title: O-desulfated heparin improves outcome after rat cerebral ischemia/reperfusion injury.
abstract: OBJECTIVE
  Inflammatory cascades play a significant role in progressive neurological injury after transient cerebral ischemia. It has been demonstrated that heparin, a potent anticoagulant, also possesses anti-inflammatory properties that diminish postreperfusion damage after stroke. However, the potential for heparin to induce hemorrhagic transformation of an infarct has deterred its use in cases of focal cerebral ischemia. In this study, we examined whether or not administration of a novel O-desulfated heparin (ODSH), with significantly decreased anticoagulant activity but active anti-inflammatory effects, would ameliorate inflammatory neurological injury without increasing intracerebral hemorrhage in a rat model of transient middle cerebral artery occlusion.
  
  
  METHODS
  Rats were injected immediately before ischemia with phosphate-buffered saline or ODSH (5 mg/kg, intravenously) and then every 12 hours (15 mg/kg, subcutaneously) for 72 hours. The animals were assessed for neurological function using a foot fault test and modified Bederson scale on Days 1, 2, and 5; plasma samples were analyzed for activated clotting time at multiple time points after the initial ODSH dose. After sacrifice on Day 5, infarct volume was determined and brain tissue was examined for evidence of hemorrhage both grossly and using a previously validated spectrophotometric hemoglobin assay.
  
  
  RESULTS
  ODSH-treated animals demonstrated significantly improved foot fault performance (P = 0.03) on Day 5 and reduced stroke volumes (P = 0.03) relative to controls. Although the brains of ODSH-treated rats exhibited significantly higher hemoglobin levels in a standardized assay (P = 0.01), there were no incidences of gross hemorrhage observed in either group, and activated clotting time measurements for the treated animals were not significantly elevated over baseline at any time point.
  
  
  CONCLUSIONS
  Our findings indicate that ODSH can be administered at a dose that provides postischemic anti-inflammatory neuroprotection without an increased risk of intracerebral hemorrhage.
authors.affiliation: Department of Neurological Surgery, Columbia University, New York, New York 10032, USA. jdm32@columbia.edu
authors.forename: J
authors.initials: J
authors.lastname: Mocco
authors.forename: Corbett E
authors.initials: CE
authors.lastname: Shelton
authors.forename: Paulina
authors.initials: P
authors.lastname: Sergot
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ducruet
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Komotar
authors.forename: Marc L
authors.initials: ML
authors.lastname: Otten
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Sosunov
authors.forename: Robert B
authors.initials: RB
authors.lastname: Macarthur
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Kennedy
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
mesh_terms: D000818:Animals; D002544:Cerebral Infarction / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006493:Heparin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D016166:Free Radical Scavengers; C410523:heparin, O-desulfated; D006493:Heparin