The novel immunosuppressant SDZ-RAD protects rat brain slices from cyclosporine-induced reduction of high-energy phosphates

1 SDZ-RAD, 40-O-(2-hydroxyethyl)-rapamycin, is a novel macrolide immunosupp ressant. Because of its synergistic interaction, SDZ-RAD is under clinical investigation as immunosuppressant in combination with cyclosporine after o rgan transplantation. Neurotoxicity is a critical side-effect of cyclospori ne. 2 We studied the effect of SDZ-RAD and its combination with cyclosporine on high-energy phosphates, phosphocreatine (PCr) and nucleoside triphosphates (NTP), in brain slices using P-31-magnetic resonance spectroscopy (MRS). 3 Cyclosporine significantly reduced high-energy phosphates after 2 h in a dose-dependent manner (100 mu g l(-1): 93 +/- 3% of control (NTP), 91 +/- 3 % (PCr); 500 mu g l(-1): 84 +/- 2% (NTP), 73 +/- 2 (PCr); 5000 mu g l(-1): 68 +/- 3% (NTP), 55 +/- 5% (PCr); n = 6; P < 0.02). 4 In contrast, after perfusion for 2 h, SDZ-RAD (500 mu g l(-1) and 5000 mu g l(-1)) significantly increased high-energy phosphate concentrations in t he brain slices (P < 0.02). Even at the lowest concentration, SDZ-RAD prote cted brain energy metabolism against cyclosporine toxicity: 100 mu g l(-1) SDZ-RAD+ 5000 mu g l(-1) cyclosporine: 86 +/- 3% (NTP), 83 +/- 7% (PCr), n = 3, P < 0.03 compared to cyclosporine alone. 5 As evaluated using an algorithm based on Loewe isobolograms, the effects of SDZ-RAD/cyclosporine combinations on brain energy reduction were antagon istic. Both drugs were found in mitochondria using h.p.l.c-MS analysis. 6 We conclude that cyclosporine inhibits mitochondrial high-energy phosphat e metabolism, which can be antagonized by SDZ-RAD.