Nf-κb: A Target for Synchronizing the Functioning Nervous Tissue Progenitors of Different Types in Alzheimer's Disease.

BACKGROUND: The efficacy of Alzheimer's disease (AD) treatment can be enhanced by developing neurogenesis regulation approaches by synchronizing regenerative-competent cell (RCCs) activity. As part of the implementation of this direction, the search for drug targets among intracellular signaling molecules is promising. OBJECTIVE: This study aims to test the hypothesis that NF-кB inhibitors are able to synchronize the activities of different types RCCs in AD. METHODS: The effects of NF-κB inhibitor JSH-23 on the functioning of neural stem cells (NSCs), neuronal-committed progenitors (NCPs), and neuroglial cells were studied. Individual populations of C57B1/6 mice brain cells were obtained by immunomagnetic separation. Studies were carried out under conditions of modeling ß-amyloid-induced neurodegeneration (ßAIN) in vitro. RESULTS: We showed that ß-amyloid (Aß) causes divergent changes in the functioning of NSCs and NCPs. Also demonstrated that different populations of neuroglia respond differently to exposure to Aß. These phenomena indicate a significant discoordination of the activities of various RCCs. We revealed an important role of NF-κB in the regulation of progenitor proliferation and differentiation and glial cell secretory function. It was found that the NF-κB inhibitor causes synchronization of the pro-regenerative activities of NSCs, NCPs, as well as oligodendrocytes and microglial cells in ßAIN. CONCLUSION: The results show the promise of developing a novel approach to Alzheimer's disease treatment with NF-κВ inhibitors.

A case of xenon inhalation therapy for respiratory failure and neuropsychiatric disorders associated with COVID-19.

Acute respiratory distress syndrome (ARDS) is the main danger to the life of patients with pneumonia caused by SARS-CoV-2. At the same time, respiratory failure (RF) after ARDS can persist for a long time despite intensive therapy. Therefore, it is important to develop new effective approaches for restoring the ventilation function of the lungs after COVID-19. Here, we present a case report of effective application of short-term inhalations of xenon-oxygen (Xe/O2) gas mixture for treatment of RF and neuropsychiatric disorders (NPD) associated with COVID-19. The patient inhaled a gas mixture of 70 % Xe and 30 % O2. We used multispiral computed tomography, evaluated psychometry, studied hematological and biochemical blood parameters, and applied some other methods of clinical studies to assess the therapeutic effectiveness of Xe inhalation. Also, we studied the mechanism of action of xenon with computer modeling. The clinical case showed the high efficacy of Xe/O2 mixture for treating severe RF and NPD after SARS-CoV-2 infection. Xenon inhalations dramatically increased oxygen saturation and the degree of pneumatization of the lungs. We found out that in coronavirus pneumonia, saturated phospholipids of surfactant are transferred to the solid-ordered phase, which disrupts the surface tension of the alveoli and alveolar gas exchange. Using molecular modeling methods, we demonstrated that the xenon atom increases the distance between the acyl chains of phospholipids due to the van der Waals dispersion interaction. These changes allow for the phase transition of phospholipids from the solid-ordered phase to the liquid phase and restore the functional activity of the surfactant. The findings suggest the feasibility of conducting studies on the effectiveness of Xe/O2 inhalations for treating ARDS in SARS-CoV-2 infection.

Targeting cAMP-pathway in Regeneration-competent Cells of Nervous Tissue: Potential to Create a Novel Drug for Treatment of Ethanol-induced Neurodegeneration.

BACKGROUND: Existing neuroprotective drugs are not effective enough to treat alcoholic encephalopathy. This makes the development of novel pharmacological approaches to treating patients with ethanol-induced neurodegeneration(EIN) relevant. Therefore, the search for new targets among intracellular signaling molecules of regeneration-competent cells of nervous tissue is promising. OBJECTIVE: This study aims to explore the involvement of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in the realization of the functions of nervous tissue progenitors and glial cells in EIN. METHODS: Experiments were conducted on mice of C57B1/6. EIN was modeled in vitro and in vivo. The effects of the adenylate cyclase (AC) and PKA inhibitors on the colony-forming capacity of neural stem cells (NSC) and neuronal-committed progenitors (NCP), their proliferative activity, and intensity of specialization were investigated. The secretion of neurotrophins by astrocytes, oligodendrocytes, and microglial cells was also evaluated. Individual fractions of cells were obtained using the immunomagnetic separation method. RESULTS: The cAMP/PKA signaling is shown to stimulate the proliferation of the NSC and inhibit the mitotic activity of the NCP under the conditions of their optimal vital activity. cAMP reduces the specialization intensity of both types of progenitors. EIN leads to the inversion of the role of the cAMP/PKA-pathway in the regulation of NSC functions. cAMP-pathway has varying influences on the secretion of neurotrophic growth factors by glial cells depending on their living conditions. AC blockage stimulates the realization of the NSC and NCP growth potential and production of neurotrophins by astrocytes and microglial cells in EIN. CONCLUSION: These findings show the potential for the use of AC inhibitors as novel effective drugs for the therapy of alcoholic encephalopathy.

Intracellular signaling molecules of nerve tissue progenitors as pharmacological targets for treatment of ethanol-induced neurodegeneration.

OBJECTIVES: The development of approaches to the treatment of neurodegenerative diseases caused by alcohol abuse by targeted pharmacological regulation of intracellular signaling transduction of progenitor cells of nerve tissue is promising. We studied peculiarities of participation of NF-кB-, сАМР/РКА-, JAKs/STAT3-, ERK1/2-, p38-pathways in the regulation of neural stem cells (NSC) and neuronal-committed progenitors (NCP) in the simulation of ethanol-induced neurodegeneration in vitro and in vivo. METHODS: In vitro, the role of signaling molecules (NF-кB, сАМР, РКА, JAKs, STAT3, ERK1/2, p38) in realizing the growth potential of neural stem cells (NSC) and neuronal-committed progenitors (NCP) in ethanol-induced neurodegeneration modeled in vitro and in vivo was studied. To do this, the method of the pharmacological blockade with the use of selective inhibitors of individual signaling molecules was used. RESULTS: Several of fundamental differences in the role of certain intracellular signaling molecules (SM) in proliferation and specialization of NSC and NCP have been revealed. It has been shown that the effect of ethanol on progenitors is accompanied by the formation of a qualitatively new pattern of signaling pathways. Data have been obtained on the possibility of stimulation of nerve tissue regeneration in ethanol-induced neurodegeneration by NF-кB and STAT3 inhibitors. It has been found that the blockage of these SM stimulates NSC and NCP in conditions of ethanol intoxication and does not have a «negative¼ effect on the realization of the growth potential of intact progenitors (which will appear de novo during therapy). CONCLUSIONS: The results may serve as a basis for the development of fundamentally new drugs to the treatment of alcoholic encephalopathy and other diseases of the central nervous system associated with alcohol abuse.