Failure of deferoxamine, an iron chelator, to improve outcome after collagenase-induced intracerebral hemorrhage in rats

Brain Res. 2010 Jan 14;1309:95-103. doi: 10.1016/j.brainres.2009.10.058. Epub 2009 Oct 30.

Abstract

Intracerebral hemorrhage (ICH) is a devastating stroke with no clinically proven treatment. Deferoxamine (DFX), an iron chelator, is a promising therapy that lessens edema, mitigates peri-hematoma cell death, and improves behavioral recovery after whole-blood-induced ICH in rodents. In this model, blood is directly injected into the brain, usually into the striatum. This mimics many but not all clinical features of ICH (e.g., there is no spontaneous bleed). Thus, we tested whether DFX improves outcome after collagenase-induced striatal ICH in rats. In the first experiment, 3- and 7-day DFX regimens (100 mg/kg twice per day starting 6 h after ICH), similar to those shown effective in the whole-blood model, were compared to saline treatment. Functional recovery was evaluated from 3 to 28 days with several behavioral tests. Except for one instance, DFX failed to lessen ICH-induced behavioral impairments and it did not lessen brain injury, which averaged 43.5 mm(3) at a 28-day survival. In the second experiment, 3 days of DFX treatment were given starting 0 or 6 h after collagenase infusion. Striatal edema occurred, but it was not affected by either DFX treatment (vs. saline treatment). Therefore, in contrast to studies using the whole-blood model, DFX treatment did not improve outcome in the collagenase model. Our findings, when compared to others, suggest that there are critical differences between these ICH models. Perhaps, the current clinical work with DFX will help identify the more clinically predictive model for future neuroprotection studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Brain Edema / chemically induced
  • Brain Edema / drug therapy
  • Brain Edema / physiopathology
  • Brain Infarction / chemically induced
  • Brain Infarction / drug therapy*
  • Brain Infarction / physiopathology
  • Cerebral Hemorrhage / chemically induced
  • Cerebral Hemorrhage / drug therapy*
  • Cerebral Hemorrhage / physiopathology
  • Chelating Agents / pharmacology
  • Chelating Agents / therapeutic use
  • Collagenases / toxicity
  • Corpus Striatum / drug effects
  • Corpus Striatum / pathology
  • Corpus Striatum / physiopathology
  • Deferoxamine / pharmacology*
  • Deferoxamine / therapeutic use
  • Disease Models, Animal
  • Drug Evaluation, Preclinical / methods
  • Iron / antagonists & inhibitors*
  • Iron / metabolism
  • Male
  • Matrix Metalloproteinase Inhibitors
  • Rats
  • Rats, Sprague-Dawley
  • Siderophores / pharmacology
  • Siderophores / therapeutic use
  • Treatment Failure

Substances

  • Chelating Agents
  • Matrix Metalloproteinase Inhibitors
  • Siderophores
  • Iron
  • Collagenases
  • Deferoxamine