title: The novel immunosuppressant SDZ-RAD protects rat brain slices from cyclosporine-induced reduction of high-energy phosphates.
abstract: 1. SDZ-RAD, 40-O-(2-hydroxyethyl)-rapamycin, is a novel macrolide immunosuppressant. Because of its synergistic interaction, SDZ-RAD is under clinical investigation as immunosuppressant in combination with cyclosporine after organ transplantation. Neurotoxicity is a critical side-effect of cyclosporine. 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 31P-magnetic resonance spectroscopy (MRS). 3. Cyclosporine significantly reduced high-energy phosphates after 2 h in a dose-dependent manner (100 micrograms l-1: 93 +/- 3% of control (NTP), 91 +/- 3% (PCr); 500 micrograms l-1: 84 +/- 2% (NTP), 73 +/- 2 (PCr); 5000 micrograms l-1: 68 +/- 3% (NTP), 55 +/- 5% (PCr); n = 6; P < 0.02). 4. In contrast, after perfusion for 2 h, SDZ-RAD (500 micrograms l-1 and 5000 micrograms l-1) significantly increased high-energy phosphate concentrations in the brain slices (P < 0.02). Even at the lowest concentration, SDZ-RAD protected brain energy metabolism against cyclosporine toxicity: 100 micrograms l-1 SDZ-RAD + 5000 micrograms 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 antagonistic. Both drugs were found in mitochondria using h.p.l.c-MS analysis. 6. We conclude that cyclosporine inhibits mitochondrial high-energy phosphate metabolism, which can be antagonized by SDZ-RAD.
authors.affiliation: Department of Biopharmaceutical Sciences, University of California, San Francisco 94143, USA.
authors.forename: N
authors.initials: N
authors.lastname: Serkova
authors.forename: L
authors.initials: L
authors.lastname: Litt
authors.forename: D
authors.initials: D
authors.lastname: Leibfritz
authors.forename: B
authors.initials: B
authors.lastname: Hausen
authors.forename: R E
authors.initials: RE
authors.lastname: Morris
authors.forename: T L
authors.initials: TL
authors.lastname: James
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
authors.forename: U
authors.initials: U
authors.lastname: Christians
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D000068338:Everolimus; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010477:Perfusion; D010710:Phosphates / Q000378:metabolism*; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D010710:Phosphates; D010725:Phosphocreatine; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D000068338:Everolimus; D020123:Sirolimus