{"title":"靶向神经组织再生能力细胞中的camp通路:可能创造一种治疗乙醇性神经退行性疾病的新药。","authors":"Gleb Nikolaevich Zyuz'kov, Larisa Arkad Evna, Tatyana Yur Evna Polykova, Elena Vladislavovna Simanina, Larisa Alexandrovna Stavrova","doi":"10.2174/1871524921666210907102847","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>These findings show the potential for the use of AC inhibitors as novel effective drugs for the therapy of alcoholic encephalopathy.</p>","PeriodicalId":9799,"journal":{"name":"Central nervous system agents in medicinal chemistry","volume":"21 3","pages":"172-180"},"PeriodicalIF":0.0000,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"14","resultStr":"{\"title\":\"Targeting cAMP-pathway in Regeneration-competent Cells of Nervous Tissue: Potential to Create a Novel Drug for Treatment of Ethanol-induced Neurodegeneration.\",\"authors\":\"Gleb Nikolaevich Zyuz'kov, Larisa Arkad Evna, Tatyana Yur Evna Polykova, Elena Vladislavovna Simanina, Larisa Alexandrovna Stavrova\",\"doi\":\"10.2174/1871524921666210907102847\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>These findings show the potential for the use of AC inhibitors as novel effective drugs for the therapy of alcoholic encephalopathy.</p>\",\"PeriodicalId\":9799,\"journal\":{\"name\":\"Central nervous system agents in medicinal chemistry\",\"volume\":\"21 3\",\"pages\":\"172-180\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2021-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"14\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Central nervous system agents in medicinal chemistry\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2174/1871524921666210907102847\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"Psychology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Central nervous system agents in medicinal chemistry","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/1871524921666210907102847","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Psychology","Score":null,"Total":0}
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.
期刊介绍：
Central Nervous System Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new central nervous system agents. Containing a series of timely in-depth reviews written by leaders in the field covering a range of current topics, Central Nervous System Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in the field.
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