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

Pub Date : 2024-08-29 DOI:10.1134/s002209302404029x

M. B. Pazi, I. V. Ekimova

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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.

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鼻内给药 GRP78 蛋白 (HSPA5) 可抑制大鼠慢性睡眠限制模型中灶叶的神经退行性变

摘要由于工作量大和睡眠质量下降导致的慢性睡眠限制（SR）（每天睡眠不足 6 小时）是现代社会的一种地方病。长期睡眠不足会导致严重的神经精神功能障碍，并伴有不可逆转的脑神经退行性病变。寻找能够降低因长期睡眠不足而导致神经变性风险的药物是生物医学的一个紧迫问题。葡萄糖调节 78 kDa 热休克蛋白（GRP78）的鼻内给药对帕金森病（PD）大鼠模型具有神经保护作用。关于鼻内注射 GRP78 在慢性 SR 中的神经保护潜力，此前尚未进行过研究。本研究的目的是了解预防性鼻内注射 GRP78 是否能够削弱和/或阻止慢性 SR 大鼠模型中神经节的神经变性过程。研究对象是 6 个月大的雄性 Wistar 大鼠。对于 SR，采用了一种经过验证的振荡平台方法：连续 5 天剥夺睡眠 3 小时，休息 1 小时。在 SR 开始前两天和 SR 的 5 天内，经鼻给药重组人蛋白 GRP78。使用免疫组化和Western印迹法研究了SR期间和服用GRP78期间小脑的细胞和分子变化。结果表明，慢性肾上腺素水平降低会导致垂体部位31%的去甲肾上腺素能神经元变性，这与活化的caspases-3和-9水平升高有关。在大鼠慢性 SR 模型中未发现反应性小胶质细胞增多的迹象。我们已经证明，鼻内给药的 GRP78 可渗透并蓄积在脑室神经元中，GRP78 可抵消神经元通过凋亡途径的死亡。这些数据表明，GRP78是一种潜在的神经保护剂，可用于预防慢性SR的病理后果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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