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Perinatal treatment with glucocorticoids and the risk of maldevelopment of the brain
1Psychiatric Research Institute, Prague, Czechoslovakia.
Abstract:
Drugs administered during the perinatal period reach the developing organism at the vulnerable stage of intensive brain histogenesis and cytodifferentiation. They may interfere with the programme of developmental processes in the brain and lead to disturbances at the cellular/subcellular level and to biochemical alterations. These abnormalities form the basis for the functional pathology which becomes apparent gradually during maturation or even in adulthood as neuropsycho-behavioural deviations. A model experimental study in rats was carried out with synthetic glucocorticoids, which are widely used in obstetrics and neonatology for the prevention and treatment of neonatal idiopathic respiratory distress syndrome. As the developmental stage of the brain of the human foetus in late pregnancy closely resembles the ontogenetic phases of the brain of the rat in the early postnatal period, the neonate rat was taken as a model. The administration of dexamethasone to 7-day-old rats resulted in significant depletion of glucocorticoid receptors from the cytosol of the brain in a dose-dependent manner, beginning with the dose of 0.04 mg/kg (s.c.), i.e. a dose one order lower than the clinical dose used in obstetrics (0.4-0.5 mg/kg). Long-term follow-up of a single neonatal injection of dexamethasone (0.2 or 1 mg/kg s.c. on postnatal day 7) revealed an acceleration of some developmental landmarks in the preweaning period (incisor eruption, eye opening, motor skill) on the one hand, but a retardation of body growth and vaginal opening on the other hand. Adult animals exhibited a deficit in motor co-ordination, behavioural deviations (hyperactivity with stereotypy, decreased adaptability, increased emotional reactivity) and disturbances in reproduction in both males and females.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Neonatal exposure to synthetic glucocorticoids like dexamethasone can disrupt brain development, leading to long-term neurobehavioral and reproductive issues in adult rats. This highlights potential risks of these commonly used medications.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Perinatal drug administration impacts developing organisms during critical brain development.
- Synthetic glucocorticoids are widely used in obstetrics and neonatology, particularly for respiratory distress syndrome.
- Neonatal brain development in rats models human fetal brain development.
Purpose of the Study:
- To investigate the long-term effects of neonatal dexamethasone exposure on brain development and neurobehavior in rats.
- To determine the dose-dependent effects of dexamethasone on glucocorticoid receptors in the neonatal rat brain.
Main Methods:
- Neonatal rats (postnatal day 7) were administered varying doses of synthetic glucocorticoids (dexamethasone).
- Glucocorticoid receptor levels in the brain cytosol were measured.
- Long-term follow-up assessed developmental landmarks, physical growth, motor coordination, behavior, and reproductive function in adult rats.
Main Results:
- Dexamethasone significantly depleted brain glucocorticoid receptors in a dose-dependent manner, even at sub-clinical doses.
- Neonatal dexamethasone exposure altered developmental milestones, including accelerated pre-weaning development and retarded growth.
- Adult rats exhibited impaired motor coordination, behavioral changes (hyperactivity, stereotypy, emotional reactivity), and reproductive disturbances.
Conclusions:
- Neonatal exposure to synthetic glucocorticoids can induce lasting alterations in brain structure and function.
- These findings suggest potential risks associated with the perinatal use of glucocorticoids, necessitating careful consideration of benefits versus risks.
- The study underscores the vulnerability of the developing brain to pharmacological interventions during critical developmental windows.