Gleb Nikolaevich Zyuz’kOv

Introduction: Extracts of the Aconite genus are used for medicinal purposes in China, Korea, Japan, and India. Extracts of the Aconite genus contain the highly toxic alkaloid aconitine and a number of low-toxicity alkaloids with medicinal properties. One of these alkaloids is songorine. The objective of the review is an analysis of data on the anxiolytic, antinociceptive, antiinflammatory, anticancer, cardioprotective, and proliferative effects of songorine. Methods: The information was retrieved from PubMed between from 1835 and 2026. Results: It was demonstrated that songorine has anxiolytic, antinociceptive, anti-inflammatory, anticancer, cardioprotective, and proliferative properties. The anti-inflammatory effect of songorine is accompanied by a decrease in pro-inflammatory cytokine production and a reduction of neutrophil invasion in injured tissue. The role of the GABAA, dopamine D2, peripheral κ-opioid, cannabinoid CB1, and other receptors in the effects of songorine is discussed. The involvement of protein kinases in the proliferative effect of songorine is demonstrated. The role of transcription factors NF-κB, Nrf2, STAT3, and protein synthesis in the effects of songorine is discussed. Discussion: Despite accumulated experimental data demonstrating a broad spectrum of pharmacological effects of songorine, including anxiolytic, analgesic, anti-inflammatory, and cardioprotective effects, a number of unresolved questions remain related to an incomplete understanding of the molecular targets and signaling pathways. Furthermore, most results were obtained in preclinical models, limiting their direct extrapolation to clinical practice. Conclusion: Songorine is discussed for use in the treatment of depression, chronic pain, chronic inflammation, and cancer. It can be used to accelerate wound healing, in the treatment of sepsis, doxorubicin-induced cardiomyopathy, and stress-induced cardiac injury.

Recent evidence indicating that ethanol-induced neurodegeneration disrupts the function of neural stem cells (SCs) and other brain progenitor populations provides a strong pathogenetic rationale for developing drugs with neuroregenerative properties. The aim of the present investigation was to elucidate the effect of an inhibitor of Nuclear Factor kappa B (NF-kappa B, NF-κB) on both the neuropsychiatric profile and the neural progenitor cell pool within the brains of a preclinical model of alcoholic encephalopathy (AE). JSH-23 (Sigma-Aldrich, Germany), with activity guaranteed by the manufacturer, was used as an NF-κB inhibitor. The experimental protocol involved inducing alcoholic encephalopathy (AE) in C57BL/6 mice. To evaluate the effects of the NF-kappa B inhibitor JSH-23, we assessed cognitive performance via the open field test and the retention of a conditioned passive avoidance reflex (CPAR). Concurrently, in vitro assays were conducted to determine the content and functional activity of multipotent SCs and committed neuronal progenitors (NPs) derived from the subventricular zone (SVZ). Furthermore, we analyzed the secretion of progenitor-active growth factors by distinct neuroglial subpopulations. The administration of JSH-23 after AE induction corrected impairments in both exploratory behavior and CPAR reproducibility in mice with AE. This cognitive recovery was accompanied by a significant increase in the population of neuronal SCs and committed NPs within the SVZ. On day 7, these cell populations reached 152.6% and 211.1% of the corresponding levels in untreated AE animals. Furthermore, both progenitor types exhibited enhanced proliferative activity and differentiation intensity. This was paralleled by an increase in growth factor production by oligodendrocytes, which rose to 174.3% and 190.8% of control values (mice with AE without treatment) on days 3 and 7 following JSH-23 treatment. These results support further investigation into the possibility of using NF-κB blockers as a basis for the development of novel neuroregenerative therapies for AE.

The role of the transcription factor Myc in the functioning of multipotent neural stem cells (NSCs), committed neuronal progenitors (CNPs), and neuroglial

Introduction. Impaired central nervous system function resulting from chronic ethanol consumption is often associated with suppressed neurogenesis. The GPCR/cAMP-dependent pathway and JAK/STAT signaling are considered to be among the key signaling cascades involved in regulating the proliferation and differentiation of neural and neuronal stem cells. Clearly, the search for fundamentally new approaches to treating ethanol-induced neurodegeneration by targeting intracellular signaling molecules is highly relevant and in demand in practical medicine. Aim. The aim of this study was to investigate the effect of JAC/STAT and GPCR/cAMP inhibitors on the psychoneurological status of mice, the state of neural stem cells, and the secretion of neurotrophins by glia under conditions of chronic toxic brain injury. Material and methods. The studies were conducted on 90 C57BL/6 mice. Alcohol-induced neurodegeneration was modeled by per os administration of 30 % C ₂ H ₅ OH solution at a dose of 3 g/kg/day for 8 weeks. JAC/STAT and GPCR/cAMP inhibitors were administered subcutaneously once a day for 7 days at a dose of 15 and 10 μg/kg, respectively. The psychopharmacological effects of the blockers were assessed in the open field test and by the degree of preservation of the conditioned passive avoidance reflex. The content of neural stem cells and committed neuronal precursors in the subventricular zone of the brain, their proliferative activity and maturation intensity were studied using cultural methods; the production of neurotrophic factors by glial cells was investigated. Results and discussion. The introduction of JAC/STAT and GPCR/cAMP inhibitors corrected the functional signs of alcoholic brain pathology (changes in exploratory behavior were abolished). At the same time, the course use of a GPCR/cAMP inhibitor leveled out, and the introduction of a JAC/STAT blocker aggravated the decrease in the level of reproduction of the conditioned passive avoidance reflex in alcoholized mice. In the groups of animals receiving JAC/STAT and GPCR/cAMP inhibitors, an increase in the number of neural stem cells and committed neuronal precursors was observed, accompanied by an increase in their mitotic activity and intensity of specialization. The introduction of a GPCR/cAMP inhibitor after modeling ethanol-induced brain damage was accompanied by an increase in the secretion of neurotrophins by astrocytes and microglia. Conclusion. The obtained results indicate the prospects of developing a new approach to the treatment of chronic alcohol-induced brain damage by targeting individual links in the intracellular signal transduction system, in particular, the use of GPCR/cAMP inhibitors.

Introduction . Opioid and cannabinoid receptors are involved in the antinociceptive effects of songorine, a diterpene alkaloid isolated from the above-ground parts of Aconitum barbatum, as demonstrated in various models of chemical and thermal pain. The involvement of opioid receptors in songorine is antinociceptive mechanism necessitates studying its potential side effects, characteristic of narcotic analgesics. TRPA1 receptor involvement in songorine is analgesic mechanism is possible, requiring further investigation in models of mechanical hyperalgesia with formalin. Aim: To study the antinociceptive activity of the diterpenoid alkaloid songorine at a dose of 25 μg/kg in the Randall-Selitto test against formalin-induced hyperalgesia and its potential opioid-like side effects. Material and Methods . The study was performed on outbred male CDI and mice male CBA mice obtained from the Department of Experimental Biological Models at the E.D. Goldberg Research Institute of Pharmacology and Regenerative Medicine Tomsk NRMC. Songorine, a diterpene alkaloid of the atizine series, was administered orally to the animals at a previously established effective dose of 25 μg/kg. Tramadol (KRKA) at a dose of 20 mg/kg and ketorolac (Dr. Reddy´s Laboratories Ltd.) at a dose of 6 mg/kg were used as reference drugs. Antinociceptive activity was studied using the Randall-Selitto test with a Ugo Basile (Italy) analgesy-meter on a mechanical pain model, with and without formalin-induced hyperalgesia. To study the effect of songorine on the frequency of breathing in non-narcotized mice, the number of respiratory movements per minute was recorded after 5-fold administration of the alkaloid and the reference drug tramadol. The withdrawal syndrome was assessed using the non-selective opioid receptor antagonist naloxone (Sigma). The effect of the alkaloid on gastrointestinal smooth muscle was studied in the “charcoal meal” test. Results. Songorine is antinociceptive effect in the Randall-Selitto test upon single administration is comparable to ketorolac and tramadol, but less prolonged than the latter. Songorine is pronounced analgesic activity in formalin-induced hyperalgesia suggests the possible involvement of TRPA1 receptors in its mechanism of action. The study of possible undesirable effects of the course per os administration of the diterpene alkaloid songorine at a dose of 25 μg/kg showed that it does not cause the development of respiratory depression, withdrawal syndrome and drug-induced obstipation. Conclusion. In the Randall-Selitto test, TRPA1 receptor involvement in the antinociceptive activity of songorine was established against a background of formalin hyperalgesia. The diterpene alkaloid songorine at subchronic administration at a dose of 25 μg/kg does not show the side effects characteristic of morphine-like drugs.

Introduction: The study was aimed at a comparative analysis of the anti-inflammatory and analgesic activities of diterpene alkaloid songorine obtained from Aconitum barbatum and its cell culture. Materials and Methods: Experiments were performed on 60 male mice of the CBA line. The object of the study was the diterpene alkaloid of songorine (25 µg/kg) isolated from Aconitum barbatum, as well as obtained from the callus culture of cells. Comparative study of analgesic and anti-inflammatory activities of the alkaloid obtained from different sources was carried out under conditions of the formalin test and abdominal constriction test. Diclofenac sodium (10 mg/kg) and paracetamol (85 mg/kg) were used as comparison drugs. Control animals received distilled water. All substances were administered to mice per os for 5 days, the last time – 1 hour before the onset of the damaging effect. Results and Discussion: Under the formalin test conditions, the analgesic activity of songorine from both sources was manifested in the second phase of pain response. The anti-inflammatory activity in this model of both “standard” and ”culture” songorine was comparable to that of diclofenac sodium. Probably, pharmacological activity of alkaloid in the formalin test is provided by suppression of proinflammatory mediators and TRPA1-receptors. In the abdominal constriction test, all investigated substances showed a pronounced analgesic effect maximum under the action of songorine in vitro. In addition, songorine from both sources, in contrast to the reference drug, provided a reliable phlogolytic effect. Probably, the pharmacological activity of songorine in this model is provided by its suppressive action against endogenous mediators of pain and inflammation and of TRPV1-receptors. Conclusion: Comparative analysis of the analgesic and anti-inflammatory effects of songorine (25 µg/kg) from Aconitum barbatum after a 5-dose regimen demonstrated comparability with “culture” songorine (25 µg/kg).

We studied the effect of a protein kinase A (PKA) inhibitor and the content of different types of progenitor cells in the subventricular zone of the brain

We studied the psychopharmacological effects of a NF-κB inhibitor, a stimulator of the functions of progenitor cells of the nervous tissue, under cond

Background: The low effectiveness of existing pharmacotherapy strategies for Alzheimer's disease (AD) makes it necessary to develop a new concept for the treatment of this type of dementia. This search is promising to be carried out within the framework of the paradigm of targeting intracellular signaling pathways in Regenerative-Competent Cells (RCCs). Objective: The purpose of the research is to study the impact of adenylate cyclase (AC) inhibitor on disorders of the psychoemotional status in aged male C57BL/6 mice, as well as on the dynamics of the content and functioning of RCCs nervous tissue. Methods: We examined the effect of the AC inhibitor (2ʹ,5ʹ-Dideoxyadenosine) on conditioned reflex activity, behavioral and emotional profile in a mouse AD model (16-month-old (aged) male C57BL/6 mice), as well as the functioning of neural stem cells (NSCs), neuronal-committed progenitors (NCPs), and neuroglial cells in the subventricular zone of the cerebral hemispheres (SVZ). Results: In aged C57BL/6 mice, we found impairments in exploratory behavior, emotional reactivity, and memory, which are the characteristics of senile dementia. Therapy based on AC inhibition led to an increase in the number of NSCs and NPCs in the SVZ due to an increase in their proliferative activity. These changes were more pronounced in NCPs. At the same time, a decrease in the specialization intensity was recorded in NSCs. These phenomena developed against the background of increased secretion of neurotrophic growth factors by oligodendrocytes and microglial cells. The neuroregenerative effects of 2ʹ,5ʹ-dideoxyadenosine correlated with the correction of age-related disorders of the psychoemotional status in aged mice. Conclusion: The results provide the basis for the development of targeted drugs based on AC inhibitors to stimulate neurogenesis as an approach for the effective treatment of AD.