Early undernutrition is associated with attenuated inflammatory response and alteration in pharmacological efficacy of indomethacin in rats.

Aim: The intent of this study is to examine whether intrauterine malnutrition provokes alterations in the progression of the acute and subchronic inflammatory response, and its influence on the pharmacological effect of indomethacin.

Methods Design: Rat offspring of dams which were fed from the first day of their gestation to term receiving a balanced diet (Labina) or a basic regional diet (BRD) from northeastern Brazil. According to their dams, the offspring were divided in two groups: Control-N (nourished) and BRD-g (undernourished during gestation). At 2 months of age, the animals were divided into groups (n=06): (1) Animals that were subjected to carrageenan or (2) zymosan-induce paw edema (acute inflammation models) and (3) Animals that were subjected to cotton pellet-induced granuloma (subchronic inflammation model). All animals received (saline 0.9%; p.o.). Another set of adult offspring was submitted to the same procedure as above, but instead of saline they received (via gavage) a single oral dose of indomethacin (10mg/kg) for the animals subjected to acute inflammation models or 2mg/kg for seven consecutive days for the animals subjected to subchronic inflammation model. The animals were further divided in two groups: Control-NI (Control-N treated with indomethacin), and BRDI-g (BRD-g treated with indomethacin). The volume of hind paw swelling (mL) was measured at time zero (before), 30, 60, 120, 180 and 240 min after carrageenan or zymosan injection. In the subchronic model of inflammation, the pellets were removed and dried to a constant weight. Hind paw swelling, weight of granuloma, blood albumin and C-reactive protein (CRP) levels, leukocyte count and cytokine levels were evaluated as indicators of inflammation.

Results: Undernutrition during pregnancy caused fetal growth retardation which was shown in terms of low birth weight (5.38±0.28), when compared to the Control-N (7.26±0.64) group. The volume of paw edema, the serum levels of CRP and albumin and cytokine levels were lower than those in the BRD-g group when compared to those in the Control-N groups, in both models of acute inflammation studied. However, no difference was found in the total leukocyte count. When compared to the respective groups treated with saline (Control-N and BRD-g), the antiinflammatory effect of indomethacin in the animals of BRDI-g groups was lower than in the Control-NI groups, in the model of acute inflammation. In the model of subchronic inflammation, the pharmacological effect of indomethacin was effective only in nourished animals.

Conclusion: Malnutrition in the early stages of development attenuated the severity of the acute inflammatory response, but there was no statistically significant change in subchronic inflammation induced by granulomatous lesion. Our findings provide impetus for larger trials to assess the influence of undernutrition on the pharmacokinetics/pharmacodynamics of indomethacin.