Failure of deferoxamine, an iron chelator, to improve outcome after collagenase-induced intracerebral hemorrhage in rats.
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.
Warkentin
Lindsey M
LM
Centre for Neuroscience and Department of Psychology, University of Alberta, Edmonton, AB, Canada.
Auriat
Angela M
AM
Wowk
Shannon
S
Colbourne
Frederick
F
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001929:Brain Edema / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D020520:Brain Infarction / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002614:Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use; D017364:Collagenases / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003676:Deferoxamine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007501:Iron / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017262:Siderophores / Q000494:pharmacology / Q000627:therapeutic use; D017211:Treatment Failure
D002614:Chelating Agents; D061965:Matrix Metalloproteinase Inhibitors; D017262:Siderophores; D007501:Iron; D017364:Collagenases; D003676:Deferoxamine