Brain mitochondrial responses to postischemic reperfusion: a role for calcium and hydrogen peroxide?
During early recirculation following global brain ischemia, mitochondria are exposed to markedly elevated Ca(2+) concentrations and a short-lived production of reactive oxygen species, including hydrogen peroxide (H(2)O(2)). A brief increase in mitochondrial Ca(2+) and a subsequent increase in mitochondrial glutathione content have been observed. In the present study, we have confirmed the increase in mitochondrial glutathione in a rat model of global forebrain ischemia. This change was not inhibited by treatment of the rats with FK506, contrasting with our previous finding that cyclosporin A partially blocked the increase. These results suggest that induction of the mitochondrial permeability transition may be necessary for the increase in glutathione content in these organelles. To further investigate possible mitochondrial responses during early postischemic reperfusion, mitochondria isolated from normal brain were exposed to Ca(2+) and H(2)O(2), under conditions similar to those in intact cells. Respiratory activity was substantially modified when the mitochondria were exposed to Ca(2+) and H(2)O(2) together. Two distinct and largely noninteracting mechanisms apparently accounted for the responses to these agents. The effects of Ca(2+), but not H(2)O(2), were inhibited by cyclosporin A, again implicating the permeability transition in some of the mitochondrial changes.
Sims
N R
NR
Department of Medical Biochemistry, School of Medicine, Flinders University, Adelaide, South Australia, Australia.Neil.Sims@flinders.edu.au
Anderson
M F
MF
Hobbs
L M
LM
Powell
J A
JA
Zaidan
E
E
D000244:Adenosine Diphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D008293:Malates / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D016548:Prosencephalon / Q000098:blood supply / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015424:Reperfusion; D019802:Succinic Acid / Q000378:metabolism / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D004791:Enzyme Inhibitors; D008293:Malates; D014475:Uncoupling Agents; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000244:Adenosine Diphosphate; C030298:malic acid; D016572:Cyclosporine; D019289:Pyruvic Acid; D020122:tert-Butylhydroperoxide; D019802:Succinic Acid; D006861:Hydrogen Peroxide; D005978:Glutathione; D002118:Calcium; D016559:Tacrolimus