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.

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.