Vol 88, No 4 (2023)

According to modern concepts, the susceptibility to certain diseases, especially to cognitive and neuropsychiatric disorders, can be formed during the period of embryonic development. Adverse factors that affect the mother during pregnancy increase the risk of the pathology development in the postnatal period. Despite the relationship found between elevated maternal blood levels of the amino acid homocysteine (Hcy) and fetal brain formation impairments, as well as cognitive deficits in offspring, the role of brain plasticity in the development of these pathologies is still insufficiently studied. This review allows to be acquainted with the available data on the negative impact of hyperhomocysteinemia (HHcy) on the neural plasticity. An important aspect of the problem considered in the review is the possible influence of maternal HHcy on the offspring brain plasticity through the epigenetic mechanisms. Data on changes in intracellular methylation potential, activity of DNA methyltransferases, and DNA methylation in brain cells under the influence of HHcy are presented, and possible effects of HHcy on histone modifications and microRNA expression are considered. Since placenta plays a key role in the transport of nutrients and modulation of signals from mother to fetus, its dysfunction due to epigenetic mechanisms disturbances may affect the development of the fetal CNS. In this regard, the review presents data on the impact of maternal HHcy on the epigenetic regulation in the placenta. The data presented in the review are not only of theoretical significance, but are also of interest for understanding the role of epigenetic mechanisms in the pathogenesis of diseases for which HHcy is a risk factor (pregnancy pathologies accompanied by delayed fetal brain development, cognitive impairments in childhood and neuropsychiatric and neurodegenerative disorders later in life), as well as the search for approaches to their prevention using neuroprotectors.

The processes of biotransformation of pantothenic acid (Pan) in the biosynthesis and hydrolysis of CoA, the key role of pantothenate kinase (PANK) and CoA synthetase (CoASY) in the formation of the priority mitochondrial pool of CoA, with a high metabolic turnover of the coenzyme and limited transport of Pan across the blood-brain barrier are considered. The system of acetyl-CoA, a secondary messenger, the main substrate of acetylation processes, including the formation of N-acetylaspartate and acetylcholine, post-translational modification of histones, determines the protection of neurons from degenerative signals and cholinergic neurotransmission. The biochemical mechanisms of neurodegenerative syndromes in PANK and CoASY defects and the possibility of correcting the development of CoA biosynthesis in knockout models for these enzymes are described. The data of a post-mortem study of the brain of patients with Huntington’s and Alzheimer’s diseases are presented, proving Pan deficiency in the CNS, which is especially pronounced in pathognomonic neurostructures. In the frontal cortex of patients with Parkinson’s disease, combined immunofluorescence of anti-CoA- and anti-tau protein was detected, reflecting CoAlation during dimerization of the tau protein and its redox sensitivity. The redox activity and antioxidant properties of the precursors of CoA biosynthesis were confirmed in vitro on synaptosomal membranes and mitochondria in the modeling of aluminum neurotoxicosis, accompanied by a decrease in the level of CoA in the CNS. The ability of CoA biosynthesis precursors to stabilize the glutathione pool in neurostructures, in particular, in the hippocampus, is considered as a pathogenetic protection mechanism when exposed to neurotoxins, the development of neuroinflammation and neurodegeneration, and justifies the combined use of Pan derivatives (for example, D-panthenol) and glutathione precursors (N-acetylcysteine). Taking into account the discovery of new functions of CoA - redox-dependent processes of CoAlation of proteins, the possible association of oxidative stress and deficiency of Pan (CoA) in neurodegenerative pathology, the study of the bioavailability and biotransformation of Pan derivatives, in particular, D-panthenol, 4′-phospho-pantetheine, its acylated derivatives and compositions with redox pharmacological compounds are promising as potential etiopathogenetic agents.

There is described the existence of the syndrome of endogenous intoxication in patients with mental disorders. Oxidative stress, middle-mass endotoxic molecules, disorders in functional properties of the blood albumin and the thiols of the albumin, disturbances in the state of the neurotrophic factors and in the activity of several enzymes, including monoamine oxidase and semicarbazide-sensitive amine oxidase, contribute to the development of the endogenous intoxication. We introduce the scheme of the possible pathogenetic mechanisms of the development of the endogenous intoxication and the ways of its overcoming.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in the world. Despite numerous studies, the causes of this pathology remain completely unknown. This is, among other things, due to the difficulty of obtaining biological material for analysis. Neural cell cultures derived from induced pluripotent stem cells (iPSCs) serve as a great potential for studying the molecular events underlying the pathogenesis of PD. This paper presents the results of bioinformatic analysis of data obtained using RNA-seq technology in the study of neural precursors (NP) obtained from iPSCs of healthy donors and patients with PD carrying various mutations that are a common cause of familial PD. This analysis showed that in NP cells obtained from PD patients, unlike healthy donors, the level of transcription of genes actively expressed in the nervous system at the embryonic stage of development was significantly increased. Bioinformatic data are generally confirmed by real-time PCR. The data obtained suggest that one of the causes of PD may be an abnormal process of enhancing the expression of embryonic genes during differentiation of neural cells (dematuration).

Among the responses in the early stages of stroke, activation of neurodegenerative and proinflammatory processes in the hippocampus is of key importance for the development of negative post-ischemic functional consequences. However, it remains unclear which genes are involved in these processes. The aim of this work was a comparative study of the expression of genes encoding glutamate and GABA transporters and receptors, as well as inflammation markers in the hippocampus one day after two types of ischemic exposure (according to Koizumi - MCAO-MK, and Longa - MCAO-ML), as well as after direct pro-inflammatory activation by central administration of lipopolysaccharide (LPS). The results obtained revealed both differences and similarities between the responses to the impacts applied in the work. A greater number of genes that changed the expression associated with the activation of apoptosis and neuroinflammation, glutamate reception, and markers of the GABAergic system were found after MCAO-ML and LPS, than after MCAO-MK. In turn, MCAO-MK and LPS were characterized, in comparison with MCAO-ML, by changes in a larger number of genes involved in glutamate transport. The most pronounced difference between MCAO-ML and MCAO-MK and LPS was changes in the expression of genes for calmodulin and calmodulin-dependent kinases. The revealed features of the responses of the hippocampal transcriptome to two types of ischemia and a pro-inflammatory stimulus will contribute to further understanding of the causes of the diversity of stroke consequences, both in model studies and in the clinic.