Brain maldevelopment and neurobehavioural deviations in adult rats treated neonatally with indomethacin.

The risk of neurodevelopmental toxicity was studied in indomethacin (INDO), an inhibitor of prostaglandin synthesis, which is used in at-risk neonates to prevent the consequences of brain intraventricular haemorrhage or to accelerate the closure of patent ductus arteriosus. Model experiments were carried out in rats of the Wistar strain and Konárovice breed. The drug dose (2 mg/kg, s.c.) was applied to rat pups either once or twice in the following way: (1) on postnatal day 4 (PD:4) or postnatal days 4 and 5 (PD:4-5), i.e. model of brain ontogenic developmental stage in human fetus/preterm neonate of 7-month-gestational age; (2) on postnatal day 9 (PD:9) or postnatal days 9-10 (PD:9-10), i.e. model of brain ontogenic stage in full-term human newborn. The rats were followed up during development (body weight, maturation) until adulthood (age 3-9 months) using tests of behaviour (open field, social memory), nociception (tail flick, plantar test), reproduction and brain neurobiological analysis. The results were evaluated by comparison of litter-mates: treated vs control. No differences between INDO and controls were found in developmental landmarks, adult social memory or reproduction. The pattern of behavioural and neuroendocrine deviations in adult animals was dependent on the ontogenic stage exposed to drug insult. INDO rats of the groups PD:4 and PD:4-5 revealed depression of open field motor activity and emotional reactivity, and higher pituitary weight with lower TSH content. On the other hand, deviations in adult INDO groups PD:9 and PD:9-10 were characterized by pain hypersensitivity, lower pituitary weight with unchanged TSH content and deficit of monoamine transmission in the hypothalamus.