Effect of the Antioxidant Idebenone on Adverse Events Under Mycophenolate Mofetil Therapy in a Rat Model

• Published in: Transplantation Vol. 85; no. 5; pp. 739 - 747
• Main Authors: HELLER, Tanja, GEIDE, Anna, BONITZ, Ulrike, WEGNER, Ulrike, GRÖNE, Hermann-Josef, ARMSTRONG, Victor W, OELLERICH, Michael
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott 15-03-2008
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antioxidants - pharmacology; Antiviral agents; Biological and medical sciences; Catalase - genetics; Colon - pathology; DNA, Complementary - genetics; Erythropoietin - genetics; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation; Hemoglobins - genetics; Immunosuppressive Agents - adverse effects; Jejunum - pathology; Medical sciences; Models, Animal; Mycophenolic Acid - adverse effects; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - blood; Mycophenolic Acid - pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Wistar; Receptors, Erythropoietin - genetics; Reverse Transcriptase Polymerase Chain Reaction; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tissue, organ and graft immunology; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology; Mofetil; Animal model; Mycophenolic acid; Rat; Psychotropic; Toxicity; Benzoquinone derivatives; Rodentia; Idebenone; Antioxidant; Immunomodulator; Vertebrata; Antibiotic; Mammalia; Treatment; Nootropic agent; Secondary effect; Antiviral; Complication; Graft; Immunosuppressive agent; Mycophenolate mofetil; Inosine monophosphate dehydrogenase inhibitor
• ISSN: 0041-1337; 1534-6080
• DOI: 10.1097/TP.0b013e3181664e54

Diarrhea and anemia are side effects of mycophenolic acid (MPA), but underlying mechanisms are not fully understood. Gene expression of major-alpha-hemoglobin and catalase was suppressed in livers of mycophenolate mofetil (MMF)-treated rats, suggesting MPA attenuates cellular defense against reactive oxygen species (ROS). We investigated whether the antioxidant idebenone might alleviate MPA-related side effects.
Rats were treated as follows: group 1: controls; group 2: idebenone; group 3: MMF; and group 4: MMF/idebenone. Blood was collected weekly to determine cell counts, hemoglobin, MPA, plasma albumin, total protein, creatinine, and urea concentrations. On day 28 RNA was extracted from liver, kidneys, and bone marrow (BM). Colon and jejunum were examined histologically.
High-dose MMF-treated rats developed diarrhea, dehydration, and weight loss. After a week, a significant decrease (P=0.001) in erythrocyte count and hemoglobin concentration was observed that was not influenced by idebenone. Degenerative changes in the jejunum were slightly attenuated by idebenone. Idebenone did not influence MPA-induced suppression of catalase. A significant suppression of major-alpha-hemoglobin and the erythropoietin (EPO)-receptor in BM of MMF-treated groups and almost complete absence of hemopoietic progenitor cells were observed. EPO-mRNA was markedly upregulated in the MMF-group and even more in the MMF/idebenone-group.
Idebenone showed minimal benefit on MMF-related diarrhea and anemia. BM of MMF-treated rats revealed erythroid aplasia as a possible reason for anemia. Marked upregulation of EPO-mRNA presumably reflects a compensatory mechanism. Because ROS have the potential to suppress EPO expression, it can be hypothesized that enhanced EPO-mRNA expression in MMF/idebenone-treated rats is caused by antagonism of ROS.