Pathogenesis Of Postoperative Cognitive Dysfunction Research Articles

Association between BDNF rs6265 polymorphisms and postoperative cognitive dysfunction in Chinese Han Population.

IntroductionBrain‐derived neurotrophic factor (BDNF) plays a critical role in the pathogenesis of postoperative cognitive dysfunction (POCD). In present study, we aimed to assess the possible association between POCD and BDNF rs6265 polymorphisms.Methods124 patients aged 60 years or older scheduled for elective surgery under general anesthesia and 25 age‐ and gender‐matched healthy volunteers were recruited. POCD was identified using a neuropsychological test battery administered preoperatively, 7 days, and 3 months after surgery. Genotyping of rs6265 was performed using polymerase chain reaction amplification and restriction fragment length polymorphism analysis.Results99 patients and 25 healthy controls were finally enrolled in the analysis. 29(29.3%) and 18(18.2%) of 99 patients had POCD at 7 days and 3 months after surgery, respectively. The patients carrying a G allele at the rs6265 locus showed a lower risk for POCD than an A allele carriers on postoperative 7 days, but not 3 months after surgery (OR = 0.67; 95% CI: 0.47–0.96; p = .017; OR = 0.69; 95% CI: 0.42–1.13; p = .14, respectively). The risk of POCD at 7 days following surgery was significantly lower in additive model (OR = 0.41; 95% CI: 0.2–0.84; p = .015) and dominant model (OR = 0.35; 95% CI: 0.13–0.96; p = .042).ConclusionWe tentatively demonstrate that BDNF rs6265 polymorphisms might be associated with occurrence of POCD at 7 days after surgery and the A > G mutant at the rs6265 locus be likely a protective factor for early POCD in Chinese Han population.

Silencing SP1 Alleviated Sevoflurane-Induced POCD Development via Cholinergic Anti-inflammatory Pathway.

Postoperative cognitive dysfunction (POCD) is a common complication induced by anesthesia or surgery, which affects the concentration, cognition and memory of patients. Sevoflurane, a clinical anesthetic, could stimulate neuro-inflammation and lead to POCD. Recent studies found that specificity protein 1 (SP1) participates in the development of neurological diseases. Our study aims to elucidate the role of SP1 in sevoflurane-induced POCD pathogenesis. We anesthetized Sprague-Dawley rats and treated the primary hippocampal neurons with sevoflurane to construct the in vivo and in vitro POCD models. Besides, the expression and regulatory mechanism of SP1 in the pathogenesis of POCD were explored. According to the results, sevoflurane anesthesia impaired the cognitive functions of rat, significantly elevated SP1 expression and inactivated the cholinergic anti-inflammatory pathway (CAP) both in vivo and in vitro. Moreover, the sevoflurane-treated rats and neurons also exhibited obvious inflammatory responses and enhanced apoptosis. Loss-of-function assay indicated that SP1 knockdown rescued the deactivation of CAP and alleviated the sevoflurane-induced neuro-inflammation and apoptosis in rat hippocampus. Generally, our study documented that the sevoflurane-induced SP1 up-regulation affected the activation of CAP, leading to the aggravated neuro-inflammation and apoptosis. This may provide a novel sight for POCD therapy.

Could intraoperative magnesium sulphate protect against postoperative cognitive dysfunction?

Although there is much concern about the pathogenesis of postoperative cognitive dysfunction (POCD); no effective prevention strategies are currently described. The aim of this work was to study whether intraoperative magnesium sulphate could have a protective effect against developing POCD and to study its impact on serum level of S100B, a marker of neuronal degeneration. This is a prospective randomized controlled trial carried out on 80 participants undergoing elective laparoscopic cholecystectomy, 40 participants received conventional general anesthesia (conventional anesthesia group) and 40 participants received conventional general anesthesia with extra administration of intraoperative magnesium sulphate (Mg sulphate group). Cognitive assessment for both groups was done preoperatively and 1 week postoperatively using Paired Associate Learning test (PALT) and Benton Visual Retention Test (BVRT). Quantitative determination of serum S100B was done for both groups preoperatively and one week postoperatively by using an enzyme- linked immunoabsorbent assay technique. Postoperative PALT and BVRT were significantly lower than preoperative PALT and BVRT in the conventional anesthesia group (P value =0.043, P value =0.015 respectively), but not in the Mg sulphate group (P value =0.134, P value =0.151 respectively). Postoperative S100B was significantly higher than preoperative S100B in the conventional anesthesia group (P value =0.006), but not in the Mg sulphate group (P value =0.293). Administration of intravenous infusion of magnesium sulphate during conventional general anesthesia can protect against POCD and attenuate the post operative elevation of serum S100B.

Research progress of the role of postoperative pain in the development of postoperative cognitive dysfunction in geriatric patients

Previous studies have shown that postoperative cognitive dysfunction (POCD) is related to multiple factors including age, postoperative trauma, inflammation, postoperative pain, and anesthesia, among which postoperative pain is thought to play an important role in the development of POCD. This review summarizes the recent findings in the study of the role of postoperative pain in the pathogenesis of POCD in light of nerve injuries, neural remodeling and stress, and the progress in the prevention and treatment of POCD in elderly patients. It is of vital important to assess the postoperative pain and formulate adequate analgesic regimens for effective prevention and management of POCD to protect the brain functions of elderly patients.

Identification of the Potential Key Long Non-coding RNAs in Aged Mice With Postoperative Cognitive Dysfunction.

Postoperative cognitive dysfunction (POCD) is a significant complication of surgery, particularly in elderly patients. Emerging researches showed that long non-coding RNA (lncRNA) may play a vital role in the pathogenesis of POCD. Here we aimed to identify potential key lncRNAs involved in the development of POCD. LncRNA and mRNA expression profiles in hippocampal tissues from POCD and control mice were analyzed by microarray assay. Gene ontology (GO) and KEGG pathway enrichment analyses were conducted to probe the functions of dysregulated genes. Then, important factors of the mainly affected biological processes were measured in the hippocampus. Correlated coding–non-coding co-expression (CNC) networks were constructed. Finally, the potential key pairs of lncRNA and target mRNA implicated in POCD were probed. Our data showed that 868 differentially expressed lncRNAs and 690 differentially expressed mRNAs were identified in total. GO and KEGG analyses indicated that the differentially expressed genes were mainly associated with inflammatory and apoptotic signaling pathways. Surgery-induced inflammatory cytokines and apoptosis were significantly increased in hippocampal tissues of aged mice. In CNC network analysis, we found that LncRNA uc009qbj.1 was positively correlated with apoptosis-associated gene Vrk2 level. LncRNA ENSMUST00000174338 correlated positively with expression of the inflammation and apoptosis-associated gene Smad7. LncRNA NONMMUT00000123687 mediated gene expression by binding the inflammation-regulated transcription factor Meis2. Our results suggested that these potential key lncRNAs and mRNAs may play a crucial role in the development of POCD through mediating neuronal inflammation or apoptosis.

Isoflurane-Induced Postoperative Neurovascular and Cognitive Dysfunction Is Associated with VEGF Overexpression in Aged Rats.

Postoperative cognitive dysfunction (POCD) is a common complication in older adults; however, its aetiology remains unclear. Although vascular endothelial growth factor (VEGF) is associated with blood-brain barrier (BBB) disorders and neurological disease, its role in POCD is unknown. Here, we investigated the effect of brain VEGF inhibition on isoflurane-induced cognitive impairment in an aged rat model of POCD. VEGF protein expression was increased in the hippocampus after isoflurane exposure, suggesting that inhalation anaesthesia induces hippocampal VEGF protein overexpression in aged rats. Pretreatment with 2mg/kg RB-222, an anti-VEGF neutralizing antibody, may partially abolish the degradation of occludin protein in cerebral capillaries, thereby maintaining the ultrastructural and functional integrity of the hippocampal BBB. Inhibition of VEGF also significantly attenuated the isoflurane-induced cognitive deficits in the Morris water maze task. Together, our findings show, for the first time, that elevated expression of brain VEGF after isoflurane exposure contributes to POCD in aged rats. Therefore, therapeutic strategies involving VEGF should take into consideration its role in the pathogenesis of POCD.

Research progress of biomarkers of postoperative cognitive dysfunction

Elderly patients are more vulnerable to postoperative cognitive dysfunction (POCD) which clinical features include cognitive deterioration, attention disorder and reduced consciousness of the environment. It can lead to more postoperative complications, longer hospital stays, lower quality of life, increased medical costs, and even increased mortality in elderly patients. In recent years, people are trying to find the ideal biological markers of POCD in order to reduce the occurrence of POCD. This review summarized the various known biomarkers of POCD and integrate possible factors for future studies so as to provide evidence for prevention, diagnosis and treatment of POCD. In this review, preoperative predictive biomarkers and postoperative diagnostic biomarkers were classified to explore the biomarkers of POCD. The pathogenesis of POCD is complex and diverse. Further studies are needed to identify predictive and diagnostic biomarkers and to provide effective preventive and diagnostic measures for the clinic. Key words: Postoperative cognitive dysfunction; Biomarkers; Predictive biomarkers; Diagnostic biomarkers

Anesthesia and surgery induce cognitive dysfunction in elderly male mice: the role of gut microbiota.

It is well known that the incidence of postoperative cognitive dysfunction (POCD) is high in elderly patients. The pathogenesis and therapeutic mechanisms of POCD, however, have not yet been completely elucidated. The effects of gut microbiota, particularly in terms of regulating brain function, have gradually attracted increasing attention. In this study, we investigated the potential role of gut microbiota in POCD in aged male mice and attempted to determine whether alterations in gut microbiota would be helpful in the diagnosis of POCD. POCD and non-POCD mice were classified by hierarchical cluster analysis of behavioral results. Additionally, α- and β-diversity of gut microbiota showed a differential profile between the groups. In total, 24 gut bacteria were significantly altered in POCD mice compared with those in non-POCD mice, in which 13 gut bacteria were significantly correlated with escape latency in the Morris water maze test (MWMT). Remarkably, receiver operating characteristic curves revealed that the Dehalobacteriaceae family and Dehalobacterium genus are potentially important bacteria for the diagnosis of POCD. These findings indicate that alterations in the composition of gut microbiota are probably involved in the pathogenesis of POCD in aged mice. Novel therapeutic strategies regulating specific gut bacteria may be helpful for the prevention and treatment of POCD.

Sevoflurane exposure has minimal effect on cognitive function and does not alter microglial activation in adult monkeys

Postoperative Cognitive Dysfunction (POCD) is a complication that has been observed in a subset of adult and elderly individuals after general anesthesia and surgery. Although the pathogenesis of POCD is largely unknown, a growing body of preclinical research suggests that POCD may be caused by general anesthesia. A significant amount of research has examined the effects of general anesthesia on neurocognitive function in rodents, yet no studies have assessed the adverse effects of general anesthesia on brain function in adult nonhuman primates. Thus, this study sought to determine the effects of an extended exposure to sevoflurane anesthesia on cognitive function and neural inflammation in adult rhesus macaques. Five adult rhesus macaques (16–17 years of age) were exposed to sevoflurane anesthesia for 8 h and, and micro-positron emission tomography (PET)/computed tomography (CT) imaging and a battery of operant tasks were used to assess the effects of anesthesia exposure on 18F-labeled fluoroethoxybenzyl-N-(4-phenoxypyridin-3-yl) acetamide ([18F]-FEPPA) uptake, a biomarker of microglia activation, and aspects of complex cognitive function. Exposure to sevoflurane anesthesia for 8 h did not increase [18F]-FEPPA uptake in the adult monkey brain. Sevoflurane anesthesia significantly decreased accuracy (mean difference = 22.79) on a learning acquisition task 6 days after exposure [t(3) = 6.92, p = 0.006], but this effect did not persist when measured 1 week and 2 weeks after additional exposures. Further, sevoflurane anesthesia had no impact on performance in 4 additional cognitive tasks. These data suggest that exposure to anesthesia alone may not be sufficient to cause persistent POCD in adult populations.

Inhibiting RIPK1 Limits Neuroinflammation and Alleviates Postoperative Cognitive Impairments in D-Galactose-Induced Aged Mice.

Neuroinflammation plays a critical role in the pathogenesis of postoperative cognitive dysfunction (POCD) of the elderly patients. Receptor-interacting protein kinase1 (RIPK1) is a key molecular switch modulating inflammation, apoptosis and necroptosis. Here, we investigated whether inhibiting RIPK1 by necrostatin-1 (Nec-1) could limit neuroinflammation and attenuate POCD in D-Galactose (D-Gal)-induced aged mice. The mice were subjected to anesthesia and partial hepatectomy, and necrostatin-1 was administered intraperitoneally 1 h prior to anesthesia and surgery. Cognitive function and movement were tested 24 h after surgery by open field, Barnes maze and puzzle box. The hippocampal tissues were collected to detect the following: neuroinflammation (Iba-1, IL-1α, IL-1β, TNF-α), Necroptosis (Propidium Iodide (PI) labeling, RIPK1, nuclear transcription factor kappa B (NF-κB) and neuroplasticity (doublecortin (DCX), NR2B, GluA1, GluA2). We found that anesthesia and surgery induced a significant deficit in spatial memory acquisition and impairment of executive function and memory to simple task in D-Galactose-induced aged mice. Inhibiting RIPK1 by necrostatin-1 strikingly mitigated cognitive impairment and alleviated postoperative amplified neuroinflammation, necroptosis and GluA1 loss in hippocampus. These suggest that targeting RIPK1 by necrostatin-1 may serve as a promising therapeutics for prevention of POCD in elderly patients.

Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment

BackgroundElderly patients are more likely to suffer from postoperative cognitive dysfunction (POCD) after surgery and anesthesia. Except for declined organ function, the particular pathogenesis of POCD in elderly patients remains unknown. This study is carried out to determine the critical role of the NOD-like receptor protein 3 (NLRP3)-caspase-1 pathway in isoflurane-induced cognitive impairment.MethodsYoung (6–8 months old) and aged (14 months old) healthy male C57BL/6 mice were exposed to 1.5% isoflurane for 2 h. Some mice received intraperitoneal injection of Ac-YVAD-cmk (8 mg/kg), a specific inhibitor of caspase-1, 30 min before the isoflurane exposure. Morris water maze test was carried out 1 week after the isoflurane anesthesia. Brain tissues were harvested 24 h after the isoflurane anesthesia. Western blotting was carried out to detect the expression of NLRP3, interleukin (IL)-1β, and IL-18 in the hippocampus. Mouse microglial cell line BV-2 and primary microglial cultures were primed by lipopolysaccharide for 30 min before being exposed to isoflurane. NLRP3 was downregulated by RNA interference.ResultsCompared to young mice, aged mice had an increased expression of NLRP3 in the hippocampus. Isoflurane induced cognitive impairment and hippocampal inflammation in aged mice but not in young mice. These effects were attenuated by Ac-YVAD-cmk pretreatment (P < 0.05). Isoflurane activated NLRP3-caspase-1 pathway and increased the secretion of IL-18 and IL-1β in cells pretreated with lipopolysaccharide but not in cells without pretreatment. Downregulation of NLRP3 attenuated the activation of NLRP3 inflammasome by isoflurane.ConclusionsNLRP3 priming status in aged mouse brain may be involved in isoflurane-induced hippocampal inflammation and cognitive impairment.

Activation of AMP-activated protein kinase (AMPK) aggravated postoperative cognitive dysfunction and pathogenesis in aged rats

The upstream signal molecule modulating neuro-inflammation and synaptic changes during the pathogenesis of postoperative cognitive dysfunction (POCD) is still elusive. Here, we examined the effects and mechanisms of energy sensor AMP-activated protein kinase (AMPK) in the pathogenesis of POCD. Our data showed that surgery significantly increased the expression of p-AMPK in aged rats (p < 0.05), but not in adult rats (p > 0.05). Moreover, inhibiting AMPK activation via compound C during operation significantly improved surgery-induced impairment of the learning and memory of aged rats in water maze (p < 0.05). Further mechanism studies showed that corresponding to the impairment of learning and memory after surgery, surgery significantly increased the activation of microglia, decreased the expressions of NR2B and p-NR2B, and increased the expressions of Tau and p-Tau, which also were obviously restored by inhibiting AMPK during operation. In contrast, Inhibiting AMPK activation during operation didn’t change ATP level in the hippocampus of aged rats after surgery. These data suggest that surgery induced activation of AMPK in hippocampus in an age-dependent manner. AMPK plays important roles in POCD of aged rats via multiple mechanisms, and is a possible molecular target for the prevention and treatment of POCD.

Postoperative cognitive dysfunction: A case report and literature review

Background: Postoperative cognitive dysfunction (POCD) is loss of cognition especially in memory and executive function that can extend from a few days to a few weeks after surgery. It is more common in older adult patients. We present a case featuring a typical progression of POCD along with its associated preoperative risk factors.Case report: A 65-year-old male patient with an extensive past medical history including generalized anxiety disorder, hypertension and hyperlipidemia initially presented to the emergency department for chest pain. Coronary artery bypass graft (CABG) was performed under general anesthesia with Propofol, Fentanyl, Rocuronium and Midazolam. The patient tolerated the procedure well. After the procedure, his stay was complicated by delirium and altered mental status. All reversible causes were investigated and eliminated as likely causes. Later, the patient was sent home after a prolonged hospital stay. Following discharge, he had multiple admissions to the hospital for altered mental status, and his mental status has not reached baseline again. Family has been confident that the patient’s psychological and cognitive symptoms began following the CABG.Conclusion: We present this case to highlight the heightened incidence of postoperative cognitive decline in patients over sixty undergoing major surgery. We also present a comprehensive review of the current literature on the risk factors, clinical manifestations, and pathogenesis of POCD.

Differentially expressed lncRNAs and miRNAs with associated ceRNA networks in aged mice with postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication observed in elderly patients. Using microarray analyses, we comprehensively compared long non-coding RNA (lncRNA), messenger RNA (mRNA), and microRNA (miRNA) expression profiles in hippocampal tissues from a mouse model of POCD and control mice. A total of 175 lncRNAs, 117 mRNAs, and 26 miRNAs were differentially expressed between POCD and control mice. Gene ontology (GO) and KEGG pathway enrichment analyses were performed to explore the principal functions of dysregulated genes. Correlated coding-noncoding co-expression (CNC) and competing endogenous RNA (ceRNA) expression networks were constructed using bioinformatics methods. lncRNA NONMMUT000708 correlated positively with expression of the inflammation-related gene Hif3a. lncRNAs NONMMUT043249 and NONMMUT028705 mediated gene expression by binding the transcription factor cAMP response element-binding protein (CREB). The constructed ceRNA network suggested lncRNA NONMMUT055714 binds competitively with miR-7684-5p, increasing expression of its target gene, Sorl1. Finally, eight dysregulated lncRNAs, four miRNAs, and ten mRNAs were confirmed via quantitative real-time polymerase chain reaction (PCR) in 10 POCD-healthy mouse paired samples. These results suggest that lncRNAs and miRNAs are involved in POCD pathogenesis and progression. Our ceRNA network will improve understanding of lncRNA-mediated ceRNA regulatory mechanisms operating during the pathogenesis of POCD.

Circulating TNF-α levels increased and correlated negatively with IGF-I in postoperative cognitive dysfunction.

Signaling pathways of tumor necrosis factor-α (TNF-α) and insulin-like growth factor-I (IGF-I) are found to be functionally interrelated in some experimental studies. IGF-I may be involved in the pathogenesis of postoperative cognitive dysfunction (POCD). In order to investigate the possible interaction of TNF-α and IGF-I in POCD, the plasma levels of IGF-I and TNF-α were determined in 44 patients under general anesthesia. As compared with non-POCD patients, POCD patients showed increased TNF-α and decreased IGF-I levels in plasma, as well as a significant negative correlation between TNF-α and IGF-I values. The present results suggest that interaction of increased TNF-α levels and decreased IGF-1 levels might lead to a vicious circle, which may contribute to POCD.

Electroacupuncture Alleviates Postoperative Cognitive Dysfunction in Aged Rats by Inhibiting Hippocampal Neuroinflammation Activated via Microglia/TLRs Pathway.

Neuroinflammation has been suggested to be involved in the pathogenesis of postoperative cognitive dysfunction (POCD). Electroacupuncture (EA) is an irreplaceable method in traditional Chinese medicine that is used for treating neurodegenerative diseases in clinical and experimental studies. The aim of this study was to examine whether EA improves cognitive dysfunction caused by surgery and to investigate the pathological mechanism of TLR2 and TLR4 in the hippocampus of aged rats. A rat model of POCD was established and treated with EA or minocycline. Both EA- and minocycline-treated rats performed significantly better than untreated operated rats in spatial memory tasks of the Morris water maze (MWM) test, spending comparatively greater amounts of time in the target zone during the probe test. Additionally, decreased levels of proinflammatory cytokines (IL-1β, IL-6, TNF-α, and HMGB1) and decreased TLR2 and TLR4 protein expression in the hippocampus of EA- and minocycline-treated rats were detected. Our data suggested that EA treatment alleviated the cognition performance deficit and neuroinflammation in aged rats following surgery, which may be mediated by inhibiting the expression of hippocampal neuroinflammatory cytokines through the microglia/TLR2/4 pathway.

Berberine alleviates postoperative cognitive dysfunction by suppressing neuroinflammation in aged mice

Postoperative cognitive dysfunction (POCD) is a significant cause of morbidity after surgery, especially for the elderly. Accumulating evidence has demonstrated that neuroinflammation plays a key role in the pathogenesis of POCD. Thus, we hypothesized that berberine, an isoquinoline alkaloid with anti-inflammatory effects, could improve surgery-induced cognitive impairment. Twenty-month-old male C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. For the interventional studies, mice received berberine (10mg/kg) or vehicle intraperitoneally. For the in vitro study, we examined the effects of berberine on lipopolysaccharide (LPS)-induced inflammatory mediators by cultured BV2 cells. Behavioral tests, expressions of IBA1, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 were performed at the indicated time points. In the present study, we showed that surgery impaired the contextual fear memory, as evidenced by the significantly decreased freezing time to the context. This behavioral change coincided with marked increases in IBA1, TNF-α, IL-1β, and IL-6 in the prefrontal cortex and hippocampus only at 24h but not 7 d after surgery. In BV2 cells, LPS induced significantly increased TNF-α and IL-1β expressions. Notably, berberine treatment rescued surgery-induced cognitive impairment and inhibited the release of IBA1, IL-1β, and IL-6 in the hippocampus. In line with the in vivo study, berberine treatment suppressed LPS-stimulated production of TNF-α and IL-1β in BV2 cells. In conclusion, our study suggests that berberine could alleviate POCD by suppressing neuroinflammation in aged mice.

Attenuation of neuroinflammation by dexmedetomidine is associated with activation of a cholinergic anti-inflammatory pathway in a rat tibial fracture model

Sustained neuroinflammation contributes to the pathogenesis of postoperative cognitive dysfunction. Dexmedetomidine, a selective α-2 adrenergic receptor agonist, exhibits a protective role in the brain. This study investigated whether dexmedetomidine pretreatment attenuates neuroinflammation induced by tibial fracture in rats, as well as the mechanism by which dexmedetomidine provides its neuroprotection. In our study, we observed that tibial fracture significantly increased the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and the expression of nuclear factor-kappa B (NF-κB) in the hippocampus. Overexpression of microglial (CD11b) and astrocytic (GFAP) responses to injury were observed in the hippocampus. Dexmedetomidine pretreatment significantly suppressed the inflammatory responses, as evidenced by lower TNF-α and IL-1β levels, significantly inhibited NF-κB activity, and alleviated overexpression of microglia and astrocytes in the hippocampus. However, pretreatment with dexmedetomidine failed to attenuate cytokine responses and activity of NF-κB, CD11b and GFAP after vagotomy or treatment with methyllycaconitine, an α-7 nicotinic acetylcholine receptor (α7nAChR) antagonist. These results suggest that pretreatment with dexmedetomidine may attenuate neuroinflammation caused by tibial fracture in rats through vagal-dependent and α7nAChR-dependent mechanisms.

Impact of Preoperative Environmental Enrichment on Prevention of Development of Cognitive Impairment Following Abdominal Surgery in a Rat Model

Background:Sustained neuroinflammation may contribute to the pathogenesis of postoperative cognitive dysfunction (POCD). Here, the authors evaluated the preventive effect of preoperative environmental enrichment (PEE) on the development of neuroinflammation and concomitant POCD in a rat abdominal su

Impact of Preoperative Environmental Enrichment on Prevention of Development of Cognitive Impairment following Abdominal Surgery in a Rat Model.

Sustained neuroinflammation may contribute to the pathogenesis of postoperative cognitive dysfunction (POCD). Here, the authors evaluated the preventive effect of preoperative environmental enrichment (PEE) on the development of neuroinflammation and concomitant POCD in a rat abdominal surgery model. Young and aged rats were assigned to one of four groups using a 2 × 2 experimental design: PEE versus sedentary condition for 14 days, by abdominal surgery versus anesthesia alone (n = 8 in each group). After a 7-day postsurgical recovery period, cognitive function was assessed using a novel object recognition test, followed by measurement of hippocampal levels of proinflammatory cytokines. Under identical conditions, microglia were isolated from the hippocampus for assessment of cytokine response to lipopolysaccharide. In the sedentary group, aged, but not young, rats receiving surgery showed memory deficits (novel object preference during testing phase of 54.6 ± 7.8% vs. 76.9 ± 11.3% in nonsurgery group, P < 0.05) and increased hippocampal levels of cytokines compared with nonsurgical rats. PEE had no effects on novel object preference in nonsurgery animals (78.6 ± 10.7%), whereas it attenuated surgery-induced impairment of novel object preference (70.9 ± 15.0%, P < 0.05 vs. sedentary/surgery group) as well as increase of cytokine levels in hippocampus. Furthermore, upon ex vivo stimulation with lipopolysaccharide, cytokines release from hippocampal microglia isolated from aged rats before intervention was significantly higher in comparison with young rats. PEE resulted in reduction of these age-related microglial phenotypic changes. PEE could prevent the development of neuroinflammation and related POCD in aged rats by reversion of a proinflammatory phenotype of hippocampal microglia.