Author: Chayikovskyi, Alexander Vasil Evich ; Polykova, Tatyana Yur Evna ; Simanina, Elena Vladislavovna ; Zyuz'kov, Gleb Nikolaevich ; Miroshnichenko, Larisa Arkad Evna

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 (2ʹ,5ʹ-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 2ʹ,5ʹ-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.

01 Oct 2021·Central Nervous System Agents in Medicinal Chemistry

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

Article

Author: Simanina, Elena Vladislavovna ; Arkad`evna, Larisa ; Stavrova, Larisa Alexandrovna ; Polykova, Tatyana Yur`evna ; Zyuz’kov, Gleb Nikolaevich

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.

22 Apr 2021·Depression Research and Treatment

Adenylyl Cyclase (AC) Mediates the Antidepressant-Like Effects of Tropisetron on a Mouse Model of Maternal Separation Stress

Article

Author: Dehkordi, Saeid Habibian ; Loriooini, Zahra ; Rahimi-Madiseh, Mohammad ; Amini-Khoei, Hossein ; Boroujeni, Shakiba Nasiri ; Saghaei, Elham ; Hosseinzadeh, Ali ; Balali-Dehkordi, Shima

The adenylyl cyclase (AC) pathway is involved in the pathophysiology of depression. Finding new antidepressants with high medicinal properties and low side effects is warranted. Therefore, this study was designed to determine the antidepressant-like effect of tropisetron on a maternal separation (MS) model in mice, considering the possible role of AC. NMRI male mice were divided into eleven groups. The control group was treated with saline and MS groups were treated with saline, tropisetron (a 5-HT3 receptor antagonist) at doses of 1, 3, and 5 mg/kg; forskolin (an activator of AC) at doses of 5, 10, and 25 mg/kg; a subeffective dose of forskolin with a subeffective dose of tropisetron; and an effective dose of tropisetron plus an effective dose of NB001 (3 mg/kg) (an AC inhibitor). After treatment, animals were subjected to behavioral tests including the forced swimming test (FST), splash test, and open field test (OFT). We showed that MS caused depressive-like behaviors determined as an increase in the immobility time in the forced swimming test (FST) and decreased grooming time in the splash test. Our results showed that administration of tropisetron, as well as forskolin, mitigated the depressive-like behaviors in MS mice. We found that coadministration of a subeffective dose of tropisetron plus a subeffective dose of forskolin potentiated the antidepressant-like effect of tropisetron. However, coadministration of an effective dose of NB001 with an effective dose of tropisetron did not significantly affect the antidepressant-like effect of tropisetron. We concluded that the antidepressant-like effects of tropisetron on MS mice are partially mediated through the adenylyl cyclase pathway.

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Indication	Highest Phase	Country/Location	Organization	Date
Gram-Negative Bacterial Infections	Preclinical	US	University of Minnesota	13 Mar 2013

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