Rossijskij fiziologičeskij žurnal im. I.M. Sečenova
Russian Journal of Physiology (p-ISSN 0869-8139, e-ISSN 2658-655X) is issued monthly and publishes the works in all fields of physiology and physiological aspects of related sciences — zoology, anatomy, histology, embryology, molecular biology, biochemistry.
The journal is peer-reviewed and is included in the VAK list of journals for publishing the works of degree candidates. Currently, the papers are indexed in the VINITI, RISC (elibrary.ru), EBSCO, Google Scholar, and RSCI (on the Web of Science platform) databases. The papers are submitted in electronic form.
Articles are translated and published in the Journal of Evolutionary Biochemistry and Physiology (indexed in WoS, impact factor (2022) - 0.6).
The chief editor is a member of the RAS L.G. Magazanik
Media registration certificate: ПИ № ФС 77 – 67154 от 16.09.2016
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Vol 111, No 5 (2025)
REVIEW
Possibilities and Limitations of Using the Olfactory Bulb Removal Model in Rodents
Abstract
Here, we review current data that provide a basis for using the olfactory bulbectomy model as a model of mental disorders in humans. Based on extensive literature and our own data, we have shown the possibilities of using the olfactory bulbectomy model in rodents as a model of depression and Alzheimer's disease, taking into account the correspondence of the observed changes with modern criteria of validity. The removal of olfactory bulbs causes a complex of molecular, structural, and behavioral changes in animals, which cannot serve as an ideal model for certain disease. The review discusses the limitations of using this model and interpreting the results. Nevertheless, this model can be a useful tool for both basic and applied studies of brain pathologies, taking into account these limitations.
639-658
Necroptosis, Autophagy and Parthanatos in the Pathogenesis of Brain Diseases
Abstract
Necroptosis, autophagy and parthanatos are three interrelated mechanisms of programmed cell death that exert a significant impact on the health and pathology of the central nervous system. They participate in maintaining cellular homeostasis by eliminating damaged or nonfunctional cells, as well as in shaping the neuroinflammatory response. Dysregulation of these processes is associated with a range of neurological and psychiatric disorders – from neurodegeneration in Alzheimer’s and Parkinson’s diseases to depressive and schizophrenic conditions. This paper summarizes clinical and preclinical data describing the roles of necroptosis, autophagy and parthanatos in the pathogenesis of brain diseases. It also discusses experimental models that enable the study of these forms of cell death and the testing of new therapeutic approaches. A thorough understanding of the molecular mechanisms underlying these processes opens up opportunities for the development of drugs capable of simultaneously modulating multiple signaling pathways, thereby improving the prevention, diagnosis, and treatment of central nervous system disorders.
659-692
EXPERIMENTAL ARTICLES
Behavioral Impairments in Rats with Focal Cortical Dysplasia Following Febrile Seizures
Abstract
Disruptions in cerebral cortex development during early ontogenesis often lead to pharmacoresistant epilepsy and mental disorders. One such disruption is focal cortical dysplasia (FCD), which can be modeled in experimental animals by inducing cryogenic injury to the neocortex on the first day after birth. FCD is frequently associated with the development of epilepsy and behavioral impairments, such as deficits in learning, memory, and social interaction. These effects may be more pronounced when the brain is exposed to additional challenges, such as the combination of FCD with neonatal febrile seizures (FS). However, the specific characteristics of behavioral impairments in this combined pathology remain poorly understood. This study aimed to investigate behavioral impairments in adult male Wistar rats with FCD who had experienced FS. FCD was induced in rat pups on the first day of life (P0) by localized freezing of the somatosensory cortex. On the 10th day of life (P10), FS were triggered in the rat pups through hyperthermia (exposure to warm air) for 30 minutes. Only animals with FS lasting at least 15 minutes were included in the study. The control group consisted of sham-operated rat pups that were separated from their mother for 30 minutes at P10 without exposure to heat. At 2–2.5 months of age, the animals' behavior was evaluated using the following tests: Open Field, Elevated Plus Maze, Social Interaction Test, and Spontaneous Alternation Test in the Y-Maze. The results revealed that the combination of FCD and FS in early life led to increased social activity and alterations in exploratory behavior and anxiety levels in adult rats. These findings suggest that the combined pathology selectively affects behavioral functions, potentially due to the reorganization of neural networks in the brain. The study expands our understanding of the consequences of FCD and FS on brain function development and highlights the need for further research into the mechanisms underlying these changes. This work may contribute to the development of new therapeutic strategies for patients with similar conditions.
693-707
Biocompatibility of Nicotinamide Riboside at Varying Dosages via Intravenous Administration
Abstract
Nicotinamide riboside (NR) serves as a precursor to NAD+. Numerous studies in the literature report on the oral administration of NR, demonstrating its beneficial effects on the progression of diseases such as cardiovascular, neurodegenerative, renal, hepatic, and others. Previously, a hypothesis was proposed by the authors suggesting a protective effect of intravenous NR administration against doxorubicin-induced myocardial damage. However, under this mode of administration, special attention must be given to the biocompatibility of NR when used at therapeutically effective doses. Thus, the aim of this study was to assess the biocompatibility of various NR doses with repeated intravenous administration in Wistar rats. The study employed doses of 150, 300, 450, and 600 mg/kg of NR (cumulative doses of 900, 1800, 2700, and 3600 mg/kg, respectively). During the study, the biocompatibility of NR was demonstrated at doses of 150, 300, and 450 mg/kg with repeated intravenous administration in rats. Even at the highest dose of 450 mg/kg, repeated intravenous administration showed no adverse effects on the parasympathetic ganglia of the autonomic nervous system in the heart. However, increasing the dose of NR led to several adverse side effects, including animal mortality, reduced tolerance to physical exertion, impaired cardiovascular function, and morphological and functional changes in the myocardium, liver, and kidneys.
708-728
Effects of Assisted Reproductive Technologies on the Behavior and Brain Development in the Mouse Model of Parkinson’s Disease
Abstract
This study investigated the long-term effects of assisted reproductive technologies (ART), i.e. in vitro embryo culture and embryo transfer, on behavior and brain development in B6.Cg-Tg mice, a model of Parkinson’s disease (PD), and wild-type C57BL/6 mice. Male offspring obtained using ART were compared with naturally conceived offspring. At six months of age, mice were assessed for anxiety in the elevated plus maze test; body and brain weights were measured as well. The results of the study demonstrated that naturally conceived B6.Cg-Tg mice exhibited lower anxiety levels and larger brain weights compared to wild-type mice. Using ART resulted in a decreased brain weight in B6.Cg-Tg offspring, as well as significantly decreased anxiety levels compared to the control groups. In wild-type C57BL/6 mice, ART did not cause significant changes in brain weight or anxiety levels. The results demonstrate effects of ART on behavior and brain development in offspring, particularly in those genetically predisposed to neurodegenerative diseases. These results demonstrate that further studies of the long-term effects of ART are warrant, particularly in the context of its impact on neurodevelopment and behavior, which has important medical implications.
729-743
Thermosensitive TRP-Ion Channels Gene Expression in the Spleen in Normo- and Hypertensive Rats. Effect of the Cold and the Peripheral TRPM8 Ion Channel Activation
Abstract
Arterial hypertension leads to changes in the functioning of various organism systems, including the immune system. TRP-ion channels are increasingly attracting attention as targets for the correction of visceral organs, including for therapeutic purposes. The gene expression of the thermosensitive TRP-ion channels (TRPM8, TRPA1, TRPV1, TRPV2, TRPV3 and TRPV4) was studied in the immunocompetent organ, the spleen, using quantitative RT-PCR in normotensive and hypertensive animals under normal conditions, during cooling, and stimulation of the peripheral cold-sensitive ion channel TRPM8. The investigated genes express differently in the spleen of animals of both lines. The expression of cold-sensitive ion channel genes TRPM8 and TRPA1 is reduced in the spleen of hypertensive rats. This is consistent with obtained data on the decrease expression of the TRPM8 ion channel gene in the hypothalamus of hypertensive animals. Deep cooling of the organism, as well as activation of the peripheral (cutaneous) TRPM8-ion channel by menthol, lead to increase expression of the TRPA1 and TRPV1 ion channels genes in the spleen of hypertensive rats, without affecting the expression of genes in normotensive animals. Considering that the ion channels TRPA1 and TRPV1 are involved in inflammation processes, this may indicate a change in the nature of inflammatory reactions in hypertensive animals when organism is exposed to cold. The obtained data expand knowledge about the representation of thermosensitive TRP-ion channels in immunocompetent organs and may indicate a change in the immune status of organism with arterial hypertension.
744-760
Development of Positive Allosteric Modulators of the Thyroid Stimulating Hormone Receptor Based on the Thieno[2,3-d]-Pyrimidine Structure and their Effect on Thyroid Status in Rats
Abstract
Thyroid stimulating hormone (TSH) levels in autoimmune hypothyroidism and hypothyroidism caused by inactivating mutations in the TSH receptor are normal or elevated, which is due to increased thyroliberin (TRH)-stimulated TSH production in thyroid hormone (TH) deficiency. The main cause of hypothyroidism is a weakened thyroid response to TSH. This requires the development of approaches to increase the sensitivity of thyrocytes to TSH. One of them is the use of positive allosteric modulators (PAMs) of the TSH receptor, which enhance the effects of TSH on TH production. However, such PAMs are currently lacking. The aim of the work was to synthesize new thieno[2,3-d]-pyrimidine derivatives TPYox and TPYmp with PAM activity of the TSH receptor and to study their effects on basal and TRH-stimulated blood TH concentration and expression of genes involved in TH synthesis in the rat thyroid. When administered to rats, TPYox and TPYmp (20 mg/kg) had little effect on blood TH concentration and expression of TH synthesis genes, except for an increase in tT3 concentration and expression of the Dio2 gene encoding type 2 deiodinase when using TPYmp. At the same time, despite the absence of differences with the control, in the TPYox-treated group, the blood TH concentrations and the expression of the Tg, Tpo, Dio2, and Tshr genes decreased as compared to the TPYmp-treated rats, which we believe is due to the high reactivity of the oxirane cycle in TPYox and its inhibitory effect on some components of the thyroid system in the thyroid gland. Pretreatment of rats with TPYox and TPYmp preserved the stimulatory effects of TRH on TH concentration and thyroid gene expression, and in some cases significantly enhanced them. However, the dynamics and severity of the potentiating effect of TPYox and TPYmp differed. TPYox potentiated the stimulatory effects of TRH on blood tT4, fT3, and tT3 concentrations 1.5 h after TRH treatment, while TPYmp enhanced the stimulatory effects of TRH on fT3 and tT3 concentrations 3 h later, when the potentiating effect of TPYox had already disappeared. In the thyroid gland, TPYox enhanced TRH-induced Tpo gene expression, while TPYmp enhanced Dio2 and Nis gene expression. Based on the data obtained, it was concluded that the most promising drug for increasing the TSH receptor response to endogenous TSH is TPYmp, 5-amino-N-(tert-butyl)-4-{4-[3-(2-hydroxy-3-morpholinopropoxy)pro-1-yn-1-yl]phenyl}-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxamide, the first functionally active PAM of the TSH receptor that we developed.
761-776
Peculiarities of IBD Clinical Symptoms Manifestation in Muc2- Mice During Siblings Cohousing
Abstract
Clinical symptoms of inflammatory bowel diseases (IBD) are one of the indicators of the severity of the disease. A clear understanding of the variability in the manifestation of clinical symptoms and the time of their manifestation is extremely important to monitor the effect of treatment methods on the course of inflammatory bowel diseases. One of the effective models of inflammatory bowel diseases is the Muc2- mouse line, which is characterized by the manifestation of similar clinical symptoms of IBD as in humans. In this regard, we decided to study the features of IBD symptoms in male and female Muc2- line mice, so that in the future we could create a protocol for assessing the effect of drugs on the development and course of the disease. In our work, we observed that clinical symptoms tend to manifest themselves differently depending on the sex of the animal. Thus, rectal prolapse with bleeding was manifested mainly in males of the Muc2- lineage, while signs of exhaustion were characteristic mainly of females.
777-789
The GluN3A Subunit Forms GluN3A-NMDAR and the Excitatory Glycine Receptor in the Olfactory Sensory Neurons of Adult Wistar Rats
Abstract
The article presents experimental data obtained on isolated olfactory sensory neurons (OSN) of adult Wistar rats. The aim of the study was to show by in vivo fluorescent confocal microscopy using pharmacological analysis whether the GluN3A-subunit is localized in the olfactory sensory neurons of adult animals. Analysis of the results have revealed the presence of GluN3A-subunit in the OSN of adult rats as part of the excitatory glycine receptor and GluN3A containing N-methyl-D-aspartate receptor (GluN3A-NMDAR). In addition to them, the typical NMDAR and non-NMDAR are localized in the OSN. All these receptors can be located both in the same and in different receptor cells, which manifests the heterogeneity of the OSN in the olfactory epithelium.
790-805
Nos3 Gene Knockout in Mice Enhances Kidney Sensitivity to Furosemide
Abstract
Nitric oxide (NO) regulates renal hemodynamics and inhibits tubular sodium reabsorption. NO formation is catalyzed by NO synthases (NOS), and it is important to study the role of individual NO synthases for renal functions. The purpose of the study was to obtain a line of mice with a knockout of the nos3 gene (NOS KO) and to evaluate their ion-regulatory renal function. A homozygous line of NOS KO mice was developed at the background of the C57Bl/6 line using the CRISPR-Cas9 editing method. The physiological study included 39 animals (10 female and 10 male C57Bl/6 mice; 10 female and 9 male NOS KO mice); genotyping was carried out using PCR and sequencing methods at the age of 4 weeks. To identify differences in the transport of sodium and potassium in the kidneys of NOS KO mice, experiments were conducted to assess ion excretion in animals when given water (control), with a NaCl load (7.7 μmol/g) and with the administration of a loop diuretic. In the control, no differences were detected in the excretion of sodium and potassium ions in NOS KO and C57Bl/6 mice. Under conditions of excess NaCl intake, no significant interstrain differences were also revealed: sodium and potassium excretion increased by 8.8 and 1.3 times in NOS KO mice and by 8.4 and 1.7 times in wild-type mice, respectively. The natriuretic effect of furosemide (5 μg/g) in NOS KO mice was greater than in C57Bl/6 mice. Urinary sodium excretion was 4.1 ± 0.3 µmol/g during 2 hours of observation in NOS KO and 2.7 ± 0.2 µmol/g in wild-type mice (p < 0.001). Thus, the work revealed for the first time an increase in sensitivity to furosemide in mice with a knockout of the nos3 gene, which may indicate the importance of the activity of endothelial NO synthase for the regulation of sodium transport in the thick ascending limb of the loop of Henle.
806-818