Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65162310.31857/S0869813924080022BCRJTFEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleIntranasal administration of GRP78 protein (HSPA5) counteracts the neurodegeneration in the locus coeruleus in a model of chronic sleep restriction in ratsИнтраназальное введение белка GRP78 (HSPA5) противодействует гибели нейронов в голубом пятне в модели хронической депривации сна у крысPaziM. B.ПазиМ. Б.
Russian Federation
pazimariia@gmail.comEkimovaI. V.ЕкимоваИ. В.
Russian Federation
pazimariia@gmail.comSechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesИнститут эволюционной физиологии и биохимии им. И. М. Сеченова РАН1508202411081238125201022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/651623

Chronic sleep restriction (sleep less than 6 hours per day) due to the workload and a decrease in sleep quality is an endemic disease in modern society. Chronic sleep deprivation causes serious neuropsychiatric disorders associated with irreversible neurodegenerative changes in the brain. The search for pharmacological agents that can reduce the risk of neurodegeneration as a result of chronic sleep loss is an urgent task issue for biomedicine. Intranasal administration of glucose-regulated 78 kDa heat shock protein (GRP78) has a neuroprotective effect in a rat model of Parkinson´s disease. The neuroprotective potential of intranasally administered GRP78 in chronic sleep deprivation has not been previously studied. The aim of the study is to find out whether preventive intranasal administration of GRP78 is able to weaken and/or stop the process of neurodegeneration in the locus coeruleus in the model of chronic sleep restriction (SR) in rats. The study was conducted on 6 months old male Wistar rats. For sleep deprivation, a validated method of a swinging platform was used in the mode: 3 hours of sleep deprivation and 1 hour of rest continuously for 5 days. Recombinant human protein GRP78 was administered intranasally two days before the start of SR and during 5 days of SR. Cellular and molecular changes in the locus coeruleus during SR and during the administration of GRP78 were studied using immunohistochemistry and Western blotting. It was shown that chronic SR leads to the degeneration of 30% of noradrenergic neurons in the locus coeruleus, that was associated with an increase in the levels of activated caspases-3 and 9. This indicates the development of apoptosis along the mitochondrial pathway. No signs of reactive microgliosis were found in the model of chronic SR in rats. We have demonstrated that intranasally administered GRP78 penetrates and accumulates in the neurons of the locus coeruleus, GRP78 counteracts the death of neurons along the path of apoptosis. The data obtained allows to consider GRP78 as a potential neuroprotective agent for the prevention of pathological consequences of chronic sleep deprivation.

Хроническое недосыпание (сон менее 6 ч в сутки) в связи с производственной необходимостью и снижением качества сна является эндемическим заболеванием в современном обществе. Хроническое недосыпание вызывает серьезные нейроповеденческие нарушения, сопряженные с необратимыми нейродегенеративными изменениями в головном мозге. Поиск фармакологических агентов способных снизить риск развития нейродегенерации в результате хронической потери сна является актуальной задачей биомедицины. Интраназальное введение глюкозо-регулируемого белка теплового шока 78 кДа (GRP78) оказывает нейропротективный эффект в модели болезни Паркинсона у крыс. Нейропротективный потенциал интраназально введенного GRP78 при хроническом недосыпании ранее не исследовался. Задача исследования – выяснить, способно ли профилактическое интраназальное введение GRP78 ослабить и/или остановить процесс нейродегенерации в голубом пятне в модели хронического ограничения сна (ОС) у крыс. Исследование проведено на 6-месячных самцах крыс популяции Вистар. Для депривации сна был применен валидизированный метод качающейся платформы в режиме: 3 ч лишения сна и 1 ч покоя непрерывно в течение 5 суток. Рекомбинантный белок GRP78 человека вводили интраназально за два дня до начала ОС и в течение 5 суток ОС. Клеточно-молекулярные изменения в голубом пятне при ОС и при введении GRP78 исследовались с помощью иммуногистохимии и вестерн-блоттинга. Показано, что хроническое ОС приводит к гибели 30% норадренергических нейронов в голубом пятне, которое было сопряжено с повышением уровней активированных каспаз-3, 9. Это свидетельствует о развитии апоптоза по митохондриальному пути. Признаков реактивного микроглиоза не обнаружено в модели хронического ОС у крыс. Мы продемонстрировали, что интраназально введенный GRP78 проникает и накапливается в норадренергических нейронах голубого пятна, это противодействует гибели нейронов по пути апоптоза. Полученные данные позволяют считать GRP78 потенциальным нейропротекторным средством для профилактики патологических последствий хронического недосыпания.

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