Abstract
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.
Highlights
Postoperative cognitive dysfunction (POCD), characterized by the progressive deterioration of intellectual/cognitive function, is a major complication following various surgical procedures [1]
Stress-induced GCs played a pivotal role in enhancing surgeryinduced neuroinflammatory processes by modulation of microglia functions
We explored whether stress and the consequent increase of circulating GCs modulated the immunophenotype of microglia, thereby sensitizing neuroinflammatory responses to the subsequent surgical challenge
Summary
Postoperative cognitive dysfunction (POCD), characterized by the progressive deterioration of intellectual/cognitive function, is a major complication following various surgical procedures [1]. Mounting evidence indicates that POCD is associated with surgery-induced neuroinflammatory processes, which may influence neuronal functioning either directly or through modulation of intraneuronal pathways, such as brain derived neurotrophic factor (BDNF) mediated pathway [2, 3]. Acute and chronic stress sensitized or primed neuroinflammatory responses to both peripheral and central immunologic challenges [5, 6]. Chronic unpredictable stress (CUS) potentiated LPS-induced pro-inflammatory mediators (e.g., IL-1β, inducible nitric oxide synthase, and TNF-α) in frontal cortex and hippocampus of rats [7]. Treatment with exogenous glucocorticoids (GCs) is sufficient to replicate the phenomenon of stress-induced priming of neuroinflammatory responses to peripheral immune challenges [8]. Pretreatment with glucocorticoid receptors (GR) antagonist RU486 blunted the potentiating effects of stress on nuclear factor kappa B (NF-κB) expression [8, 9]
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