Gut microbiota dysbiosis contributes to depression-like behaviors via hippocampal NLRP3-mediated neuroinflammation in a postpartum depression mouse model.

Postpartum depression (PPD) is a severe mental disorder that affects approximately 10---20% of women after childbirth. The precise mechanism underlying PPD pathogenesis remains elusive, thus limiting the development of therapeutics. Gut microbiota dysbiosis is considered to contribute to major depressive disorder. However, the associations between gut microbiota and PPD remain unanswered. Here, we established a mouse PPD model by sudden ovarian steroid withdrawal after hormone-simulated pseudopregnancy-human (HSP-H) in ovariectomy (OVX) mouse. Ovarian hormone withdrawal induced depression-like and anxiety-like behaviors and an altered gut microbiota composition. Fecal microbiota transplantation (FMT) from PPD mice to antibiotic cocktail-treated mice induced depression-like and anxiety-like behaviors and neuropathological changes in the hippocampus of the recipient mice. FMT from healthy mice to PPD mice attenuated the depression-like and anxiety-like behaviors as well as the inflammation mediated by the NOD-like receptor protein (NLRP)-3/caspase-1 signaling pathway both in the gut and the hippocampus, increased fecal short-chain fatty acids (SCFAs) levels and alleviated gut dysbiosis with increased SCFA-producing bacteria and reduced Akkermansia in the PPD mice. Also, downregulation of NLRP3 in the hippocampus mitigated depression-like behaviors in PPD mice and overexpression of NLRP3 in the hippocampal dentate gyrus induced depression-like behaviors in naïve female mice. Intriguingly, FMT from healthy mice failed to alleviate depression-like behaviors in PPD mice with NLRP3 overexpression in the hippocampus. Our results highlighted the NLRP3 inflammasome as a key component within the microbiota-gut-brain axis, suggesting that targeting the gut microbiota may be a therapeutic strategy for PPD.

Familiar observers attenuate surgery-induced neuroinflammation and cognitive dysfunction in mice.

AIMS: Postoperative cognitive dysfunction (POCD) is a common complication associated with poor outcome. Our previous study has shown that living with familiar observers in the same cage reduces anxiety of mice with surgery. Anxiety can impair learning and memory. Thus, this study was designed to determine whether living with familiar observers attenuated the dysfunction of learning and memory of mice with surgery. METHODS: Six- to eight-week-old CD-1 male mice or 18-month-old C57BL/6 male mice had left carotid artery exposure under isoflurane anesthesia. They lived with non-surgery male mice at 2 (number of surgery mice) to 3 (number of non-surgery mice) ratio or with other surgery mice. Mice were subjected to light and dark box test 3 days after surgery to measure their anxiety levels and novel object recognition and fear conditioning tests from 5 days after surgery to measure their learning and memory. Blood and brain were harvested for biochemical analysis. RESULTS: Living with familiar observers that lived with surgery mice for at least 2 weeks before the surgery and then after surgery reduced the anxiety and dysfunction of learning and memory in young adult male mice. Living with unfamiliar observers that lived with surgery mice after the surgery but not before the surgery did not have those effects on the mice with surgery. Living with familiar observers attenuated learning and memory dysfunction after surgery also in old male mice. Living with familiar observers attenuated inflammatory response in the blood and brain and the activation of the lateral habenula (LHb)-ventral tegmental area (VTA) neural circuitry, which has been shown to be important for POCD. Wound infiltration with bupivacaine attenuated the activation of LHb-VTA. CONCLUSION: These results suggest that living with familiar observers attenuates POCD and neuroinflammation, possibly via inhibiting the activation of the LHb-VTA neural circuitry.

Impact of functional status on 30-day resource utilization and organ system complications following index bariatric surgery: a cohort study.

BACKGROUND: Bariatric surgical procedures carry an appreciable risk profile despite their elective nature. Identified risk factors for procedural complications are often limited to medical comorbidities. This study assesses the impact of functional status on resource utilization and organ system complications following bariatric surgery. MATERIALS AND METHODS: This retrospective cohort study analyzed patients undergoing elective, index bariatric surgery from American College of Surgeons National Surgical Quality Improvement Program participating hospitals from 2015 to 2019 ( n =65 627). The primary independent variable was functional status. The primary outcome was unplanned resource utilization. Secondary outcomes included composite organ system complications and mortality. The impact of functional status was first investigated with univariate analyses. Survival and multivariate analyses were then performed on select complications with clinically and statistically significant incidence in the dependent cohort. RESULTS: On univariate analysis, dependent functional status was associated with unplanned resource utilization [12.1% (27/223) vs. 4.1% (2661/65 404)]; relative risk, 2.98 (95% CI, 2.09-4.25); P < 0.001] and haematologic/infectious complications [6.7% (15/223) vs. 2.4% (1540/65 404); relative risk, 2.86 (95% CI, 1.75-4.67); P < 0.001]. Survival analysis demonstrated a significantly shorter time to both events in patients with dependent functional status ( P < 0.001). On multivariate analysis, dependent functional status was an independent predictor of unplanned resource utilization[adjusted odds ratio 2.17 (95% CI, 1.27-3.50); P = 0.003; model c-statistic, 0.572]) and haematologic/infectious complications [adjusted odds ratio, 2.20 ([95% CI, 1.14-3.86); P = 0.011; model c-statistic, 0.579]. CONCLUSION: Patients with dependent functional status are at an elevated risk of unplanned resource utilization and haematologic/infectious complications following index bariatric surgery. The increased risk cannot be explained by medical comorbidities alone.

Anatomical Substrates of Rapid Eye Movement Sleep Rebound in a Rodent Model of Post-sevoflurane Sleep Disruption.

BACKGROUND: Previous research suggests that sevoflurane anesthesia may prevent the brain from accessing rapid eye movement (REM) sleep. If true, then patterns of neural activity observed in REM-on and REM-off neuronal populations during recovery from sevoflurane should resemble those seen after REM sleep deprivation. In this study, the authors hypothesized that, relative to controls, animals exposed to sevoflurane present with a distinct expression pattern of c-Fos, a marker of neuronal activation, in a cluster of nuclei classically associated with REM sleep, and that such expression in sevoflurane-exposed and REM sleep-deprived animals is largely similar. METHODS: Adult rats and Targeted Recombination in Active Populations mice were implanted with electroencephalographic electrodes for sleep-wake recording and randomized to sevoflurane, REM deprivation, or control conditions. Conventional c-Fos immunohistochemistry and genetically tagged c-Fos labeling were used to quantify activated neurons in a group of REM-associated nuclei in the midbrain and basal forebrain. RESULTS: REM sleep duration increased during recovery from sevoflurane anesthesia relative to controls (157.0 ± 24.8 min vs. 124.2 ± 27.8 min; P = 0.003) and temporally correlated with increased c-Fos expression in the sublaterodorsal nucleus, a region active during REM sleep (176.0 ± 36.6 cells vs. 58.8 ± 8.7; P = 0.014), and decreased c-Fos expression in the ventrolateral periaqueductal gray, a region that is inactive during REM sleep (34.8 ± 5.3 cells vs. 136.2 ± 19.6; P = 0.001). Fos changes similar to those seen in sevoflurane-exposed mice were observed in REM-deprived animals relative to controls (sublaterodorsal nucleus: 85.0 ± 15.5 cells vs. 23.0 ± 1.2, P = 0.004; ventrolateral periaqueductal gray: 652.8 ± 71.7 cells vs. 889.3 ± 66.8, P = 0.042). CONCLUSIONS: In rodents recovering from sevoflurane, REM-on and REM-off neuronal activity maps closely resemble those of REM sleep-deprived animals. These findings provide new evidence in support of the idea that sevoflurane does not substitute for endogenous REM sleep.

Gut microbiota of old mice worsens neurological outcome after brain ischemia via increased valeric acid and IL-17 in the blood.

BACKGROUND: Aging is a significant risk factor for ischemic stroke and worsens its outcome. However, the mechanisms for this worsened neurological outcome with aging are not clearly defined. RESULTS: Old C57BL/6J male mice (18 to 20 months old) had a poorer neurological outcome and more severe inflammation after transient focal brain ischemia than 8-week-old C57BL/6J male mice (young mice). Young mice with transplantation of old mouse gut microbiota had a worse neurological outcome, poorer survival curve, and more severe inflammation than young mice receiving young mouse gut microbiota transplantation. Old mice and young mice transplanted with old mouse gut microbiota had an increased level of blood valeric acid. Valeric acid worsened neurological outcome and heightened inflammatory response including blood interleukin-17 levels after brain ischemia. The increase of interleukin-17 caused by valeric acid was inhibited by a free fatty acid receptor 2 antagonist. Neutralizing interleukin-17 in the blood by its antibody improved neurological outcome and attenuated inflammatory response in mice with brain ischemia and receiving valeric acid. Old mice transplanted with young mouse feces had less body weight loss and better survival curve after brain ischemia than old mice transplanted with old mouse feces or old mice without fecal transplantation. CONCLUSIONS: These results suggest that the gut microbiota-valeric acid-interleukin-17 pathway contributes to the aging-related changes in the outcome after focal brain ischemia and response to stimulus. Valeric acid may activate free fatty acid receptor 2 to increase interleukin-17.

Formyl peptide receptor 1 is involved in surgery-induced neuroinflammation and dysfunction of learning and memory in mice.

Postoperative cognitive dysfunction (POCD) is a common complication after surgery. Peripheral immune cells may contribute to the development of POCD. However, molecules that are important for this contribution are not known. We hypothesize that formyl peptide receptor 1 (FPR1), a molecule critical for the migration of the monocytes and neutrophils into the brain after brain ischemia, is central to the development of postoperative neuroinflammation and dysfunction of learning and memory. Male C57BL/6 (wild-type) mice and FPR1-/- mice received right carotid artery exposure surgery. Some wild-type mice received cFLFLF, an FPR1 antagonist. Mouse brains were harvested 24 h after the surgery for biochemical analysis. Mice were subjected to the Barnes maze and fear conditioning tests to determine their learning and memory from 2 weeks after the surgery. We found that surgery increased FPR1 in the brain and proinflammatory cytokines in the blood and brain of wild-type mice. Surgery also impaired their learning and memory. cFLFLF attenuated these effects. Surgery did not induce an increase in the proinflammatory cytokines and impairment of learning and memory in FPR1-/- mice. These results suggest that FPR1 is important for the development of neuroinflammation and dysfunction of learning and memory after surgery. Specific interventions that inhibit FPR1 may be developed to reduce POCD.

Desflurane Post-treatment Reduces Hypoxic-ischemic Brain Injury via Reducing Transient Receptor Potential Ankyrin 1 in Neonatal Rats.

Perinatal hypoxic-ischemic (HI) brain injury leads to mortality and morbidity in neonates and children. There are no effective and practical methods to attenuate this brain injury. This study determined whether desflurane, a volatile anesthetic with limited effect on the cardiovascular system, protected against HI-induced brain damage and the role of transient receptor potential ankyrin 1 (TRPA1), a mediator for simulated ischemia-induced myelin damage, in this protection. Seven-day-old male and female Sprague-Dawley rats had brain HI. They were exposed to 4.8%, 7.6% or 11.4% desflurane immediately or 4.8% desflurane at 0.5, 1 or 2 h after the HI. Brain tissue loss was evaluated 7 days later. Neurological functions and brain structures of rats with HI and 4.8% desflurane post-treatment were evaluated 4 weeks after the HI. TRPA1 expression was determined by Western blotting. HC-030031, a TRPA1 inhibitor, was used to determine the role of TRPA1 in the HI-induced brain injury. HI induced brain tissue and neuronal loss, which was attenuated by all tested concentrations of desflurane. Desflurane post-treatment also improved motor function, learning and memory in rats with brain HI. Brain HI increased the expression of TRPA1 and this increase was inhibited by desflurane. TRPA1 inhibition reduced HI-induced brain tissue loss and impairment of learning and memory. However, the combination of TRPA1 inhibition and desflurane post-treatment did not preserve brain tissues, learning and memory better than TRPA1 inhibition or desflurane post-treatment alone. Our results suggest that desflurane post-treatment induces neuroprotection against neonatal HI. This effect may be mediated by inhibiting TRPA1.

Effect of regional versus general anesthesia on thirty-day outcomes following carotid endarterectomy: a cohort study.

BACKGROUND: The effect of regional versus general anesthesia on carotid endarterectomy outcomes is debated. This study assesses the effect of anesthetic technique on major morbidity and mortality and additional secondary endpoints following carotid endarterectomy. MATERIALS AND METHODS: This was a retrospective propensity-matched-cohort analysis investigating elective carotid endarterectomy patients in the 2015-2019 American College of Surgeons National Surgical Quality Improvement Program ( n =37 204). The primary endpoint was 30-day mortality and major morbidity, defined as stroke, myocardial infarction, or death. Secondary endpoints included minor morbidity, bleeding events, healthcare resource utilization, and length of hospital stay. Univariate, multivariable, and survival analyses were applied. RESULTS: The 1 : 1 propensity-matched-cohort included 8304 patients (4152 in each group). Regional anesthesia was associated with similar incidences of major morbidity and mortality [odds ratio (OR), 0.81 (95% CI, 0.61-1.09); P = 0.162] and unplanned resource utilization [OR, 0.93 (95% CI, 0.78-1.11); P = 0.443], but lower incidences of minor morbidity [OR, 0.60 (95% CI, 0.44-0.81); P < 0.001] and bleeding events [OR, 0.49 (95% CI, 0.30-0.78); P = 0.002], and a shorter length of hospital stay [1.4 vs. 1.6 days; mean difference, -0.16 days (95% CI, -0.25 to -0.07); P < 0.001]. On multivariable analysis, regional anesthesia remained independently predictive of minor morbidity [adjusted odds ratio (AOR), 0.58 (95% CI, 0.42-0.79); P = 0.001] and bleeding events [AOR, 0.49 (95% CI, 0.30-0.77); P = 0.003]. Significance was maintained on survival analysis for these two endpoints. A mortality benefit was observed on univariate [OR, 0.50 (95% CI, 0.25-1.00); P = 0.045], multivariable [AOR, 0.49 (95% CI, 0.24-0.96); P = 0.043], and survival analysis ( P = 0.045). CONCLUSIONS: Carotid endarterectomy patients receiving regional anesthesia experience favorable outcomes compared to propensity-matched general anesthesia controls.

Microglial IL-1RA ameliorates brain injury after ischemic stroke by inhibiting astrocytic CXCL1-mediated neutrophil recruitment and microvessel occlusion.

Acute ischemic stroke (AIS), one of the leading causes of mortality worldwide, is characterized by a rapid inflammatory cascade resulting in exacerbation of ischemic brain injury. Microglia are the first immune responders. However, the role of postischemic microglial activity in ischemic brain injury remains far from being fully understood. Here, using the transgenic mouse line CX3 CR1creER :R26iDTR to genetically ablate microglia, we showed that microglial deletion exaggerated ischemic brain injury. Associated with this worse outcome, there were increased neutrophil recruitment, microvessel blockade and blood flow stagnation in the acute phase, accompanied by transcriptional upregulation of chemokine (C-X-C motif) ligand 1 (CXCL1). Our study showed that microglial interleukin-1 receptor antagonist (IL-1RA) suppressed astrocytic CXCL1 expression induced by oxygen and glucose deprivation and inhibited neutrophil migration. Furthermore, neutralizing antibody therapy against CXCL1 or the administration of recombinant IL-1RA protein reduced brain infarct volume and improved motor coordination performance of mice after ischemic stroke. Our study suggests that microglia protect against acute ischemic brain injury by secreting IL-1RA to inhibit astrocytic CXCL1 expression, which reduces neutrophil recruitment and neutrophil-derived microvessel occlusion.

Effect of spinal versus general anesthesia on thirty-day outcomes following total hip arthroplasty: A matched-pair cohort analysis.

STUDY OBJECTIVE: It has not yet been established whether total hip arthroplasty complications are associated with anesthetic technique (spinal versus general). This study assessed the effect of spinal versus general anesthesia on health care resource utilization and secondary endpoints following total hip arthroplasty. DESIGN: Propensity-matched cohort analysis. SETTING: American College of Surgeons National Surgical Quality Improvement Program participating hospitals from 2015 to 2021. PATIENTS: Patients undergoing elective total hip arthroplasty (n = 223,060). INTERVENTIONS: None. MEASUREMENTS: The a priori study duration was 2015 to 2018 (n = 109,830). The primary endpoint was 30-day unplanned resource utilization, namely readmission and reoperation. Secondary endpoints included 30-day wound complications, systemic complications, bleeding events, and mortality. The impact of anesthetic technique was investigated with univariate analyses, multivariable analyses, and survival analyses. MAIN RESULTS: The 1:1 propensity-matched cohort included 96,880 total patients (48,440 in each anesthesia group) from 2015 to 2018. On univariate analysis, spinal anesthesia was associated with a lower incidence of unplanned resource utilization (3.1% [1486/48440] vs 3.7% [1770/48440]; odds ratio [OR], 0.83 [95% CI, 0.78 to 0.90]; P < .001), systemic complications (1.1% [520/48440] vs 1.5% [723/48440]; OR, 0.72 [95% CI, 0.64 to 0.80]; P < .001), and bleeding events requiring transfusion (2.3% [1120/48440] vs 4.9% [2390/48440]; OR, 0.46 [95% CI, 0.42 to 0.49]; P < .001). On multivariable analysis, spinal anesthesia remained an independent predictor of unplanned resource utilization (adjusted odds ratio [AOR], 0.84 [95% CI, 0.78 to 0.90]; c = 0.646), systemic complications (AOR, 0.72 [95% CI, 0.64 to 0.81]; c = 0.676), and bleeding events (AOR, 0.46 [95% CI, 0.42 to 0.49]; c = 0.686). Hospital length of stay was also shorter in the spinal anesthesia cohort (2.15 vs 2.24 days; mean difference, -0.09 [95% CI, -0.12 to -0.07]; P < .001). Similar findings were observed in the cohort from 2019 to 2021. CONCLUSIONS: Total hip arthroplasty patients receiving spinal anesthesia experience favorable outcomes compared to propensity-matched general anesthesia patients.

Late surgical start time is associated with increased blood transfusion following gastric bypass surgery.

BACKGROUND: Surgical start time (SST) has demonstrated conflicting effects on perioperative outcomes due to confounding factors, such as increased acuity in later SST cases. This study investigated the effect of SST on blood transfusion after gastric bypass surgery, a complication-prone elective surgical procedure. METHODS: This retrospective cohort study included all patients undergoing gastric bypass surgery at a single academic medical center from 2016 through 2021 (n = 299). The primary independent variable was SST (before vs. after 15:00). The primary outcome was blood transfusion. Secondary outcomes included postoperative respiratory failure, length of stay, acute kidney injury, and mortality. The associations between SST and outcomes were investigated with univariate analyses. Multivariate and receiver operating characteristic (ROC) analyses were applied to the primary outcome, adjusting for demographic and operative characteristics. RESULTS: On univariate analysis, 15:00-18:43 SST was associated with an increased risk of blood transfusion (relative risk 4.32, 95% confidence interval 1.27 to 14.63, p = 0.032), but not postoperative respiratory failure, acute kidney injury, length of stay, or mortality. On multivariate analysis, the only independent predictor of postoperative blood transfusion was a 15:00-18:43 SST (adjusted odds ratio 4.32, 95% confidence interval 1.06 to 15.96, c-statistic = 0.638). ROC analysis demonstrated that compared to the 15:00 threshold, a 14:34 threshold predicted postoperative blood transfusion with better accuracy (sensitivity = 70.0%, specificity = 83.0%). CONCLUSIONS: Despite having similar demographic and operative characteristics, gastric bypass patients in the late SST cohort had a greater incidence of postoperative blood transfusion in this single-center study.

Triptolide injection reduces Alzheimer's disease-like pathology in mice.

Triptolide is an epoxidized diterpene lactone isolated from Tripterygium wilfordii. Studies have shown that triptolide exerts organ-protective effects. However, it remains unknown whether triptolide improves Alzheimer's disease (AD)-like presentations. Thirty healthy 8-week-old male C57BL/6J mice were randomly divided into control (n = 10), model (n = 10), and triptolide (n = 10) groups. Amyloid-ß (Aß)42 was injected bilaterally into the ventricles of mice in the model group. Triptolide was injected intraperitoneally daily after injecting Aß42 (a total of 30 days) in the triptolide group. Learning and memory were tested using the Morris water maze test. The deposition of Aß42 in the hippocampus was detected using immunohistochemical staining. In the hippocampus, three synaptic-associated proteins-gephyrin, collybistin, and GABRA1 -were detected by western blotting. Furthermore, we used ELISA to detect proinflammatory cytokines, including TNF-α and IL-1ß, in the blood and hippocampus. Moreover, superoxide dismutase (SOD), malondialdehyde (MDA), and GSH levels were measured using the corresponding kits. We found that triptolide improved spatial learning and memory in AD-like mice. Additionally, triptolide maintained the expression of gephyrin, collybistin, and GABRA1 and reduced Aß in these mice. Additionally, triptolide reduced the expression of inflammatory cytokines and decreased oxidative damage in AD-like mice. Our study suggests that triptolide attenuates AD-like changes in the mouse brain.

Efficacy and safety of Ciprofol for procedural sedation and anesthesia in non-operating room settings.

STUDY OBJECTIVE: Ciprofol, a novel intravenous anesthetic, provides rapid recovery in patients undergoing colonoscopy. We aimed to examine the efficacy and safety of ciprofol in comparison with propofol for sedation or anesthesia in non-operating room settings including endoscopic submucosal dissection, endoscopic retrograde cholangiopancreatography, and flexible bronchoscopy (FB). DESIGN: Prospective, randomized, double-blind, parallel-group clinical trial. SETTING: University-affiliated teaching hospital. PATIENTS: We recruited 207 patients scheduled for an endoscopic procedure from October 2021 to December 2021. INTERVENTIONS: Patients were randomized into three groups according to the dose during induction (n = 69 each): 1) ciprofol 6 mg/kg/h, 2) ciprofol 8 mg/kg/h, or 3) propofol 40 mg/kg/h. Ciprofol or propofol was administered throughout the procedure. MEASUREMENTS: The primary outcome was the success rate of sedation or anesthesia for the procedures. Secondary outcomes included induction time, endoscope insertion time, recovery time, discharge time, incidence of drug-related adverse events (AEs), neurological and inflammatory outcomes. MAIN RESULTS: The procedure success rates in the three groups were 100%. The induction time in the 6 (3.3 ± 1.0 min) and 8 mg/kg/h (2.9 ± 0.6 min) ciprofol groups was longer than that in the propofol group (2.5 ± 0.6 min) only in patients undergoing FB (p = 0.004). The time for patients to be fully alert and discharged from the post-anesthesia care unit was comparable across the three groups (p > 0.05). The incidence of drug-related AEs in the propofol and 6 and 8 mg/kg/h ciprofol groups was 84.1%, 76.8%, and 79.7%. No pain on injection was reported by ciprofol groups. Neurological outcomes and inflammatory responses were comparable among the three groups. CONCLUSIONS: Ciprofol induced a level of sedation or anesthesia equivalent to that induced by propofol in non-operating room settings except for a prolonged induction time in patients undergoing FB. Ciprofol had a safety profile similar to that of propofol. No pain on injection was reported by ciprofol.

Endoplasmic Reticulum Stress-Activated Neuronal and Microglial Autophagy Contributes to Postoperative Cognitive Dysfunction in Neonatal rats.

Surgery and anesthesia in neonates may lead to cognitive impairment or abnormal behaviors. It has been shown that autophagy plays a critical role in neuropsychiatric disorders, while the role of autophagy in postoperative cognitive impairment in neonates is not known. Here, we determined this role and the involvement of endoplasmic reticulum (ER) stress in regulating brain cell autophagy after surgery. Seven-day old neonatal rats (P7) had right common carotid artery exposure under anesthesia with 3% sevoflurane for 2 h. Learning and memory were tested using Barnes maze (BM) and fear conditioning (FC) on P31-42 and P42-44, respectively. In another experiment, rat brains were harvested for biochemical studies. The ratio of microtubule-associated protein 1 light chain 3 (LC3) BII/I was increased and sequestosome 1 (P62/SQSTM1) levels were decreased in the brain 24 h after surgery and anesthesia in neonatal rats. Immunofluorescent staining of LC3B was co-localized with a neuronal or a microglial marker but was not co-localized with a marker for astrocytes in rats with surgery. These rats had a poorer performance in the BM and FC tests than control rats when they were adolescent. Pretreatment with an autophagy inhibitor, 3-methyladenine, attenuated the poor performance. Surgery and anesthesia increased the expression of 78 kDa glucose-regulated protein (BIP/GRP78), an indicator of ER stress, 6 h after surgery and anesthesia. The ER stress activator tunicamycin and inhibitor tauroursodeoxycholic acid increased the markers for autophagy in control rats and decreased the autophagy markers in rats with surgery, respectively. Our results suggest that surgery in neonatal rats induces ER stress that then activates neuronal and microglial autophagy, which contributes to learning and memory impairment later in life.

Inhibition of ERK/CREB signaling contributes to postoperative learning and memory dysfunction in neonatal rats.

Exposure to surgery with anesthesia early in life may lead to abnormal behavior, learning, and memory in humans. Pre-clinical studies have suggested a critical role of glial cell-derived neurotrophic factor (GDNF) in these effects. We hypothesize that the inhibition of extracellular signal-regulated kinase (ERK)-cAMP response element-binding protein (CREB) pathway contributes to GDNF decrease and the dysfunction of learning and memory. To address this hypothesis, 7-day-old Sprague-Dawley male and female rats were subjected to right carotid artery exposure (surgery) under sevoflurane anesthesia. Their learning and memory were tested by the Barnes maze, and novel object recognition tests started 23 days after the surgery. Blood and brain were harvested at various times after surgery for biochemical analyses. Rats with surgery and anesthesia performed poorly in the Barnes maze and novel object recognition tests compared with control rats. Rats with surgery had a decreased GDNF concentration in the brain and urine. The concentrations of urine GDNF were negatively correlated with the performance of rats in a delayed memory phase of the Barnes maze test. Surgery increased proinflammatory cytokines in the blood and brain. Intracerebroventricular injection of GDNF attenuated the increased inflammatory response in surgery rats. Surgery inhibited ERK and CREB. Inhibiting ERK reduced GDNF and induced poor performance in the Barnes maze and novel object recognition tests of rats without surgery. Surgery also increased brain-derived natriuretic peptide (BNP) in the brain. Intracerebroventricular injection of BNP inhibited ERK and CREB, reduced GDNF, and impaired learning and memory. Surgery, ERK inhibition, and BNP reduced the expression of synaptic proteins. Our results suggest that surgery increases BNP that inhibits ERK-CREB signaling to reduce GDNF, which leads to an unbalanced inflammatory response and a reduced synaptic protein expression for the development of postoperative cognitive dysfunction. KEY MESSAGES: Surgery increases BNP and decreases ERK/CREB signaling to reduce GDNF. The increase in BNP and decrease in ERK/CREB signaling contribute to postoperative cognitive dysfunction. GDNF reduction contributes to neuroinflammatory response after surgery. Urine GDNF concentrations are negatively corrected with poor spatial memory performance.

Postoperative Learning and Memory Dysfunction Is More Severe in Males But Is Not Persistent and Transmittable to Next Generation in Young Adult Rats.

BACKGROUND: Postoperative cognitive dysfunction (POCD) affects numerous patients each year and is associated with poor outcomes. Currently, the duration of POCD is not known. This preclinical study determined whether POCD was persistent, different between sexes and transmittable to the next generation. METHODS: Two-month-old Sprague-Dawley rats had left carotid artery exposure under isoflurane anesthesia and their learning and memory were assessed from 5 days, 2 months, and 4 months after surgery. Rats with or without surgery were mated when they were 4 or 6 months old, and the learning and memory of the offspring were tested at 2 months of age. RESULTS: Males exposed to surgery took a longer time to identify the target box after training sessions in a Barnes maze and had less freezing behavior in context-related fear conditioning than control rats when the tests were started 5 days after surgery. Similarly, female rats had a poorer performance than control rats in the Barnes maze test from 5 days after surgery. However, these poorer performances were not observed when the tests were administered 2 or 4 months after surgery. The offspring of rats with surgery had a performance similar to that of the offspring of control rats. CONCLUSIONS: Our results suggest that both male and female rats develop POCD but that the learning and memory dysfunction appears to be more severe in male rats. POCD may not be persistent and does not transmit to the next generation.

Cognitive function and delirium following sevoflurane or propofol anesthesia for valve replacement surgery: A multicenter randomized controlled trial.

Cognitive dysfunction is a common postoperative neurological complication in patients undergoing valve replacement surgery. This study aimed to compare the effects of sevoflurane versus propofol-based total intravenous anesthesia on the incidence of cognitive dysfunction following valve replacement surgery. This multicenter, randomized, controlled double-blinded study was conducted in three teaching hospitals in China. Patients receiving on-pump valve replacement surgery were enrolled. Stratified block randomization was used to randomly assign patients 1:1 to receive sevoflurane (1.0-1.5 MAC) or propofol (2.0-3.0 mg/kg/h) for anesthesia maintenance. The primary outcome was the incidence of cognitive dysfunction assessed by four cognitive tests before, as well as 7-14 days after surgery. Patients were randomly assigned to receive sevoflurane anesthesia (n = 144) or propofol-based total intravenous anesthesia (n = 145). The incidence of postoperative cognitive dysfunction in the sevoflurane anesthesia group (31.9%) was significantly lower than that in the total intravenous anesthesia group (43.4%; relative risk 0.61, 95% confidence interval [CI]: 0.38-0.97, p = 0.044). There was no difference in the incidence of delirium between patients receiving sevoflurane and total intravenous anesthesia (27.8% [35/144] vs. 25.9% [35/145], 1.10, 95% CI: 0.64 to 1.90, p = 0.736). There was a significant difference in the Katz Index on day 3 after surgery (3 [0.9) vs. 3 (1.0], 0.095, 95% CI: 0.05 to 0.43, p = 0.012). No difference was observed in other outcomes between the two groups. For patients undergoing on-pump valve replacement surgery, sevoflurane anesthesia had a smaller effect on cognitive function and independence in daily life activities compared with propofol anesthesia.