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

Chronic sleep restriction (SR) (sleep less than 6 hours perday) due to the workload and a decrease in sleep quality is an endemicdisease in modern society. Chronic sleep deprivation causes serious neuropsychiatricdisfunctions associated with irreversible neurodegenerative changesin the brain. The search for pharmacological agents that can reducethe risk of neurodegeneration as a result of chronic sleep lossis a pressing issue for biomedicine. Intranasal administration ofglucose-regulated 78 kDa heat shock protein (GRP78) has a neuroprotectiveeffect in a rat model of Parkinson’s disease (PD). The neuroprotectivepotential of intranasally administered GRP78 in chronic SR has notbeen previously studied. The aim of the present study was to findout whether preventive intranasal administration of GRP78 is ableto weaken and/or stop the process of neurodegeneration in the locuscoeruleus in the rat model of chronic SR. The study was conductedon 6 months old male Wistar rats. For SR, a validated method ofa oscillating platform was used: 3 hours of sleep deprivation and1 hour of rest continuously for 5 days. Recombinant human proteinGRP78 was administered intranasally two days before the start ofSR and during 5 days of SR. Cellular and molecular changes in thelocus coeruleus during SR and during the administration of GRP78were studied using immunohistochemistry and Western blotting. It wasshown that chronic SR leads to the degeneration of 31% of noradrenergicneurons in the locus coeruleus, that is associated with an increasein the levels of activated caspases-3 and -9. This indicates thedevelopment of apoptosis along the mitochondrial pathway. No signsof reactive microgliosis were found in the model of chronic SR inrats. We have demonstrated that intranasally administered GRP78 penetratesand accumulates in the neurons of the locus coeruleus, GRP78 counteractsthe death of neurons via the apoptosis pathway. The data obtainedallows to consider GRP78 as a potential neuroprotective agent forthe prevention of pathological consequences of chronic SR.