Midazolam induced cerebral cortex changes in 30-day-old mice treated from 8 to 29 days of age.

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.