant human TIMP-1 ((125)I-rhTIMP-1) half-life in blood and its distribution in rat brain tissue after cerebral ischemia/reperfusion as part of a therapeutic development paradigm.
  
  
  METHODS
  A suture model of the middle cerebral artery occlusion was used. (125)I-labeled rhTIMP-1 at 60 μg/kg (11.23 μCi/μg) was administered to rats intravenously at the beginning of reperfusion. Blood and brain tissue were collected. The radioactivity was detected with a gamma counter and analyzed by autoradiography.
  
  
  RESULTS
  The blood half-life T(1/2) of (125)I-rhTIMP-1 was 42.2 hours. Thirty minutes after (125)I-rhTIMP-1 administration, an increased accumulation of (125)I-rhTIMP-1 in the ischemic hemisphere was observed. The maximum brain tissue concentration C(max) was 26.1 ng/g at 1.5 hours in the striatum and 13.9 ng/g at 5 hours in the cortex when the uptake percentage of brain tissue to blood was 6.1±0.4 and 6.7±2.1%, respectively. The cortex and striatum elimination half-lives T(1/2) were 45.3 and 39.2 hours, respectively. Electrophoretic analysis of ischemic samples for (125)I-rhTIMP-1 showed a clear 28 kDa band 1.5 hours after (125)I-rhTIMP-1 administration in the cortex and striatum. The intensity of the 28 kDa band decreased after 3.0 hours of the administration. Some (125)I-rhTIMP-1 maintained its molecular integrity for 8.5 hours in ischemic striatum after reperfusion.
  
  
  CONCLUSIONS
  (125)I-labeled rhTIMP-1 was distributed quickly into ischemic brain tissue and had a slow elimination in both blood and brain tissue. These results, along with other studies suggesting therapeutic benefits, will aid in the development of TIMP-1 for protecting ischemic stroke.
authors.affiliation: Department of Neurology, College of Medicine, University of Cincinnati, OH 45267-0532, USA.
authors.forename: Yalian
authors.initials: Y
authors.lastname: Sa
authors.forename: Jinsong
authors.initials: J
authors.lastname: Hao
authors.forename: Divya
authors.initials: D
authors.lastname: Samineni
authors.forename: Joseph
authors.initials: J
authors.lastname: Clark
authors.forename: Gail
authors.initials: G
authors.lastname: Pyne-Geithman
authors.forename: Joseph
authors.initials: J
authors.lastname: Broderick
authors.forename: Aigang
authors.initials: A
authors.lastname: Lu
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D006207:Half-Life; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism; D007457:Iodine Radioisotopes; D008297:Male; D008657:Metabolic Clearance Rate; D011480:Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D007457:Iodine Radioisotopes; D011480:Protease Inhibitors; D011993:Recombinant Fusion Proteins; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1