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Brain maldevelopment and neurobehavioural deviations in adult rats treated neonatally with indomethacin
O Benesová1, H Tejkalová, Z Kristofiková
1Prague Psychiatric Center, Ustavni 91, 181 03 Prague 8, Czech Republic. benesova@pcp.lf3.cuni.cz
Insights
Indomethacin (INDO) exposure in developing rats can cause neurodevelopmental toxicity, affecting behavior and neuroendocrine function differently based on the developmental stage at exposure. This highlights critical windows for INDO
Area of Science:
- Neuroscience
- Developmental Toxicology
- Pharmacology
Background:
- Indomethacin (INDO) is a prostaglandin synthesis inhibitor used in neonates.
- It's administered to prevent intraventricular hemorrhage or close patent ductus arteriosus.
- Potential neurodevelopmental toxicity requires investigation.
Purpose of the Study:
- To assess the neurodevelopmental toxicity risk of indomethacin (INDO).
- To determine if INDO exposure at different developmental stages impacts adult neurobehavioral and neuroendocrine functions.
- To model early human fetal/neonatal and full-term newborn brain development.
Main Methods:
- Wistar and Konárovice rats were administered INDO (2 mg/kg) once or twice on postnatal days 4 or 9.
- Developmental landmarks, behavior (open field, social memory), nociception, and reproduction were assessed until adulthood.
- Neurobiological analyses included pituitary weight and TSH content, and hypothalamic monoamine transmission.
Main Results:
- No differences in developmental landmarks, social memory, or reproduction were observed between INDO-treated and control rats.
- Early exposure (PD:4, PD:4-5) led to reduced motor activity, emotional reactivity, higher pituitary weight, and lower TSH.
- Later exposure (PD:9, PD:9-10) resulted in pain hypersensitivity, lower pituitary weight, and hypothalamic monoamine deficits.
Conclusions:
- The neurodevelopmental effects of indomethacin depend on the timing of exposure during critical developmental windows.
- Early-life INDO exposure can induce long-term behavioral and neuroendocrine alterations.
- Findings suggest careful consideration of INDO's use in neonates due to potential risks.
Abstract:
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.