Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences68741510.31857/S0869813925060092TEPHHCEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleIdentifining a Therapeutic Window for Intranasal Insulin Administration in a Two-Vessel Rat Model of Forebrain Ischemia and Investigating the Mechanisms of Its Neuroprotective ActionПоиск терапевтического окна для применения интраназально вводимого инсулина у крыс с церебральной ишемией и изучение механизмов его нейропротекторного действияZorinaI. I.ЗоринаИ. И.
Russian Federation
zorina.inna.spb@gmail.comPechalnovaA. S.ПечальноваА. С.
Russian Federation
zorina.inna.spb@gmail.comChernenkoE. E.ЧерненкоЕ. Е.
Russian Federation
zorina.inna.spb@gmail.comAvrovaD. K.АвроваД. К.
Russian Federation
zorina.inna.spb@gmail.comDerkachK. V.ДеркачК. В.
Russian Federation
zorina.inna.spb@gmail.comShpakovaA. O.ШпаковА. О.
Russian Federation
zorina.inna.spb@gmail.comSechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesИнститут эволюционной физиологии и биохимии им. И.М. Сеченова Российской академии наук1506202511169579751307202513072025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/687415

Cerebral ischemia is a significant medical and social issue, necessitating the development of effective treatment strategies. Due to the complex pathogenesis and prolonged recovery period associated with this condition, drugs with pleiotropic effects, such as intranasally administered insulin (IAI), are of the greatest interest. IAI sprayed in the nasal cavity enters the brain, regulating metabolism through central mechanisms, has neuroprotective and neuro-regulatory effects. It has been proven to be effective in the treatment of neurodegenerative diseases, although data on its effectiveness in cerebral ischemia remain limited. The aim of the work was to search for a “therapeutic window” and evaluate the mechanisms of the neuroprotective effect of IAI when used in rats with cerebral ischemia. Rats with two-vessel forebrain ischemia were administered IAI 2 and 4 hours after an episode of ischemia at a dose of 0.5 IU/rat/day, and then daily for a 7-day period after ischemia. It has been demonstrated that IAI is more effective if animals were treated 2 hours after the ischemic event, compared with administration after 4 hours, despite the subsequent 7-day of IAI treatment. When administered 2 hours after an ischemic event, IAI has been shown to support the expression of components of insulin signaling genes in the hippocampus and normalize the number of cells in the CA1 region. It also stimulates the expression of the anti-apoptotic Bcl-2 gene and reduces the expression of the Gfap and Aif1 genes, which are markers of astrocytes and microglia, and this indicates the anti-inflammatory effect of IAI. In addition, for the first time IAI has been found to stimulate the activity of the thyroid system and prevent the development of post-ischemic hypothyroidism. All these effects were less pronounced or not observed when IAI was administered 4 hours after the ischemic event. Thus, for the first time, we described a “therapeutic window” for the use of IAI in cerebral ischemia and evaluated some of the mechanisms underlying its neuroprotective effects.

Ишемия головного мозга представляет собой значимую медико-социальную проблему, вследствие чего актуальной является разработка эффективных нейропротекторов для ее коррекции. Поскольку ишемия мозга имеет сложный патогенез с длительным восстановительным периодом, то наибольший интерес представляют препараты с плейотропным действием, в том числе интраназально вводимый инсулин (ИВИ), который, поступая в мозг, через центральные механизмы регулирует метаболизм, оказывает нейропротекторное и нейромодуляторное воздействие. ИВИ эффективен при нейродегенеративных заболеваниях, но данные о его нейропротекторном эффекте при церебральной ишемии фрагментарны. Целью работы был поиск “терапевтического окна” и оценка механизмов нейропротекторного эффекта ИВИ при его использовании у крыс с церебральной ишемией. ИВИ вводили крысам, перенесшим двухсосудистую ишемию переднего мозга, через 2 и 4 ч после эпизода ишемии в дозе 0.5 МЕ/крыса/сутки и далее ежедневно в течение 7 дней постишемического периода. Показано, что ИВИ более эффективен при обработке через 2 ч после ишемического эпизода в сравнении с его введением через 4 ч, несмотря на последующее семидневное введение. При введении через 2 ч ИВИ поддерживает экспрессию генов инсулинового сигналинга в гиппокампе. Он нормализует количество клеток в СА1-области гиппокампа, стимулирует экспрессию гена антиапоптотического белка Bcl-2 и снижает экспрессию генов Gfap и Aif1, маркеров астроцитов и микроглии, что свидетельствует о его противовоспалительном эффекте. Обнаружено, что ИВИ стимулирует активность тиреоидной системы, препятствуя развитию постишемического гипотиреоза, что также может вносить вклад в ИВИ-опосредуемую нейропротекцию. Все эти эффекты были слабо выражены или не выявлялись при введении ИВИ через 4 ч после ишемии. Таким образом, нами впервые описано “терапевтическое окно” для применения ИВИ при церебральной ишемии и оценены некоторые механизмы его нейропротекторного действия. Полученные данные открывают перспективы для разработки новых стратегий нейропротекции при ишемии мозга.

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