Chronic unpredictable stress exacerbates surgery-induced sickness behavior and neuroinflammatory responses via glucocorticoids secretion in adult rats

Accumulated evidence indicates that stress sensitizes neuroinflammatory responses to a subsequent peripheral immune challenge. The present study investigated whether chronic unpredictable stress (CUS) aggravated surgery-induced sickness behavior and neuroinflammatory processes via glucocorticoids secretion in the adult brain.MethodsSprague-Dawley adult male rats (12–14 weeks old) were exposed to 14-day CUS and then subjected to partial hepatectomy 24 h after the last stress session. The rats were pretreated with an antagonist of the glucocorticoids (GCs) receptor RU486 (30 mg/kg, i.p.) 1 h prior to stress exposure. The behavioral changes were evaluated with open field test and elevated plus-maze test. The hippocampal cytokines interleukin (IL)-1β and IL-6 were measured on postoperative days 1, 3 and 7. Ionized calcium binding adaptor protein (Iba)-1, microglial M2 phenotype marker Arg1, brain derived neurotrophic factor (BDNF) and CD200 were also examined at each time point.ResultsCUS exacerbated surgery-induced sickness behavior. Exposure to CUS alone failed to alter the levels of pro-inflammatory cytokines in the brain. However, CUS exaggerated surgery-induced pro-inflammatory cytokines expression (e.g. IL-1β and IL-6) and upregulated the levels of Iba-1 on postoperative days 1 and 3. An additional significant decreased BDNF, CD200 and a lower level of Arg1 were also observed in the stressed rats following surgical procedure. Pretreatment with RU486 blunted the potentiating effects of CUS on surgery-induced sickness behavior and neuroinflammatory responses.ConclusionChronic unpredictable stress enhanced surgery-induced sickness behavior and neuroinflammatory responses. Stress-induced GCs played a pivotal role in enhancing surgery-induced neuroinflammatory processes by modulation of microglia functions.

越来越多的研究证据表明，应激可使神经炎症应答对后续外周免疫攻击产生增敏作用。本研究旨在探讨慢性不可预见性应激（chronic unpredictable stress, CUS）是否通过成年大脑的糖皮质激素分泌，加重手术诱导的疾病行为与神经炎症过程。
方法：选取12~14周龄的成年雄性斯普拉格-道利（Sprague-Dawley）大鼠，先接受14天的慢性不可预见性应激造模，于末次应激24小时后行部分肝切除术；应激暴露前1小时，大鼠预先接受糖皮质激素（glucocorticoids, GCs）受体拮抗剂RU486（30 mg/kg，腹腔注射）处理。采用旷场试验与高架十字迷宫试验评估大鼠的行为学变化，于术后第1、3、7天检测海马组织中细胞因子白细胞介素（interleukin, IL）-1β与IL-6的表达水平，同时在各时间点检测离子钙接头蛋白（ionized calcium binding adaptor protein, Iba-1）、小胶质细胞M2表型标志物精氨酸酶1（Arg1）、脑源性神经营养因子（brain derived neurotrophic factor, BDNF）以及CD200的表达水平。
结果：慢性不可预见性应激可加重手术诱导的疾病行为。仅接受慢性不可预见性应激处理并不会改变大脑内促炎细胞因子的水平，但可放大手术诱导的促炎细胞因子（如IL-1β与IL-6）表达，并于术后第1、3天上调Iba-1的表达水平；此外，应激大鼠在手术后还出现了BDNF、CD200水平显著下降，以及Arg1表达水平降低的现象。预先给予RU486处理可削弱慢性不可预见性应激对手术诱导的疾病行为与神经炎症应答的增强作用。
结论：慢性不可预见性应激可增强手术诱导的疾病行为与神经炎症应答。应激诱导产生的糖皮质激素通过调控小胶质细胞功能，在增强手术诱导的神经炎症过程中发挥关键作用。