Intranasal Administration of GRP78 Protein (HSPA5) Counteracts the Neurodegeneration in the Locus Coeruleus in a Model of Chronic Sleep Restriction in Rats

Abstract

Chronic sleep restriction (SR) (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 disfunctions 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 a pressing 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 (PD). The neuroprotective potential of intranasally administered GRP78 in chronic SR has not been previously studied. The aim of the present study was 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 rat model of chronic SR. The study was conducted on 6 months old male Wistar rats. For SR, a validated method of a oscillating platform was used: 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 31% of noradrenergic neurons in the locus coeruleus, that is 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 via the apoptosis pathway. The data obtained allows to consider GRP78 as a potential neuroprotective agent for the prevention of pathological consequences of chronic SR.