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Midazolam induced cerebral cortex changes in 30-day-old mice treated from 8 to 29 days of age
María Cristina Márquez-Orozco1, María Verónica Gazca-Ramírez, Graciela de la Fuente-Juárez
1Department of Embryology, Faculty of Medicine, Universidad Nacional Autonoma de México. cmarquezor@gmail.com
Abstract:
The exposure of 8 to 29-day-old mouse pups to midazolam (MDZ) produces the same type of histological alterations in the cerebral cortex as those caused in mice by exposure in utero to diazepam (DZ) from day 6 to 17 of gestation. Two groups of 10 each ICR (Harlan Mexico) strain male mice were injected: the first with a single daily MDZ dose (2.0 mg/kg/bw, s.c.) at the age of 8 to 29 days. The control group (C), received saline solution. All mice were sacrificed with a CO2 atmosphere at day 30. The brain was fixed in 2.5% glutaraldehyde, post-fixed in 1% OsO4, and embedded in epoxy resin. Semifine sections were stained with toluidine blue and observed under the light microscope. In the MDZ group, the cerebral cortex was thinner than in the control group. Ventricular, subventricular and cortex show delayed differentiation and higher nuclear density per area (p<0.05). The nuclei showed clumps of heterochromatin. In the MDZ group, cells of the cerebral cortex were altered. The neuropile was scarce, coarse and disoriented and few myelin fibers were observed. Control animals depicted a normal cerebral cortex. MDZ could be inhibiting mitosis during prometaphase and actin and myosin synthesis, as well as modifying the metabolic pathways mediated by central and peripheral type benzodiazepine receptors. Results showed that MDZ administration to mouse pups over 21 days induced histological changes in the cerebral cortex of 30-day old mice as those observed in mice prenatally exposed to diazepam.
Insights
Early exposure to midazolam (MDZ) in mouse pups causes cerebral cortex damage similar to prenatal diazepam (DZ) exposure. This highlights potential risks of early-life sedative exposure on brain development.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Benzodiazepines like midazolam (MDZ) and diazepam (DZ) are commonly used sedatives.
- Prenatal exposure to DZ has been linked to developmental neurotoxicity.
- The effects of early postnatal MDZ exposure on brain development are less understood.
Purpose of the Study:
- To investigate the histological effects of early postnatal midazolam (MDZ) exposure on the developing mouse cerebral cortex.
- To compare MDZ-induced alterations with those caused by prenatal diazepam (DZ) exposure.
Main Methods:
- ICR strain male mice pups (8-29 days old) received daily subcutaneous injections of MDZ (2.0 mg/kg/bw) or saline (control).
- Brains were collected at day 30, processed for electron microscopy, and analyzed using light microscopy.
- Histological changes in the cerebral cortex, including thickness, cellular differentiation, and nuclear density, were assessed.
Main Results:
- MDZ-exposed mice exhibited a thinner cerebral cortex compared to controls.
- Delayed differentiation and increased nuclear density were observed in the ventricular, subventricular, and cortical zones of MDZ-exposed mice.
- Alterations in cortical cells, scarce neuropile, and reduced myelination were evident in the MDZ group, resembling changes seen with prenatal DZ exposure.
Conclusions:
- Postnatal MDZ exposure induces significant histological changes in the mouse cerebral cortex.
- These changes are comparable to those caused by prenatal diazepam exposure, suggesting a shared mechanism of neurotoxicity.
- MDZ may interfere with mitosis and cellular synthesis pathways, potentially mediated by benzodiazepine receptors, impacting brain development.
