Prenatal exposure to valproic acid is associated with altered neurocognitive function and neurogenesis in the dentate gyrus of male offspring rats.

In pregnant women with epilepsy, it is imperative to balance the safety of the mother and the potential teratogenicity of anticonvulsants, which could cause impairments such as intellectual disability and cleft lip. In this study, we examined behavioral and hippocampal neurogenesis alterations in male offspring of rats exposed to valproic acid (VPA) during pregnancy. Pregnant Wistar rats received daily intraperitoneal injections of VPA (100 mg/kg/day or 200 mg/kg/day) from embryonic day 12.5 until birth. At postnatal day 29, animals received an injection of bromodeoxyuridine (BrdU). At postnatal day 30, animals underwent the open field (OF), elevated plus-maze, and Y-maze tests. After behavioral testing, animals were decapitated, and their brains were dissected for immunohistochemistry. Of the offspring of the VPA200 mothers, 66.6% showed a malformation. In the OF test, these animals showed locomotor hyperactivity. In the elevated plus-maze, offspring of VPA-treated mothers spent significantly more time in the open arms, irrespective of the treatment dose. The number of BrdU-positive cells in the dentate gyrus of the offspring of VPA-treated mothers increased significantly in a dose-dependent manner compared with the control. A significant positive correlation between spontaneous locomotor activity in the OF and BrdU-positive cell counts was observed across groups. In conclusion, VPA administration during pregnancy results in malformations and attention-deficit/hyperactivity disorder-like behavioral abnormalities in the offspring. An increase in cell proliferation in the hippocampus may underlie the behavioral changes observed. Repeated use of high doses of VPA during pregnancy may increase the risk of neurodevelopmental abnormalities dose dependently and should be carefully considered.

Electroconvulsive stimulation transiently enhances the permeability of the rat blood-brain barrier and induces astrocytic changes.

The blood-brain barrier (BBB) plays important roles in both the physiological and pharmacological state of the brain. Transiently enhancing the permeability of the BBB may allow use of more types of medications for neuropsychiatric diseases. Several studies have demonstrated that seizures cause a transient decrease in BBB integrity. We studied the timing of BBB changes following seizures and the role of astrocytes in this process. Rats received 10 applications of electroconvulsive stimulation (ECS). They were then infused with sodium fluorescein, a fluorescent substance that rarely passes the BBB, via the inferior vena cava. After 120min of circulation, the amount of sodium fluorescein in the brain was measured by two methods in vivo fluorescence imaging (total radiant efficiency) and the brain concentration of sodium fluorescein. To assess any changes to the BBB, we measured S100Β in serum, which is a standard marker of BBB breakdown that is expressed by astrocytes. We also examined ultrastructural changes following ECS. Total radiant efficiency and the brain concentration of sodium fluorescein were significantly increased in treated rats compared to controls when sodium fluorescein was injected immediately after ECS but not when the injection was performed more than 15 min after ECS. Astrocytic endfeet showed swelling around brain capillaries following ECS. In conclusion, ECS transiently enhances the permeability of the BBB, which may be accompanied by changes in astrocytic endfeet.