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Effect of the antioxidant idebenone on adverse events under mycophenolate mofetil therapy in a rat model
Tanja Heller1, Anna Geide, Ulrike Bonitz
1Abteilung Klinische Chemie, Georg-August-Universität, 37075 Göttingen, Germany. hellertanja@web.de
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
The antioxidant idebenone offered minimal relief for diarrhea and anemia in rats treated with mycophenolate mofetil (MMF). MMF induced severe anemia by causing erythroid aplasia, with idebenone showing no significant benefit.
Area of Science:
- Pharmacology
- Toxicology
- Hematology
Background:
- Mycophenolic acid (MPA) causes diarrhea and anemia, with mechanisms unclear.
- MPA suppresses antioxidant gene expression (catalase, major-alpha-hemoglobin), suggesting increased oxidative stress.
- Idebenone, an antioxidant, was investigated for mitigating MPA side effects.
Purpose of the Study:
- To evaluate idebenone's efficacy in alleviating mycophenolate mofetil (MMF)-induced diarrhea and anemia in rats.
- To explore the underlying mechanisms of MMF-induced side effects, including effects on reactive oxygen species (ROS) and bone marrow.
Main Methods:
- Rats received control, idebenone, MMF, or MMF/idebenone treatments.
- Weekly blood analysis monitored cell counts, hemoglobin, MPA, and biochemical markers.
- Liver, kidney, and bone marrow RNA was analyzed; colon and jejunum were examined histologically.
Main Results:
- MMF induced diarrhea, dehydration, and weight loss.
- Anemia (decreased erythrocytes and hemoglobin) was observed in MMF-treated rats, unaffected by idebenone.
- Idebenone slightly attenuated jejunal damage but did not impact catalase suppression.
- MMF caused erythroid aplasia and suppressed the erythropoietin (EPO) receptor in bone marrow.
- EPO-mRNA was significantly upregulated in MMF-treated rats, further increased with idebenone co-administration.
Conclusions:
- Idebenone provided minimal benefit for MMF-induced diarrhea and anemia.
- Erythroid aplasia in bone marrow is a likely cause of MMF-related anemia.
- Upregulated EPO-mRNA suggests a compensatory response to anemia.
- Idebenone's enhancement of EPO-mRNA may result from ROS antagonism, potentially protecting EPO expression.