Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats.
OBJECTIVE
Iron catalyzes the formation of damaging reactive species during cerebral reperfusion. Brain iron concentration is highest at birth, so the brain of the asphyxiated newborn may be at increased risk of iron-dependent injury. We investigated whether the ferric iron chelator deferoxamine could reduce hypoxic-ischemic brain injury in neonatal rats. Because deferoxamine has concentration-dependent activities other than iron chelation, we measured brain deferoxamine levels and calculated deferoxamine pharmacokinetic parameters.


METHODS
We produced hypoxic-ischemic injury to the right cerebral hemisphere of 7-day-old rats by right common carotid artery ligation followed by 2.25 hours of hypoxia in 8% oxygen. At 5 minutes of recovery from hypoxia the rats received 100 mg/kg deferoxamine mesylate or saline subcutaneously. Rats (saline, n = 33; deferoxamine, n = 38) were killed at 42 hours of recovery to assess early acute edema by measurement of hemispheric water content. Other rats (saline, n = 31; deferoxamine, n = 32) were killed at 30 days of age for morphometric determination of right hemisphere atrophy. In still other rats, we measured deferoxamine levels in blood and brain after hypoxia-ischemia.


RESULTS
Deferoxamine significantly reduced right hemisphere injury as measured by early water content (P < .01) and later atrophy (P = .019). Deferoxamine brain levels peaked between 100 and 200 mumol/L at 40 to 60 minutes after injection and exceeded serum levels by +/- 70%.


CONCLUSIONS
Deferoxamine administered after induction of cerebral hypoxia-ischemia reduces injury in 7-day-old rats. Deferoxamine concentrates in the brain at levels between 100 and 200 mumol/L. At the concentrations achieved, deferoxamine might protect the brain through mechanisms unrelated to its ability to chelate iron.
Palmer
C
C
Department of Pediatrics, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey 17033.
Roberts
R L
RL
Bero
C
C
D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000097:blood / Q000473:pathology / Q000628:therapy*; D003676:Deferoxamine / Q000032:analysis / Q000627:therapeutic use*; D005260:Female; D002534:Hypoxia, Brain / Q000097:blood / Q000473:pathology / Q000628:therapy*; D008297:Male; D051381:Rats
D003676:Deferoxamine