Comparison of the effects of cyclosporin a on the metabolism of perfused rat brain slices during normoxia and hypoxia.
The authors evaluated and compared the metabolic effects of cyclosporin A in the rat brain during normoxia and hypoxia/reperfusion. Ex vivo 31P magnetic resonance spectroscopy experiments based on perfused rat brain slices showed that under normoxic conditions, 500 microg/L cyclosporin A significantly reduced mitochondrial energy metabolism (nucleotide triphosphate, 83 +/- 9% of controls; phosphocreatine, 69 +/- 9%) by inhibition of the Krebs cycle (glutamate, 77 +/- 5%) and oxidative phosphorylation (NAD+, 65 +/- 14%) associated with an increased generation of reactive oxygen species (285 +/- 78% of control). However, the same cyclosporin A concentration (500 microg/L) was found to be the most efficient concentration to inhibit the hypoxia-induced mitochondrial release of Ca2+ in primary rat hippocampal cells with cytosolic Ca2+ concentrations not significantly different from normoxic controls. Addition of 500 microg/L cyclosporin A to the perfusion medium protected high-energy phosphate metabolism (nucleotide triphosphate, 11 +/- 15% of control vs. 35 +/- 9% with 500 microg/L cyclosporin A) and the intracellular pH (6.2 +/- 0.1 control vs. 6.6 +/- 0.1 with cyclosporin A) in rat brain slices during 30 minutes of hypoxia. Results indicate that cyclosporin A simultaneously decreases and protects cell glucose and energy metabolism. Whether the overall effect was a reduction or protection of cell energy metabolism depended on the concentrations of both oxygen and cyclosporin A in the buffer solution.
Serkova
Natalie
N
Department of Biology and Chemistry, University of Bremen, Bremen, Germany.
Donohoe
Paul
P
Gottschalk
Sven
S
Hainz
Carsten
C
Niemann
Claus U
CU
Bickler
Philip E
PE
Litt
Lawrence
L
Benet
Leslie Z
LZ
Leibfritz
Dieter
D
Christians
Uwe
U
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012016:Reference Values; D015424:Reperfusion; D013997:Time Factors
D000596:Amino Acids; D017382:Reactive Oxygen Species; D010725:Phosphocreatine; D016572:Cyclosporine