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Folinic acid protects against suppression of growth by methotrexate in mice
M P Iqbal1, F Sultana, N Mehboobali
1Department of Biological & Biomedical Sciences, The Aga Khan University, PO Box 3500, Stadium Road, Karachi, Pakistan. perwaiz.iqbal@aku.edu
Abstract:
The objective of this study was to investigate whether folinic acid supplementation would protect young mice against suppression of growth by methotrexate (MTX). Four equal groups of Balb/c young male mice (5 animals in each group; mean+/-SD body weight 9.64+/-0.85 g, in their rapid growth phase) were subjected to the following drug treatment: One group was given MTX (3.5 mg/kg body weight) intraperitoneally on every 2nd day, another received folinic acid (7.0 mg/kg body weight) intraperitoneally every 2nd day. The third group was given both of these drugs (MTX on every 2nd day and folinic acid 8 h post-MTX injection). The fourth group was injected with physiological saline every other day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 3 weeks. After this period mice were sacrificed and liver, spleen and kidneys were excised, weighed and analyzed for MTX and dihydrofolate reductase activity. A small segment of the proximal part of small intestine and small pieces of liver and kidney were also removed to study morphological changes. Compared to the groups, which received folinic acid alone, folinic acid plus MTX or physiological saline, mean increase in body weight (6.8+/-0.8 g) of mice over a period of 3 weeks was minimal in the group receiving MTX alone (one-way ANOVA p=0.0001). The mean weights of liver and kidney in this group receiving MTX alone were also found to be significantly less than the mean weights of these organs in the 3 groups (p<0.001). The negative effect on growth of animals appears not only due to malabsorption but inhibition of pathway of de novo DNA synthesis may also be involved. This is supported by loss of villous pattern in small intestine of mice treated with MTX alone and increased accumulation of free MTX and decreased dihydrofolate reductase in the liver of the group receiving MTX alone as compared with the group receiving MTX plus folinic acid. The data indicate that the administration of folinic acid protects mice against suppression of growth by MTX. On the basis of these observations it can be deduced that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving MTX over a long period of time might be at a risk of experiencing short-term suppression of growth, however they could benefit from supplementation with folinic acid.
Insights
Folinic acid supplementation protects young mice from growth suppression caused by methotrexate (MTX). This study shows folinic acid can mitigate MTX
Area of Science:
- Pharmacology
- Developmental Biology
- Toxicology
Background:
- Methotrexate (MTX) is a chemotherapy agent used to treat various cancers and autoimmune diseases.
- MTX can cause significant side effects, including growth suppression, particularly in young patients.
- Folinic acid is a derivative of folic acid that can counteract some of MTX's toxic effects.
Purpose of the Study:
- To investigate the protective effect of folinic acid supplementation against MTX-induced growth suppression in young mice.
- To explore the underlying mechanisms of MTX toxicity and folinic acid's protective role.
Main Methods:
- Four groups of young male mice were treated with MTX alone, folinic acid alone, MTX plus folinic acid, or saline (control).
- Body weight, food and water consumption were monitored over 3 weeks.
- Organ weights (liver, spleen, kidneys) and histological changes in the small intestine, liver, and kidneys were analyzed.
- MTX levels and dihydrofolate reductase activity in the liver were measured.
Main Results:
- Mice treated with MTX alone exhibited minimal weight gain and reduced organ weights compared to control and folinic acid-treated groups.
- MTX treatment led to intestinal villous atrophy and altered MTX/dihydrofolate reductase levels in the liver.
- Co-administration of folinic acid with MTX significantly ameliorated these negative effects.
Conclusions:
- Folinic acid effectively protects against MTX-induced growth suppression in young mice.
- The protective mechanism involves counteracting MTX's inhibition of de novo DNA synthesis and preserving intestinal morphology.
- Patients receiving long-term MTX therapy, such as those with juvenile rheumatoid arthritis or acute lymphoblastic leukemia, may benefit from folinic acid supplementation to prevent growth suppression.