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Indomethacin, dexamethasone, and intestinal damage in infant rats
Manish R Patel1, Vincent G DeMarco, Michael Clare-Salzler
1Division of Neonatology, Department of Pediatrics, J Hillis Miller Health Center, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Insights
Infant rats are protected from indomethacin-induced intestinal ulceration compared to adults. This protection is not due to mother's milk or differences in the prostaglandin pathway.
Area of Science:
- Neonatal pharmacology
- Gastrointestinal physiology
- Developmental biology
Background:
- Indomethacin is used in Neonatal Intensive Care Units for patent ductus arteriosus and intraventricular hemorrhage prevention.
- While indomethacin causes intestinal ulceration in adults, its effects on infants are less understood.
- Dexamethasone, unlike indomethacin, caused growth failure and villous blunting in infant rats.
Purpose of the Study:
- To investigate the differential effects of indomethacin on infant and adult rat intestines.
- To explore the role of mother's milk in protecting infants from indomethacin's gastrointestinal side effects.
- To examine the developmental expression of cyclooxygenases in response to indomethacin.
Main Methods:
- Administered 10 mg/kg/d of indomethacin to mother-reared infant rats, artificially fed infant rats, and adult rats.
- Compared the incidence of indomethacin-induced intestinal ulceration across age groups.
- Analyzed the expression of cyclooxygenase-1 and cyclooxygenase-2 in control rats.
Main Results:
- Infant rats, both mother-reared and artificially fed, showed resistance to indomethacin's ulcerogenic effects.
- Adult rats exhibited susceptibility to indomethacin-induced intestinal damage.
- No significant difference in cyclooxygenase-1 and cyclooxygenase-2 expression was observed between infant and adult rats.
Conclusions:
- Infants are less susceptible to indomethacin-induced intestinal damage than adults, a finding distinct from dexamethasone's effects.
- Protection against indomethacin's intestinal effects in infants is independent of mother's milk.
- Developmental differences in the prostaglandin biosynthetic pathway do not explain the observed protection.
Background:
Indomethacin is commonly used in the Neonatal Intensive Care Unit to induce closure of the patent ductus arteriosus and to prevent intraventricular hemorrhage. It is known that indomethacin causes intestinal ulceration in adults, but its effect in infants is less clear. In a preliminary experiment, it was found that the administration of 10 mg/kg/d of indomethacin, a dose that damages the adult rat intestine, had no detrimental effects on newborn suckling rats whereas dexamethasone at 0.25 mg/kg/d caused significant growth failure and villous blunting. It was then hypothesized that the lack of intestinal damage with indomethacin in infants was related to protection given by mother's milk.
Methods:
Subsequent experiments were performed wherein 10 mg/kg/d of indomethacin was provided to infant mother-reared, infant artificially fed, and adult rats. The expression of intestinal cyclooxygenases in the prostaglandin synthetic pathway of control rats was examined to initiate an exploration into a mechanism for the developmental response to indomethacin.
Results:
Mother-reared and artificially fed infant rats demonstrated resistance to the ulcerogenic effects of indomethacin, in contrast to the adults. A differential presence of cyclooxygenase-1 and cyclooxygenase-2 was not distinctly seen between infancy and adulthood.
Conclusions:
The results indicate that a varying response to the damaging effects of indomethacin on the intestine occurs during development with the infant being less susceptible than the adult. This differed from the effects of dexamethasone administration, which caused significant intestinal atrophy in the infant rats. The intestinal protection to the effects of indomethacin in infants is not dependent on mother's milk or a developmental difference in the prostaglandin biosynthetic pathway.