O-desulfated heparin improves outcome after rat cerebral ischemia/reperfusion injury

J. Mocco, Corbett E. Shelton, Paulina Sergot, Andrew F. Ducruet, Ricardo J. Komotar, Marc L. Otten, Sergei A. Sosunov, Robert B. MacArthur, Thomas P. Kennedy, E. Sander Connolly

Research output: Contribution to journalArticle

15 Scopus citations

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. CONCLUSION: Our findings indicate that ODSH can be administered at a dose that provides postischemic anti-inflammatory neuroprotection without an increased risk of intracerebral hemorrhage.

Original languageEnglish (US)
Pages (from-to)1297-1303
Number of pages7
JournalNeurosurgery
Volume61
Issue number6
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

Keywords

  • Cerebral ischemia
  • Heparin
  • Inflammation
  • O-desulfated heparin
  • Rat
  • Reperfusion injury

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

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  • Cite this

    Mocco, J., Shelton, C. E., Sergot, P., Ducruet, A. F., Komotar, R. J., Otten, M. L., Sosunov, S. A., MacArthur, R. B., Kennedy, T. P., & Connolly, E. S. (2007). O-desulfated heparin improves outcome after rat cerebral ischemia/reperfusion injury. Neurosurgery, 61(6), 1297-1303. https://doi.org/10.1227/01.neu.0000306109.55174.e6