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

• Published in: Central nervous system agents in medicinal chemistry Vol. 21; no. 3; p. 172
• Main Authors: Zyuz'kov, Gleb Nikolaevich, Arkad Evna, Larisa, Polykova, Tatyana Yur Evna, Simanina, Elena Vladislavovna, Stavrova, Larisa Alexandrovna
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 2021
• Subjects: Animals; Cyclic AMP; Ethanol - toxicity; Humans; Mice; Neural Stem Cells; Pharmaceutical Preparations; Regeneration; neurodegenerativediseases; targeted therapy; intracellular signaling molecules; neuroglia; adenylate cyclase; PKA; Neural stem cells; cAMP
• ISSN: 1875-6166

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. 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. 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. 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. These findings show the potential for the use of AC inhibitors as novel effective drugs for the therapy of alcoholic encephalopathy.