Ischemia-induced brain iron delocalization: effect of iron chelators.
Tissue damage in cerebral ischemia may be produced by acidosis-induced delocalization of intracellular iron which acts as a catalyst in oxidative reactions. Acidosis was induced either by homogenization and incubation of rat cortical homogenates in acidified buffers or by submitting hyperglycemic rats to complete ischemia, a procedure that leads to intracellular lactic acidosis. The level of low molecular weight species (LMWS) iron was measured after filtration of tissue homogenates through a 10,000 Mr ultrafiltration membrane. When cortical tissue was homogenized in buffer pH 7, the level of LMWS iron was equal to 0.21 microgram/g. It was significantly enhanced by acidification of the homogenization medium, reaching 0.34 microgram/g at pH 6 and 0.75 microgram/g at pH 5. When the tissue was homogenized in water, the LMWS iron level reached 0.17 microgram/g in normoglycemic rats and 0.38 microgram/g (p < .05) in hyperglycemic rats. Both aerobic incubation of homogenates for 1 h at 37 degrees C and inclusion of EDTA in the homogenization medium led to further increases in the iron level. In order to demonstrate the deleterious role of iron in brain ischemia, the effect of treatment with bipyridyl, an iron-chelating agent, was assessed by measuring regional brain edema by the specific gravity method, 24 h following induction of thrombotic brain infarction. The treatment significantly attenuated the development of brain edema, reducing the water content of the infarcted area by about 2.5%. Taken together, these results support the hypothesis that a significant component of brain ischemic injury involves an iron-dependent mechanism.
Oubidar
M
M
Laboratoire de Pharmacodynamie, Faculté de Pharmacie, Dijon, France.
Boquillon
M
M
Marie
C
C
Schreiber
L
L
Bralet
J
J
D015082:2,2'-Dipyridyl / Q000494:pharmacology*; D000138:Acidosis; D000704:Analysis of Variance; D000818:Animals; D001929:Brain Edema / Q000503:physiopathology; D002545:Brain Ischemia / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D002544:Cerebral Infarction / Q000503:physiopathology; D004492:Edetic Acid / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism; D007501:Iron / Q000032:analysis / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014462:Ultrafiltration
D007502:Iron Chelating Agents; D015082:2,2'-Dipyridyl; D004492:Edetic Acid; D007501:Iron