Gleb Nikolaevich Zyuz'kov, Larisa Arkad Evna Miroshnichenko, Tatyana Yur Evna Polykova, Elena Vladislavovna Simanina, Alexander Vasil Evich Chayikovskyi
{"title":"靶向腺苷酸环化酶:刺激神经发生和阿尔茨海默病药物治疗的新概念","authors":"Gleb Nikolaevich Zyuz'kov, Larisa Arkad Evna Miroshnichenko, Tatyana Yur Evna Polykova, Elena Vladislavovna Simanina, Alexander Vasil Evich Chayikovskyi","doi":"10.2174/0118715249302264240715060630","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>We examined the effect of the AC inhibitor (2',5'-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).</p><p><strong>Results: </strong>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 2',5'-dideoxyadenosine correlated with the correction of age-related disorders of the psychoemotional status in aged mice.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":93930,"journal":{"name":"Central nervous system agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting Adenylate Cyclase: A Novel Concept for Stimulation of Neurogenesis and Pharmacotherapy of Alzheimer's Disease.\",\"authors\":\"Gleb Nikolaevich Zyuz'kov, Larisa Arkad Evna Miroshnichenko, Tatyana Yur Evna Polykova, Elena Vladislavovna Simanina, Alexander Vasil Evich Chayikovskyi\",\"doi\":\"10.2174/0118715249302264240715060630\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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).</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>We examined the effect of the AC inhibitor (2',5'-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).</p><p><strong>Results: </strong>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. 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引用次数: 0
摘要
背景:阿尔茨海默病(AD)的现有药物治疗策略效果不佳,因此有必要开发一种治疗这种类型痴呆症的新概念。这一探索有望在针对再生功能细胞(RCC)细胞内信号通路的范例框架内进行:本研究的目的是研究腺苷酸环化酶(AC)抑制剂对老年雄性 C57BL/6 小鼠精神情绪障碍的影响,以及对 RCCs 神经组织含量和功能动态的影响:方法:我们研究了AC抑制剂(2',5'-双脱氧腺苷)对小鼠AD模型(16月龄(老龄)雄性C57BL/6小鼠)的条件反射活动、行为和情感特征的影响,以及对大脑半球(SVZ)室下区神经干细胞(NSCs)、神经元结合祖细胞(NCPs)和神经胶质细胞功能的影响:在老年 C57BL/6 小鼠身上,我们发现了探索行为、情绪反应能力和记忆力的损伤,而这些正是老年痴呆症的特征。基于 AC 抑制的治疗可增加 SVZ 中的 NSCs 和 NPCs 数量,因为它们的增殖活性增加了。这些变化在 NCP 中更为明显。与此同时,NSCs 的特化强度有所下降。这些现象是在少突胶质细胞和小胶质细胞分泌更多神经营养生长因子的背景下出现的。2',5'-双脱氧腺苷的神经再生作用与纠正老年小鼠与年龄有关的精神情绪障碍相关:结论:研究结果为开发基于 AC 抑制剂的靶向药物提供了依据,这些药物可刺激神经发生,从而有效治疗注意力缺失症。
Targeting Adenylate Cyclase: A Novel Concept for Stimulation of Neurogenesis and Pharmacotherapy of Alzheimer's Disease.
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 (2',5'-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 2',5'-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.