Volume 42, Nº 3 (2025): VOL 42, NO3 (2025) Diversity of Neuroregulatory Processes (on the 100th Anniversary of I.P. Ashmarin) (Special Issue, Part 1)

The article presents the main directions of scientific and teaching activity of the academician of the Russian Academy of Medical Sciences I. P. Ashmarin at the Leningrad (St. Petersburg) State University, starting with his invitation to the Department of Biochemistry in 1963 and up to his transfer to Moscow. It is shown the further development of scientific directions, which were initiated by the brilliant ideas of Professor I. P. Ashmarin.

Reliable functioning of neuromuscular junctions in the respiratory and locomotor muscles is due to the ability of cholinergic synapses to exhibit plasticity under various conditions of the body, including high levels of physical activity, age-related changes, and a number of neurodegenerative diseases. Experimental data obtained in recent decades indicate that sympathetic innervation of neuromuscular junctions is one of the important regulatory factors involved in pre- and postsynaptic homeostatic plasticity. This review examines evidence of the close localization of sympathetic nerve endings and neuromuscular junctions, the effects of sympathectomy, adrenergic receptor activators, and adrenergic receptor blockers on synaptic transmission parameters at the cholinergic synapse, and the importance of sympathetic regulation for maintaining the efficiency of the synapse and the entire neuromuscular preparation.

The review is devoted to the analysis of published data on the normalizing and protective activity of the neuroprotective peptide HLDF-6 family. The peptide HLDF-6 (TGENHR) corresponds to fragment 41-46 of the protein differentiation factor HLDF (Human Leukemia Differentiation Factor). The neuroprotective peptide HLDF-6 and its analogue peptide HLDF-6-H (TGEXHR, where X is Hse) exhibit normalizing pharmacological activity, the targets of which are NMDA and metabotropic glutamate, serotonin and opioid systems, interacting with which the neuroprotective, nootropic, anxiolytic, differentiating, antitumor and anti-aging activity of these peptides is realized. In cellular and experimental models of Alzheimer’s disease induced by the introduction of beta-amyloid peptide Ab25–35, as well as a transgenic model of Alzheimer’s disease using B6C3-Tg(APPswe,PSEN1de9)85Dbo (Tg+) mice, the HLDF-6 peptide exhibits neuroprotective and nootropic activity. Chronic use of HLDF-6 peptide at a dose of 250 mg/kg is accompanied by a neuroprotective effect, normalizes steroidogenesis and effectively stimulates the performance of cognitive tasks. In an experimental model of Parkinson’s disease (PD), HLDF-6-H peptide exhibits neuroprotective, anxiolytic and antidepressant activity. Chronic use of HLDF-6-H peptide (intranasally, 3 weeks, 300 mg/kg/day) restores the level of dopamine and its turnover in the striatum, leads to overcoming motor dysfunctions, normalizes the levels of neurotrophin mRNA BDNF and inflammatory mediators TGFβ1, IL-1β and IFNg in parts of the brain, and also normalizes the concentrations of steroids and inflammatory factors in the bloodstream. The peptide HLDF-6-H has therapeutic potential for the creation of a pharmaceutical drug on its basis for the treatment of PD.

This review summarizes the current understanding of the antiplatelet effects of glyproline peptides (glyprolins) based on literature data and our own experimental studies. The unique properties of these bioregulators are analyzed, allowing them, along with the main neuroprotective effect in the organism, to influence the processes of vascular-platelet hemostasis, which are the main focus. The results of our own studies of PGP, PG, cGP, PGP with the addition of arginine, lysine or leucine, Semax, Selank, KKRRPGP, ACTH(6-9)PGP effects on platelet aggregation activity in normal and metabolic disorders in the organism are presented. Generalized data on the properties of the considered peptides allow us to conclude about the protective antiplatelet effect of glyprolins on the organism and to evaluate the possibility of their use in clinical practice for the prevention and complex therapy of metabolic disorders.

The endogenous opioid system, known for its unique role in the complex neurochemical regulation of physiological functions and behavior, is a bright illustration of the concept of the peptide continuum proposed by I.P. Ashmarin [1, 2]. The last of the opioid neuropeptides to be discovered was nociceptin/orphanin (N/OFQ), an endogenous ligand of the nociceptin opioid-like receptor (NOP), which functions are multiple and still not completely clear. In contrast to the active expression of the receptor in various brain regions, N/OFQ expression is more limited and predominantly localized in structures associated with stress and regulation of dopamine neurotransmission. This review presents a current view on the role of N/OFQ and NOP in the modulation of stress and related mental illnesses, including post-traumatic stress disorder. Preclinical data suggest that the use of both NOP agonists and antagonists may represent a promising approach to the treatment of these diseases.

Today the problem of regulating eating behavior is becoming increasingly relevant due to the spread of obesity and related comorbid diseases. Obesity increases the risk of many cardiovascular, respiratory and musculoskeletal diseases also accompanied by emotional disorders and the development of depressive states, which reduces life quality and duration. Endogenous peptide regulators, in particular obestatin and its derivatives, often appear among potential pharmacological correctors of body weight and eating behavior. The effects of course intranasal administration of two modified obestatin 1-4 (FNAP) fragments on body weight, feed and water intake, as well as on number of physiological parameters of functional body state were analyzed in order to assess the potential value of fragments studied as a basis for anorexic regulators creation. It was shown that anorexigenic effect of the hexapeptide FNAPEP-NH₂is due to a decrease in feed intake, in addition, the peptide had anxiolytic and analgesic effects and led to a decrease in locomotor activity of experimental animals. A decrease in body weight caused by longer FNAPVEP-NH₂ fragment was manifested without changes in food and water intake and was not accompanied by changes in spontaneous behavior, anxiety level and pain threshold, making this particular fragment preferable as a basis for eating behavior regulators creation.

At mature mouse diaphragm motor synapses of mice, we recorded miniature and evoked by phrenic nerve stimulation endplate multiquantal potentials (MEPPs and EPPs, respectively). The protease-activated receptor (PAR1) agonist TFLLR-NH₂ increased MEPP amplitude, which was prevented by inhibition of the vesicular acetylcholine transporter with vesamicol. TFLLR-NH₂ increased not only the amplitude of MEPPs, but also their frequency, when LM11A-31 (100 nM) inhibited p75 receptors for the BDNF prodomain, This indicates that after activation of PAR1, the BDNF prodomain is released from muscle fibers along with mature BDNF, whose action dominates in mature motor synapses. The extracellular matrix metalloprotease MMP-3 inhibitor NNGH (10 μM) did not prevent the potentiating effect of TFLLR-NH₂ on MEPP amplitude. Inhibition of the intracellular protease furin BOS-318 (0.5 μM) for two hours did not affect the parameters of spontaneous and evoked ACh release and was unable to prevent the TFLLR-NH₂-induced increase in MEPP amplitude. When BOS-318 was administered orally (10 mg/kg) one day before electrophysiological experiments, the PAR1 agonist lost its ability to potentiate neuromuscular transmission, which may indicate the release of proBDNF from muscle fibers under such conditions. It was concluded that intracellular furin-mediated maturation of BDNF occurs in muscle fibers with the formation of both the brain-derived neurotrophic factor itself and its prodomain, ensuring their combined retrograde presynaptic action after PAR1 activation.

According to modern concepts, the composition and diversity of the intestinal microbiota plays a significant role in maintaining immunity, homeostasis, and overall physiological functions of the host organism. An imbalance of the gut-brain axis due to intestinal dysbiosis is associated with a number of neurodegenerative diseases, including memory impairment and anxiety/depression symptoms. In this study, we assessed the effect of butyric acid, a representative of short-chain fatty acids, on anxiety and cognitive functions in mice after injection of a course of broad-spectrum antibiotics. We determined the level of oxidative stress in brain tissue, neuroinflammation, and BBB permeability in mice treated with antibiotics and a butyric acid preparation. Administration of antibiotics to adolescent mice for two weeks led to changes in behavior, including increased horizontal motor activity, decreased exploratory activity, and non-spatial and spatial short-term memory. Moreover, we found a high level of oxidative stress, neuroinflammation in brain tissues and increased BBB permeability in mice treated with antibiotics. Oral administration of the drug prevented these observed changes and improved not only behavioral disorders, but also partially reduced the level of oxidative stress and inflammation in the brain.

Hibernation is a form of adaptation of some mammals, which is characterized by a significant decrease in the metabolic rate and body temperature, suppression of a number of physiological functions. It lasts for several months and is accompanied by periodic arousal, during which the animals warm up, and the biochemical and physiological parameters return to the euthermic level. Periodic switching between two different modes of functioning of the body (hibernation – Arousal) is accompanied by significant restructuring in metabolic pathways and requires flexible mechanisms for changing the catalytic properties of their key enzymes. In this paper, the activity and kinetic parameters of LDH in the brain of ground squirrels in the hibernation-arousal cycle were studied. The study showed that hibernation is accompanied by a significant decrease in the catalytic efficiency of LDH, a change in the nature of the concentration dependence, an increase in K_m and K_i, and a shift in the position of the optimum point towards higher concentrations. A decrease in LDH activity in the brain during hibernation can prevent excessive lactate accumulation, reduce the glycolytic flow rate and glucose consumption in the brain, which will suppress the electrical activity of neurons, as well as implement a carbohydrate-saving strategy. In the dynamics of arousal, already at its early stages (25°C), when active thermogenesis begins to connect, a sharp increase in the efficiency of enzyme catalysis occurs, which can be contributed by both an increase in V_max and a decrease in K_m of the enzyme. At complete normalization of the body temperature of arous animals, the rate of catalysis becomes significantly higher than the control values. This indicates a close relationship between the enzyme and high electrical activity of the brain and demonstrates the important role of lactate in neuronal energetics, synaptic plasticity of the brain and synaptogenesis.

We searched for associations of temperament traits (introversion/extroversion and neuroticism) with prolactin levels (PRL) in young people of Yakut ethnicity, taking into account stressful situations in childhood. The sample included men aged 18 to 27 years (n = 121). The Eysenk Personality Inventory (EPI) was used to assess introversion/extroversion and neuroticism. The concentration of PRL in serum was estimated by immunofluorescence analysis using the DELFIA Prolactin kit (Perkin-Elmer-Wallac). It was found for the first time that significantly higher levels of PRL were characteristic of introverts compared to extroverts (p = 0.002) and for individuals with average neuroticism scores compared to individuals with high neuroticism scores (p = 0.01). Stressful situations experienced in childhood are associated with reduced PRL levels (p = 0.01).