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.

Prenatal Hyperhomocysteinemia Impairs Hypothalamic Regulation of Reproductive Cycles in Rat Progeny.

Effects of prenatal hyperhomocysteinemia on hypothalamic regulation of estrous cycles were studied in female rats. In mature rats exposed to prenatal hyperhomocysteinemia, changes in the catecholamine content in hypothalamic areas responsible for the formation of the preovulatory surge of gonadotropin-releasing hormone were revealed: the level of norepinephrine in the medial preoptic area decreased and concentration of dopamine in the median eminence with arcuate nuclei increased. Administration of melatonin attenuated the observed changes, which can be related to neuroprotective effects of this hormone determined by its antioxidant properties.

[The influence of hyperhomocysteinemia on monoaminoergic systems of hypothalamus and hippocampus of female rats at aging].

The data presented have shown the different effect of hyperhomocysteinemia (induced by 0,12-0,15 mg of methionine loading per os during 30 days) on monoamines content in hypothalamus and hippocampus of young (6-7 month) and old (20-22 month) female rats. It has been established that the level of catecholamines (noradrenaline, dopamine), 5 oxitryptamine and 5 oxyindolacetic acid in hypothalamic areas responsible for synthesis and secretion of gonadoliberin (medial preoptic area and medial eminence with arcuate nuclei) is considerable less in old animals compared with young ones. These data are in agreement with the low content of gonadoliberin found by us in medial eminence with arcuate nuclei. It has been also shown the decreased level of monoamines level in hippocampus of old rats, which does not depend on methionine loading. However in hippocampus of young animals hyperhomocysteinemia induced a noticeable reduction of noradrenaline and 5 oxyindolacetic acid, which can lead to weakening of animal's cognitive function.

Disturbances of diurnal rhythms of biogenic amines contents in hypothalamic nuclei as an evidence of neurotropic effects of enterotropic carcinogen 1,2-dimethylhydrazine.

OBJECTIVES: Our data on the contents of norepinephrine (NE), dopamine (DA) and the metabolite of serotonin 5-hydroxyindoleacetic acid (5-HIAA) measured in the suprachiasmatic nuclei (SCN), preoptic area (PA) and median eminence (ME) of hypothalamus of rats after single subcutaneous injection of 1,2-dimethylhydrazine (DMH) as well as the effect of this carcinogen on formation of reactive oxygen species (ROS) in the PA are presented in this paper. RESULTS: Diurnal changes of DA in all studied brain structures and of NE in the PA have been observed in the control group. Their morning levels were higher than evening ones. Rhythms of 5-HIAA in the SCN and diurnal changes of ROS formation have been shown to have contrary changes in control. Both the morning (11 a.m.) and evening (11 p.m.) subcutaneous administration of DMH at the dose of 21 mg/kg of body weight resulted in changes of all rhythms observed in control. In some cases a phase shift was found, in others the rhythms of neurotransmitters and ROS formation disappeared entirely. CONCLUSION: The data obtained confirm the idea of dopaminergic and serotoninergic systems taking part in mechanisms of a response of the hypothalamic nuclei to non-photic stimuli. It is suggested that the effect of DMH on the content and diurnal rhythms of neurotransmitters in the hypothalamic structures under study is due to its affecting activities of the enzymes of biogenic amines synthesis, synaptic transmission, melatonin synthesis and secretion rhythms. The change in ROS formation that is caused by administration of DMH is likely to be due to a disturbance of diurnal rhythms of neurotransmitters that are one of the sources of formation of free radicals in the brain.

[Disruption of circadian rhythms of biogenic amines in rat hypothalamus upon administration of 1,2-dimethylhydrazine]. / Narushenie tsirkadiannykh ritmov biogennykh aminov v gipotalamuse krys pri vvedenii 1,2-dimetilgidrazina.

Levels of norepinephrine (NE), dopamine (DA) and the main metabolite of serotonin 5-hydroxyindoleacetic acid (5-HIAA) have been measured in the suprachiasmatic nuclei (SCN), preoptic area (PA), and median eminence (ME) of hypothalamus of rats after sole subcutaneous injection of 1,2-dimethylhydrazine (SDMH). Circadian changes of DA in all the brain structures under study as well as of NE in PA were observed in the control group, their levels in the mornings being higher than in the evenings; a circadian change of 5-HIAA in SCN had an opposite tendency. Both the evening (11 p.m.) and morning (11 a.m.) administrations of SDMH at the dose of 21 mg/kg body weight resulted in disturbances of all the circadian rhythms observed in control. In some cases only a 12 hrs circadian rhythms phase shift was found, in the others these rhythms of neurotransmitters disappeared entirely. The evening administration of SDMH, unlike the morning one, resulted in an increase in total NE content in the hypothalamic structures under study. It is suggested that the effect of SDMH on the levels and circadian rhythms of neurotransmitters in the hypothalamic structures under study is due to affecting activities of the enzymes of biogenic amines synthesis, synaptic transmission, melatonin synthesis and secretion rhythms, as well as to its genotoxic influence upon the genes controlling circadian actions.