O. Benesova et al., Brain maldevelopment and neurobehavioural deviations in adult rats treatedneonatally with indomethacin, EUR NEUROPS, 11(5), 2001, pp. 367-373
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 ac
celerate the closure of patent ductus arteriosus. Model experiments were ca
rried out in rats of the Wistar strain and Konarovice breed. The drug dose
(2 mg/kg, s.c.) was applied to rat pups either once or twice in the followi
ng way: (I) 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 neo
nate 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 huma
n newborn. The rats were followed up during development (body weight, matur
ation) until adulthood (age 3-9 months) using tests of behaviour (open fiel
d, social memory), nociception (tail flick, plantar test). reproduction and
brain neurobiological analysis. The results were evaluated by comparison o
f litter-mates: treated vs control. No differences between INDO and control
s were found in developmental landmarks, adult social memory or reproductio
n. The pattern of behavioural and neuroendocrine deviations in adult animal
s 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 activit
y and emotional reactivity, and higher pituitary weight with lower TSH cont
ent. On the other hand, deviations in adult INDO groups PD:9 and PD:9-10 we
re characterized by pain hypersensitivity, lower pituitary weight with unch
anged TSH content and deficit of monoamine transmission in the hypothalamus
. (C) 2001 Elsevier Science B.V. All rights reserved.