Zyuz'kov Gleb Nikolaevich, Miroshnichenko Larisa Arkad Evna, Polykova Tatyana Yur Evna, Simanina Elena Vladislavovna, Chayikovskyi Alexander Vasil Evich
Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.
Cent Nerv Syst Agents Med Chem. 2025;25(2):169-180. doi: 10.2174/0118715249302264240715060630.
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).
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.
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).
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.
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.
现有治疗阿尔茨海默病（AD）的药物治疗策略效果不佳，因此有必要开发一种治疗此类痴呆症的新概念。有望在有再生能力的细胞（RCCs）中靶向细胞内信号通路的范式框架内进行此项探索。
本研究旨在探讨腺苷酸环化酶（AC）抑制剂对老年雄性C57BL/6小鼠心理情绪状态紊乱的影响，以及对RCCs神经组织含量和功能动态的影响。
我们研究了AC抑制剂（2',5'-二脱氧腺苷）对小鼠AD模型（16月龄雄性C57BL/6小鼠）的条件反射活动、行为和情绪特征的影响，以及对大脑半球脑室下区（SVZ）神经干细胞（NSCs）、神经元定向祖细胞（NCPs）和神经胶质细胞功能的影响。
在老年C57BL/6小鼠中，我们发现其探索行为、情绪反应性和记忆力受损，这些是老年痴呆症的特征。基于AC抑制的治疗导致SVZ中NSCs和NPCs数量增加，这是由于它们的增殖活性增强。这些变化在NCPs中更为明显。同时，记录到NSCs的分化强度降低。这些现象是在少突胶质细胞和小胶质细胞分泌神经营养生长因子增加的背景下发生的。2',5'-二脱氧腺苷的神经再生作用与老年小鼠年龄相关的心理情绪状态紊乱的纠正相关。
这些结果为开发基于AC抑制剂的靶向药物以刺激神经发生作为有效治疗AD的方法提供了依据。
