Maternal Hyperhomocysteinemia Induces Neuroinflammation and Neuronal Death in the Rat Offspring Cortex.

Maternal hyperhomocysteinemia is one of the common complications of pregnancy that causes offspring cognitive deficits during postnatal development. In the present work, we evaluated the effect of prenatal hyperhomocysteinemia on structural and ultrastructural organization, neuronal and glial cell number, apoptosis (caspase-3 content and activity), inflammatory markers (tumor necrosis factor-α, interleukin-6, and interleukin-1ß), and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation in the offspring brain cortex in early ontogenesis. Wistar female rats received methionine (0.6 g/kg body weight) by oral administration during pregnancy. Histological and biochemical analyses of 5- and 20-day-old pups' cortical tissue were performed. Lysosome accumulation and other neurodegenerative changes in neurons of animals with impaired embryonic development were investigated by electron microscopy. Neuronal staining (anti-NeuN) revealed a reduction in neuronal number, accompanied by increasing of caspase-3 active form protein level and activity. Maternal hyperhomocysteinemia also elevated the number of astroglial and microglial cells and increased expression of interleukin-1ß and p38 MAPK phosphorylation, which indicates the development of neuroinflammatory processes.

Neurotrophins of the Fetal Brain and Placenta in Prenatal Hyperhomocysteinemia.

Prenatal hyperhomocysteinemia (PHHC) in pregnant rats was induced by chronic L-methionine loading, resulting in a significant increase in the L-homocysteine content both in the mothers' blood and blood and brain of fetuses. Significant decrease in the weight of the placenta, fetus, and fetal brain was detected by the morphometric studies on day 20 of pregnancy. PHHC also activated maternal immune system due to the increase in the content of proinflammatory interleukin-1ß in the rat blood and fetal part of the placenta. PHHC elevated the levels of the brain-derived neurotrophic factor (BDNF, 29 kDa) and nerve growth factor (NGF, 31 kDa) precursors in the placenta and the content of the BDNF isoform (29 kDa) in the fetal brain. The content of neuregulin 1 (NRG1) decreased in the placenta and increased in the fetal brain on day 20 of embryonic development. An increase in the caspase-3 activity was detected in the brains of fetuses subjected to PHHC. It was suggested that changes in the processing of neurotrophins induced by PPHC, oxidative stress, and inflammatory processes initiated by it, as well as apoptosis, play an important role in the development of brain disorders in the offspring.

[Catecholamine content in the adrenal gland of rat offspring in the model of prenatal hyperhomocysteinemia].

Catecholamine content has been studied in the adrenal gland of rat females whose pregnant mothers were loaded daily with L-methionine administered per os during all the pregnancy period, on the first day of postnatal life, and in one and two months after birth. The animal model of hyperhomocysteinemia used in the experiment has been shown to result in the catecholamine content decreasing in the adrenal gland of both newly born rat offspring with high serum level of homocysteine and one-month old offspring with their homocysteine level decreased to the normal values. It was found that nitrotyrosine level increased significantly in the blood serum of the offspring aged one and two months. The data obtained may testify to oxidative stress development.