Intranasal administration of GRP78 protein (HSPA5) counteracts the neurodegeneration in the locus coeruleus in a model of chronic sleep restriction in rats

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Abstract

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.

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About the authors

M. B. Pazi

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Author for correspondence.
Email: pazimariia@gmail.com
Russian Federation, St. Petersburg

I. V. Ekimova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: pazimariia@gmail.com
Russian Federation, St. Petersburg

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2. Fig. 1. Experimental scheme. Adaptation (7 days) – animal adaptation for 7 days. Chronic sleep restriction (SR) – chronic sleep restriction. Day 1–5 – 1–5 days of sleep restriction. IHC – immunohistochemistry, taking brain biomaterial for immunohistochemical analysis. WB – western-blot, taking brain biomaterial for western blotting analysis.

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3. Fig. 2. Exogenous GRP78 administered intranasally accumulates in locus coeruleus neurons in rats under control conditions. (a) Representative photomicrographs of the locus coeruleus. (b) Optical density of locus coeruleus neurons. Data are presented as mean ± SEM. Control – control animals treated with GRP78 vehicle, sterile pyrogen-free phosphate buffer pH 7.4 (PBS) (n = 3); Grp78 – animals treated with GRP78 intranasally (n = 3). Differences between groups according to Student's t-test and are indicated as *p ≤ 0.05 compared to the control group.

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4. Fig. 3. Intranasal administration of exogenous GRP78 prevents degeneration of noradrenergic neurons of the locus coeruleus in the chronic sleep restriction model. (a, c) – representative photomicrographs of the locus coeruleus, (b) – number of TH-positive neurons in the locus coeruleus, (d) – number of Nissl-stained neurons in the locus coeruleus. Data are presented as mean ± SEM. Control – control animals (n = 5), (Grp78) – administration of Grp78 under control conditions (n ​​= 3), Sleep restriction (SR) – sleep restriction for 5 days (n = 5), SR+Grp78 – administration of Grp78 in the chronic sleep restriction model (n = 5). Differences between groups according to one-way ANOVA followed by Tukey post-hoc are indicated as: *** p < 0.001 compared to the control group; ## p < 0.01, ### p < 0.001 compared with sleep restriction effect.

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5. Fig. 4. Intranasal administration of exogenous GRP78 prevents apoptosis in the chronic sleep restriction model. (a) – cleaved caspase-9 content, (b) – cleaved caspase-3 content, (c) – representative immunoblots. Data are presented as mean ± SEM. Control – control animals (n = 5), SR – sleep restriction, sleep restriction for 5 days (n = 5), SR+Grp78 – administration of Grp78 in the chronic sleep restriction model (n = 5). Differences between groups according to one-way ANOVA followed by Tukey post-hoc are indicated as: ** p < 0.01 compared with the control group; # p < 0.05 compared with the effect of sleep restriction.

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