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Comparison of the Effects of Cyclosporin A on the Metabolism of Perfused Rat Brain Slices During Normoxia and Hypoxia


Donohoe P, Gottschalk,  S
Department High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Max Planck Society;

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Serkova, N., Donohoe P, Gottschalk, S., Hainz C, Neumann CU, Bickler PE, Benet LZ, Leibfritz, D., & Christians, U. (2002). Comparison of the Effects of Cyclosporin A on the Metabolism of Perfused Rat Brain Slices During Normoxia and Hypoxia. Journal of Cerebral Blood Flow Metabolism, 22(3), 342–352. doi:10.1097/00004647-200203000-00012.

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 mug/L cyclosporin A significantly reduced mitochondrial energy metabolism (nucleotide triphosphate, 83 plusminus 9 of controls; phosphocreatine, 69 plusminus 9) by inhibition of the Krebs cycle (glutamate, 77 plusminus 5) and oxidative phosphorylation (NAD+, 65 plusminus 14) associated with an increased generation of reactive oxygen species (285 plusminus 78 of control). However, the same cyclosporin A concentration (500 mug/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 mug/L cyclosporin A to the perfusion medium protected high-energy phosphate metabolism (nucleotide triphosphate, 11 plusminus 15 of control vs. 35 plusminus 9 with 500 mug/L cyclosporin A) and the intracellular pH (6.2 plusminus 0.1 control vs. 6.6 plusminus 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.