Molecular BiologyMolecular BiologyМолекулярная биология0026-89843034-5553The Russian Academy of Sciences69967710.7868/S3034555325060053МОЛЕКУЛЯРНАЯ БИОЛОГИЯ КЛЕТКИResearch ArticleBenzopyran Derivative Improves Synaptic Plasticity, Exploration Interest and Alleviates Amyloidogenesis and Astrogliosis in 5xFAD MiceПРОИЗВОДНОЕ БЕНЗОПИРАНА УЛУЧШАЕТ СИНАПТИЧЕСКУЮ ПЛАСТИЧНОСТЬ, ИССЛЕДОВАТЕЛЬСКУЮ АКТИВНОСТЬ И СНИЖАЕТ АМИЛОИДОГЕНЕЗ И АСТРОГЛИОЗ У МЫШЕЙ ЛИНИИ 5xFADZernovN.ЗерновН.

Laboratory of Molecular Neurobiology

Лаборатория молекулярной нейробиологии

email@example.comMelentevaD. M.МелентьеваД. М.

Laboratory of Molecular Neurodegeneration

Лаборатория молекулярной нейродегенерации

email@example.comPopugaevaE. A.ПопугаеваЕ. А.

Laboratory of Molecular Neurodegeneration

Лаборатория молекулярной нейродегенерации

lena.popugaeva@gmail.comPavlov Institute of PhysiologyИнститут физиологии им. И.П. Павлова Российской академии наукPeter the Great St. Petersburg Polytechnic UniversityСанкт-Петербургский политехнический университет Петра Великого25122025596VOL 59, NO6 (2025)ТОМ 59, №6 (2025)93895627122025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://vietnamjournal.ru/0026-8984/article/view/699677

Current Alzheimer’s disease (AD) therapies offer only symptomatic relief and fail to halt disease progression, underscoring the urgent need for novel therapeutic strategies. We have previously shown that selective positive allosteric modulator of TRPC6, benzopyran derivative (C20), exhibits synaptoprotective properties at nanomolar concentrations, restores synaptic plasticity in 5xFAD mice, and enhances hippocampus-dependent memory. Here, we further evaluate the preclinical efficacy and safety of C20, focusing on its effects on chronic toxicity, mutagenicity, amyloidosis, astrogliosis, synaptic plasticity, and behavior in a transgenic AD model. Chronic and acute toxicity studies were performed on female wild type mice. The Ames test was conducted using Salmonella typhimurium and E. coli strains to evaluate the mutagenic potential of C20. 8 months old 5xFAD were used as model of AD. Electrophysiological recordings were applied to study long term potentiation in hippocampal slices of 5xFAD mice following intraperitoneal injections of C20. Behavioral testing included the open field test. Immunohistochemical analyses were performed to quantify amyloid plaques and astrogliosis in the hippocampus. Chronic and acute toxicity studies revealed no significant adverse effects on mice weight and survival, indicating that C20 is well-tolerated at the tested dose. The Ames test confirmed that C20 is almost non-mutagenic. Behavioral testing demonstrated that C20-treated mice exhibited increased exploration in the open field test. Immunohistochemical analyses detected a significant reduction in amyloid plaques and astrogliosis. Our findings suggest that C20 is a safe and effective therapeutic candidate for AD, with the potential to restore synaptic plasticity, improve cognitive function, and reduce pathological hallmarks of the disease.

Существующие методы лечения болезни Альцгеймера обеспечивают лишь симптоматическое облегчение и не способны остановить прогрессирование заболевания, что указывает на острую потребность в новых терапевтических стратегиях. Ранее мы показали, что селективный положительный аллостерический модулятор TRPC6, производное бензопирана (C20), обладает синаптопротекторными свойствами в наномолярных концентрациях, восстанавливает синаптическую пластичность у мышей 5xFAD и улучшает гиппокампзависимую память. В представленной работе оценили эффективность и безопасность C20 у мышей, уделяя особое внимание его токсичности, влиянию на мутагенность, амилоидоз, астроглиоз, синаптическую пластичность и поведение животных. Хроническую и острую токсичность C20 оценивали на самках мышей дикого типа. Мутагенный потенциал C20 определяли в тесте Эймса на штаммах Salmonella typhimurium и Escherichia coli. В качестве модели болезни Альцгеймера использовали 8-месячных мышей 5xFAD. Для изучения долговременной потенциации в срезах гиппокампа мышей 5xFAD после внутрибрюшинных инъекций C20 применяли электрофизиологические методы. Поведенческие тесты включали тест в открытом поле. Для количественной оценки амилоидных бляшек и астроглиоза в гиппокампе использовали гистохимические методы. Исследования хронической и острой токсичности не выявили значительного влияния C20 на вес и выживаемость мышей, что указывает на хорошую переносимость C20 в испытанной дозе. Тест Эймса подтвердил, что C20 практически не является мутагенным. Поведенческие тесты выявили повышенную активность мышей, получавших C20, в тесте “Открытое поле”. Гистохимический анализ выявил значительное уменьшение амилоидных бляшек и астроглиоза. Таким образом, C20 можно рассматривать в качестве потенциально безопасного и эффективного средства для лечения болезни Альцгеймера, способного восстанавливать синаптическую пластичность, улучшать когнитивные функции и уменьшать патологические признаки заболевания.

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