Melatonin regulates the circadian rhythm to ameliorate postoperative sleep disorder and neurobehavioral abnormalities in aged mice.

BACKGROUND: Postoperative sleep disorder (PSD) and delirium, which may be associated with surgery and inhalational anesthetics, induce adverse effects in old adults. Emerging evidence indicates that circadian rhythm contributes to various neuropathological diseases, including Alzheimer's disease. Thus, we analyzed the potential role of circadian rhythm in PSD and delirium-like behavior in aged mice and determined whether exogenous melatonin could facilitate entrainment of the circadian rhythm after laparotomy under sevoflurane anesthesia. METHODS: We selected old C57BL/6J mice which receiving laparotomy/sevoflurane anesthesia as model animals. We employed buried food, open field, and Y maze test to assess delirium-like behavior, and electroencephalography/electromyography (EEG/EMG) were used to investigate sleep changes. We analyzed the transcription rhythm of clock genes in superchiasmatic nucleus (SCN) to explore the effects of surgery and melatonin pretreatment on the circadian rhythm. Then, we measured melatonin receptor levels in SCN and ERK/CREB pathway-related proteins in hippocampus and prefrontal cortex to assess their role in PSDs and delirium-like behavior. RESULTS: Laparotomy under sevoflurane anesthesia had a greater influence than sevoflurane alone, leading to sleep disorder, a shift in sleep-wake rhythm, and delirium-like behavior. Bmal1, Clock, and Cry1 mRNA expression showed a peak shift, MT1 melatonin receptor expression level was increased in the SCN, and p-ERK/ERK and p-CREB/CREB were decreased in hippocampus and prefrontal cortex of aged mice 1 day after laparotomy. Melatonin showed significant efficacy in ameliorating PSD and delirium-like behavior and restoring the circadian rhythm, reversing melatonin receptor and ERK/CREB pathway expression abnormalities. In addition, most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist. CONCLUSIONS: Melatonin receptors in SCN, circadian rhythm, and ERK/CREB signaling pathway participate in the pathophysiological processes of PSD and delirium-like behavior. Melatonin intervention could be a potential preventative approach for PSD and delirium.

Development of a Brief Cognitive Screening Tool for Predicting Postoperative Delirium in Patients with Parkinson's Disease: A Secondary Analysis.

Background: A simple, rapid, and effective cognitive screening test appropriate for fast-paced settings with limited resources and staff is essential, especially preoperatively. This study aimed to develop and validate the short versions of Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) for predicting postoperative delirium (POD) in patients with Parkinson's disease (PD) who were scheduled for surgery. Methods: The current study was a secondary analysis of data collected from 128 inpatients scheduled for deep brain stimulation of the subthalamic nuclei (STN-DBS) lasting >60 min, at Tsinghua University Yuquan Hospital, China. Preoperative cognitive screening was performed during the preoperative visit using the MMSE and MoCA. The optimal MMSE and MoCA cut-off scores for detecting PD-MCI was 27 and 23 respectively. The POD was assessed twice a day on the first postoperative day until discharge by the confusion assessment method. The backward conditional logistic regression analysis was used to organize the reduced versions of the MMSE or MoCA. Also, the areas under the receiver operating characteristic curves (AUCs) were examined using the DeLong test. Results: 125/128 PD patients were included in the analysis, and 27 (21.6%) developed POD. The MMSE reduced version (orientation to time, attention and calculation, and comprehension) demonstrated performance similar to the original MMSE in predicting POD (z=0.820, p=0.412). The AUC of the original MoCA and the short MoCA (visuospatial and executive attention and orientation) were 0.808 and 0.826, respectively. There was no significantly difference in the AUC values between the tests (z=0.561, p=0.575). Conclusion: Our simplified MMSE and MoCA could be efficiently used to identify patients at risk for POD. Also, short cognitive tests could be considered while predicting POD in fast-paced preoperative settings with limited resources and staff.

Specific antagonist of receptor for advanced glycation end­products attenuates delirium­like behaviours induced by sevoflurane anaesthesia with surgery in aged mice partially by improving damage to the blood­brain barrier.

Postoperative delirium (POD), which occurs in hospital up to 1-week post-procedure or until discharge, is a common complication, especially in older adult patients. However, the pathogenesis of POD remains unclear. Although damage to blood-brain barrier (BBB) integrity is involved in the neuropathogenesis of POD, the specific role of the BBB in POD requires further elucidation. Anaesthesia using 2% isoflurane for 4 h results in the upregulation of hippocampal receptor for advanced glycation end-products (RAGE) expression and ß-amyloid accumulation in aged rats. The present study investigated the role of RAGE in BBB integrity and its mechanisms in POD-like behaviours. The buried food, open field and Y maze tests were used to evaluate neurobehavioural changes in aged mice following 2.5% sevoflurane anaesthesia administration with exploratory laparotomy. Levels of tight junction proteins were assessed by western blotting. Multiphoton in vivo microscopy was used to observe the ultrastructural changes in the BBB in the hippocampal CA1 region. Anaesthesia with surgery decreased the levels of tight junction proteins occludin and claudin 5, increased matrix metalloproteinases (MMPs) 2 and 9, damaged the ultrastructure of the BBB and induced POD-like behaviour. FPS-ZM1, a specific RAGE antagonist, ameliorated POD-like behaviour induced by anaesthesia and surgery in aged mice. Furthermore, FPS-ZM1 also restored decreased levels of occludin and claudin 5 as well as increased levels of MMP2 and MMP9. The present findings suggested that RAGE signalling was involved in BBB damage following anaesthesia with surgery. Thus, RAGE has potential as a novel therapeutic intervention for the prevention of POD.

Detection Analysis of Perioperative Plasma and CSF Reveals Risk Biomarkers of Postoperative Delirium of Parkinson's Disease Patients Undergoing Deep Brain Stimulation of the Subthalamic Nuclei.

Objective: This study aimed to explore possible biomarkers of postoperative delirium (POD) of Parkinson's disease (PD) patients received deep brain stimulation (DBS) of the subthalamic nuclei. Materials and methods: This nested case control study analyzed perioperative plasma and cerebral spinal fluid (CSF) of patients (n = 40) who developed POD undergone DBS surgery (n = 10) and those who did not (n = 30). Blood sample was collected before surgery and on the first day postoperative, CSF sample was collected at the beginning of the operation. POD was assessed by the Confusion Assessment Method (CAM) twice a day between 7:00 am and 7:00 pm after the surgery until discharge. Plasma and CSF sample from the two groups were analyzed to investigate possible biomarkers for POD in PD patients. Results: There was no difference between POD and Non-POD groups on the concentration of Interleukin 6 and Tumor Necrosis Factor-α in CSF, preoperative plasma and postoperative plasma. There was no difference between POD and Non-POD groups on the concentration of S100 calcium-binding protein ß protein (S100ß) and Neurofilament light chain (NFL) in preoperative plasma and postoperative plasma. The concentration of C-reactive protein (CRP), NFL and S100ß were significant higher in POD group than non-POD group in CSF. The concentration of CRP was significantly higher in POD group than non-POD group in preoperative plasma and postoperative plasma. CSF concentration of S100ß might be a potential biomarker for POD via the receiver operating characteristic curve analysis and the area under the curve value of 0.973. Conclusion: For PD patients received DBS surgery, CSF S100ß might be a marker for aiding detection of high-risk patients with delirium. This requires further confirmation in clinical trials.

Association between Baseline Cognitive Score and Postoperative Delirium in Parkinson's Disease Patients following Deep Brain Stimulation Surgery.

Background: Deep brain stimulation of the subthalamic nuclei (STN-DBS) is a standard treatment option for advanced Parkinson's disease (PD) patients. Delirium following DBS electrode implantation is common, by several studies, and cognitive impairment is a risk factor for developing postoperative delirium (POD). This prospective observational study was conducted to identify whether preoperative baseline cognitive status has an association with POD in PD patients undergoing DBS surgery. Methods: Preoperatively, neuropsychiatric and neuropsychological assessments of the patients were performed including clinical dementia rating (CDR) score, instrumental activities of daily living (IADL) score, mini-mental state exam (MMSE) score, Montreal cognitive assessment (MoCA) score, Hamilton anxiety (HAMA) and Hamilton depression (HAMD) scores, and numerical cancellation test. POD was identified by the confusion assessment method (CAM) twice per day on postoperative day 1 until discharge. Results: Twenty-seven (21.6%) of 125 patients developed POD. Among the variables screened, age, CDR score, MMSE score, and HAMA score were indicated to be independent influence factors of POD. The cutoff score, AUC, sensitivity, and specificity of age, CDR score, MMSE score, and HAMA score associated with POD was 58.5, 0.751, 92.6%, 52.0%; 0.5, 0.848, 77.8%, 91.8%; 27.5, 0.827, 88.9%, 62.2%; and 12.5, 0.706, 85.2%, 54.1%, respectively. Conclusions: We observed age, CDR score, MMSE score, and HAMA score were independent influence factors of POD in PD patients who received DBS. It is necessary to assess the cognitive status of PD patients before surgery to identify high-risk patients.

The Effect of Propofol versus Sevoflurane on Postoperative Delirium in Parkinson's Disease Patients Undergoing Deep Brain Stimulation Surgery: An Observational Study.

BACKGROUND: The selection of the maintenance of general anesthesia may affect the development of postoperative delirium (POD), notably for Parkinson's disease (PD) patients, due to their lower cognitive reserve. The present study was designed to compare the potential impact of propofol vs. sevoflurane based general anesthesia maintenance methods on the development of POD in PD patients following deep brain stimulation (DBS) surgery. METHODS: A total of 125 PD patients who were scheduled to undergo DBS surgery were randomly divided into the propofol (n = 63) and the sevoflurane groups (n = 62). The patients in the two groups randomly received propofol- or sevoflurane-based general anesthesia. The Confusion Assessment Method (CAM) was employed by an investigator who was blinded to the anesthesia regimen and was administered twice per day from postoperative day 1 until discharge. RESULTS: The incidence of POD was 22.22% (14/63) with propofol anesthesia and 20.97% (13/62) with sevoflurane anesthesia (p = 0.865). In addition, no difference was noted in the duration and severity of delirium between the propofol and sevoflurane groups. CONCLUSIONS: In the present study, propofol- and sevoflurane-based general anesthesia exhibited comparable results with regard to the POD incidence in PD patients undergoing deep brain stimulation surgery.

Cholecystokinin octapeptide improves hippocampal glutamatergic synaptogenesis and postoperative cognition by inhibiting induction of A1 reactive astrocytes in aged mice.

AIMS: Delayed neurocognitive recovery (dNCR) is a common postoperative complication in geriatric surgical patients for which there is no efficacious therapy. Cholecystokinin octapeptide (CCK-8), an immunomodulatory peptide, regulates memory and learning. Here, we explored the effects and mechanism of action of CCK-8 on dNCR. METHODS: We applied laparotomy to establish a model of dNCR in aged mice. Morris water maze and fear conditioning tests were used to evaluate cognition. Immunofluorescence was used to detect the density of CCK-8, A1 reactive astrocytes, glutamatergic synapses, and activation of microglia in the hippocampus. Quantitative PCR was performed to determine mRNA levels of synapse-associated factors. A1 reactive astrocytes, activated microglia, and glutamatergic synapse-associated protein levels in the hippocampus were assessed by western blotting. RESULTS: Administration of CCK-8 suppressed the activation of microglia, the induction of A1 reactive astrocytes, and the expression of tumor necrosis factor alpha, complement 1q, and interleukin 1 alpha in the hippocampus. Furthermore, it promoted glutamatergic synaptogenesis and neurocognitive recovery in aged dNCR model mice. CONCLUSION: Our findings indicated that CCK-8 alleviated cognitive impairment and promoted glutamatergic synaptogenesis by inhibiting the induction of A1 reactive astrocytes and the activation of microglia. CCK-8 is, therefore, a potential therapeutic target for dNCR.

Inhibition of α-Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice.

Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha-synuclein (α-syn; encoded by the gene, SNCA) has recently been shown to play an important role in hippocampus-dependent working memory. Aggregated forms of α-syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α-syn improved both mitochondrial function and mitochondria-dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α-syn (including total α-syn, phosphorylated-Ser129-α-syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna. Clenbuterol significantly attenuated surgery-induced progressive accumulation of various toxic α-syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α-syn accumulation and increased mitochondria-mediated apoptosis in vitro using nerve growth factor-differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α-syn inhibition, we used a lentiviral Snca-shRNA (Lv-shSnca) to knockdown Snca. Of note, Lv-shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α-syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α-syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α-syn for dNCR.

Hundred most cited articles in perioperative neurocognitive disorder: a bibliometric analysis.

BACKGROUND: In line with aging populations and increased application of anesthesia and surgery, perioperative neurocognitive disorder (PND) has received growing attention worldwide. Considerable researches into PND are being conducted; however, the quantity and quality of such researches have not been reported. Through a retrospective bibliometric analysis, this study aims to identify and characterize the top 100 cited publications on PND. METHODS: We searched the Web of Science database to find the top 100 cited articles focusing on PND. We collected bibliographic information, including year of publication, country of origin, article type, published journal, citation count, and authorship. To determine changes with time, we compared older and newest articles. RESULTS: The top 100 cited articles were published between 1955 and 2016; the number of citations ranged from 111 to 1248. The United States had the most published papers; clinical trial was the most common article type. The specialty journals of Anesthesiology and Anesthesia & Analgesia were the two most cited journals. Newest articles had a comparable number of citations to older articles, but the former had higher annual citation rates, greater funding disclosures, more focus on basic research, and more open access publications. CONCLUSIONS: This study provides a comprehensive overview of the most cited articles and highlights the increasing attention on PND. High-quality clinical trials with a greater journal impact factor receive more citations. However, there has been a growth in the number of basic science studies as an area of research with respect to the pathogenesis of PND.

Effects of general versus subarachnoid anaesthesia on circadian melatonin rhythm and postoperative delirium in elderly patients undergoing hip fracture surgery: A prospective cohort clinical trial.

BACKGROUND: Circadian rhythm disturbance is common postoperatively in older patients with hip fractures, which may contribute to the development of postoperative delirium (POD). As a reliable biomarker of endogenous circadian rhythms, melatonin regulates the sleep-wake cycle and environmental adaptation, and its secretory rhythm may be modified by anaesthesia and surgery. This study compared the impact of subarachnoid anaesthesia (SA) and general anaesthesia (GA), on the peak of melatonin secretion (primary outcome), the circadian rhythm of melatonin, cortisol and sleep, and the POD incidence (secondary outcome). METHODS: In this prospective cohort observational study, hip fracture surgery patients were enrolled and assigned to receive either SA or GA. Postoperative plasma melatonin and cortisol levels were dynamically measured every six hours on seven time-points, and the circadian rhythm parameters including mesor, amplitude, and acrophase were calculated. Subjective and objective sleep assessments were performed by sleep diaries and sleep trackers, respectively. The Confusion Assessment Method was used twice daily by a specific geriatrician to screen for POD occurrence. FINDINGS: In a cohort of 138 patients who underwent hip fracture surgery, the circadian rhythm disruption of the patients in the GA group (n=69) was greater than the SA group (n=69). Compared with SA, GA provided the lower peak concentration, mesor, and amplitude of melatonin secretion on postoperative day 1 (p < 0.05). Patients in the GA group experienced higher awakenings, more sleep deprivation, and poor sleep quality on surgery day (p < 0.05). A proportion of 12 patients in the SA group (17.4%) and 24 patients in the GA group (34.8%) experienced POD (p = 0.020). INTERPRETATION: These results suggest that SA may be superior to GA in elderly patients undergoing hip fracture surgery as SA is associated with less impairment of the melatonin rhythm and sleep patterns, and fewer POD occurrences. FUNDING: The study was supported by the National Natural Science Foundation of China (81971012, 81873726, 81901095, 81701052, and 81801070), Key Clinical Projects of Peking University Third Hospital (BYSYZD2019027), and Peking University "Clinical Medicine plus X" Youth Project (PKU2020LCXQ016).

JNK inhibition alleviates delayed neurocognitive recovery after surgery by limiting microglia pyroptosis.

Delayed neurocognitive recovery (dNCR) is a prevalent complication after surgery in older adults. Neuroinflammation plays a pivotal role in the pathogenesis of dNCR. Recently,compelling evidence suggests that theinvolvement of microglia pyroptosis in the regulation of neuroinflammation in neurologicaldiseases. Nevertheless, the exact role of microglia pyroptosis in dNCR remains elusive. In the study, in vitro and in vivo models of dNCR were used to examine the potential effects of the mitogen­activated protein kinase signaling pathway on Nod-like receptor protein 3 (NLRP3) inflammasome-mediated microglia pyroptosis and cognitive deficits following surgery. In vivo, we observed surgery-induced upregulation of phosphorylated (p)-c-Jun N-terminal kinases (JNK) in microglia and subsequently NLRP3 inflammasome activation, pyroptosis, and inflammatory cytokines release in mice hippocampus. Interestingly, JNK inhibitor SP600125 significantly attenuated surgery-induced cognitive impairments through inhibiting pyroptosis, inflammatory responses, and reducing immunoreactivity of NLRP3 and gasdermin D N terminus (GSDMD-N) in hippocampal microglia. In vitro, NLRP3 inflammasome- and pyroptosis-associated proteins and immunoreactivity of NLRP3, GSDMD-N, and interleukin-1ß were activated in BV2 microglial cells following lipopolysaccharide (LPS) stimulation. These effects were significantly suppressed in BV2 cells by SP600125 treatment. Furthermore, treatment with NLRP3 specific inhibitor, MCC950, attenuated microglia pyroptosis induced by LPS, but did not rescue LPS-induced increased expression of p-JNK. These results indicate that the JNK pathway is largely upstream of the NLRP3 inflammasome, which exerts a crucial regulatory impact on microglia pyroptosis and inflammatory responses, thus providing a promising avenue to prevent dNCR.

The Non-peptide Angiotensin-(1-7) Mimic AVE 0991 Attenuates Delayed Neurocognitive Recovery After Laparotomy by Reducing Neuroinflammation and Restoring Blood-Brain Barrier Integrity in Aged Rats.

Delayed neurocognitive recovery (dNCR) after surgery is a common postoperative complication in older adult patients. Our previous studies have demonstrated that cognitive impairment after surgery involves an increase in the brain renin-angiotensin system (RAS) activity, including overactivation of the angiotensin 2/angiotensin receptor-1 (Ang II/AT1) axis, which provokes the disruption of the hippocampal blood-brain barrier (BBB). Nevertheless, the potential role of the counter-regulatory RAS axis, the Ang-(1-7)/Mas pathway, in dNCR remains unknown. Using an aged rat model of dNCR, we dynamically investigated the activity of both axes of the RAS following laparotomy. AVE 0991, a nonpeptide analog of Ang-(1-7), was administered intranasally immediately after laparotomy. We found that the elevation of Ang II, induced by surgery was accompanied by a decrease of Ang-(1-7) in the hippocampus, but not in the circulation. Surgery also significantly downregulated hippocampal Mas receptor expression at 24 h postsurgery. Mas activation with intranasal AVE 0991 treatment significantly improved hippocampus-dependent learning and memory deficits induced by surgery. Furthermore, it attenuated hippocampal neuroinflammation, as shown by the decreased level of the microglial activation marker cluster of differentiation 11b (CD11b) and the decreased production of several inflammatory molecules. Along with these beneficial effects, the AVE 0991 treatment also alleviated the imbalance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), modulated the expression of occludin, and alleviated the IgG extravasation, thereby restoring the integrity of the BBB. In conclusion, these data indicate that activation of Mas by AVE 0991 attenuates dNCR after surgery by reducing neuroinflammation and restoring BBB integrity. Our findings suggest that the Ang-(1-7)/Mas pathway may be a novel therapeutic target for treating dNCR after surgery in older adult patients.

Effects of general versus regional anaesthesia on circadian melatonin rhythm and its association with postoperative delirium in elderly patients undergoing hip fracture surgery: study protocol for a prospective cohort clinical trial.

INTRODUCTION: Postoperative delirium (POD) is a common neurological complication after hip fracture surgery and is associated with high morbidity and mortality in elderly patients. Although the specific mechanism of POD remains unclear, circadian rhythm disruptions have recently drawn increased attention. To date, only limited postoperative time points of plasma melatonin level measurements were recorded in previous studies, and such data cannot represent a comprehensive melatonin rhythm. The process of anaesthesia (either general anaesthesia (GA) or regional anaesthesia (RA)) is known to influence the melatonin rhythm. However, how these two anaesthesia methods differently affect the postoperative melatonin rhythm is still unknown. Therefore, we hypothesise that RA may attenuate the disruption of the melatonin rhythm, which might decrease the incidence of POD in elderly patients undergoing hip surgery. METHODS AND ANALYSIS: In this prospective cohort clinical trial, 138 patients scheduled for hip fracture surgery will be divided into two groups to receive either GA or RA. The primary aim is to compare the circadian rhythm of melatonin secretion between the two groups and explore its association with the incidence of POD. ETHICS AND DISSEMINATION: The study has been approved by the Medical Science Research Ethics Committees of Beijing Jishuitan Hospital (JLKS201901-04). The results of the study will be published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: ChiCTR1900027393.

Melatonin ameliorates the sleep disorder induced by surgery under sevoflurane anaesthesia in aged mice.

Post-operative sleep disorders induce adverse effects on patients, especially the elderly, which may be associated with surgery and inhalational anaesthetics. Melatonin is a neuroendocrine regulator of the sleep-wake cycle. In this study, we analysed the alterations of post-operative sleep in aged melatonin-deficient (C57BL/6J) mice, and investigated if exogenous melatonin could facilitate entrainment of circadian rhythm after laparotomy under sevoflurane anaesthesia. The results showed that laparotomy under sevoflurane anaesthesia had a greater influence on post-operative sleep than sevoflurane alone. Laparotomy under anaesthesia led to circadian rhythm shifting forward, altered EEG power density and delta power of NREM sleep, and lengthened REM and NREM sleep latencies. In the light phase, the number of waking episodes tended to decline, and wake episode duration elevated. However, these indicators presented the opposite tendency during the dark phase. Melatonin showed significant efficacy for ameliorating the sleep disorder and restoring physiological sleep, and most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist.

lncRNAs Are Involved in Sevoflurane Anesthesia-Related Brain Function Modulation through Affecting Mitochondrial Function and Aging Process.

Long noncoding RNAs (lncRNAs) play important roles in brain function modulation and neurodegenerative diseases. However, whether lncRNA regulations are involved in the mechanisms of perioperative neurocognitive disorders, especially in anesthesia-related brain dysfunction, remain unknown. Therefore, we explored the expression and regulation pattern profiles of lncRNAs in the hippocampus of aged rats after sevoflurane anesthesia. Three lncRNAs and 772 protein-coding genes were identified by microarray analysis and evidenced by in vitro and in vivo experiments as differentially expressed. Functional annotation and differentially expressed- (DE-) lncRNA-mRNA coexpression networks reveal that DE-lncRNAs are associated with mitochondrial dysfunction and oxidative stress, aging-related metabolism alterations, DNA damage, and apoptosis, as well as neurodegenerative features during sevoflurane anesthesia. These results suggest that lncRNAs play roles in general anesthesia-related brain function modulation during the perioperative context and provide insights into the lncRNA-related modulation mechanisms and targets.

Baicalin Ameliorates Cognitive Impairment and Protects Microglia from LPS-Induced Neuroinflammation via the SIRT1/HMGB1 Pathway.

Systemic inflammation often induces neuroinflammation and disrupts neural functions, ultimately causing cognitive impairment. Furthermore, neuronal inflammation is the key cause of many neurological conditions. It is particularly important to develop effective neuroprotectants to prevent and control inflammatory brain diseases. Baicalin (BAI) has a wide variety of potent neuroprotective and cognitive enhancement properties in various models of neuronal injury through antioxidation, anti-inflammation, anti-apoptosis, and stimulating neurogenesis. Nevertheless, it remains unclear whether BAI can resolve neuroinflammation and cognitive decline triggered by systemic or distant inflammatory processes. In the present study, intraperitoneal lipopolysaccharide (LPS) administration was used to establish neuroinflammation to evaluate the potential neuroprotective and anti-inflammatory effects of BAI. Here, we report that BAI activated silent information regulator 1 (SIRT1) to deacetylate high-mobility group box 1 (HMGB1) protein in response to acute LPS-induced neuroinflammation and cognitive deficits. Furthermore, we demonstrated the anti-inflammatory and cognitive enhancement effects and the underlying molecular mechanisms of BAI in modulating microglial activation and systemic cytokine production, including tumor necrosis factor- (TNF-) α and interleukin- (IL-) 1ß, after LPS exposure in mice and in the microglial cell line, BV2. In the hippocampus, BAI not only reduced reactive microglia and inflammatory cytokine production but also modulated SIRT1/HMGB1 signaling in microglia. Interestingly, pretreatment with SIRT1 inhibitor EX-527 abolished the beneficial effects of BAI against LPS exposure. Specifically, BAI treatment inhibited HMGB1 release via the SIRT1/HMGB1 pathway and reduced the nuclear translocation of HMGB1 in LPS-induced BV2 cells. These effects were reversed in BV2 cells by silencing endogenous SIRT1. Taken together, these findings indicated that BAI reduced microglia-associated neuroinflammation and improved acute neurocognitive deficits in LPS-induced mice via SIRT1-dependent downregulation of HMGB1, suggesting a possible novel protection against acute neurobehavioral deficits, such as delayed neurocognitive recovery after anesthesia and surgery challenges.

A study of optimal concentration range and time window of sevoflurane preconditioning for brain protection in MCAO rats.

BACKGROUND: Sevoflurane preconditioning improves brain function in MCAO rats, and there are several methods for determining appropriate concentration and time windows for preconditioning. This study investigated the brain protective effects with a single sevoflurane preconditioning at different concentrations and different time windows on MCAO rats. METHODS: Adult Sprague-dawley rats were randomly assigned to 14 groups. The rats in the sevoflurane preconditioning group inhaled 0.5 MAC, 1.0 MAC, and 1.3 MAC sevoflurane, respectively for 3 h, and then MCAO models were established at 6 h, 12 h, 24 h, and 48 h. MCAO and sham groups underwent no preconditioning with sevoflurane. The neurological severity score, cerebral infarct volume and brain water content of the rats were measured 24 h after reperfusion. RESULTS: After inhalation of 1.3 MAC sevoflurane for 3 h of preconditioning, the MCAO model was established after 24 h. This preconditioning improved the neurological severity score, reduce cerebral infarct volume and brain water content in MCAO rats. After inhalation of 1.0 MAC sevoflurane for 3 h of preconditioning, MCAO model established after 24 h reduced the cerebral infarct volume and brain water content of MCAO rats, but the neurological severity score showed no significant improvement, and no significant brain protective effects were observed at other concentrations and time windows. CONCLUSIONS: These results suggested that after inhalation of 1.3 MAC sevoflurane for 3 h of preconditioning, MCAO model established after 24 h demonstrated significant brain protective effects in MCAO rats.

Isoflurane­induced postoperative cognitive dysfunction is mediated by hypoxia­inducible factor­1α­dependent neuroinflammation in aged rats.

Elderly patients are at high risk of developing postoperative cognitive dysfunction (POCD) after prolonged exposure to inhaled anesthetics. However, the pathogenesis of POCD remains unknown. Hypoxia­inducible factor­1α (HIF­1α) is activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF­1α in isoflurane­induced neuroinflammation and the resulting cognitive impairment. Following a 4­h exposure to 1.5% isoflurane in 20­month­old rats, increased expression of HIF­1α protein, activation of nuclear factor (NF)­κB signaling and increased expression of TNF­1α were observed in the hippocampus of isoflurane­exposed rats compared with the control group. Pharmacological inhibition of HIF­1α activation by 5­[1­(phenylmethyl)­1H­indazol­3­yl]­2­furanmethanol (YC­1) markedly suppressed the enhanced expression of HIF­1α, disrupted NF­κB signaling pathway activity and inhibited the isoflurane­induced increase of TNF­1α expression. YC­1 pretreatment also significantly attenuated isoflurane­induced cognitive deficits according to the results of the Morris water maze task. These results suggest that hippocampal HIF­1α appears to be involved in an upstream mechanism of isoflurane­induced cognitive impairment. Further research is warranted to fully clarify the pathogenesis and investigate HIF­1α as a potential therapeutic target for POCD.

Preparation and physicochemistry properties of smart edible films based on gelatin-starch nanoparticles.

BACKGROUND: Among the natural polymers able to form edible films, starch and gelatin (Gel) are potential sources. Corn starch is a polysaccharide widely produced around the world, and gelatin differs from other hydrocolloids as a fully digestible protein, containing nearly all the essential amino acids, except tryptophan. Based on this, with advantages such as abundance, relatively low cost, biodegradability, and edibility, studies considering alternative systems for food protection that utilize biopolymers have increased significantly in recent years. RESULTS: A novel macromolecular crosslinker starch-BTCAD-NHS (starch-butanetetracarboxylic acid dianhydride-N-hydroxysuccinimide, SBN) was successfully prepared to modify gelatin film. Compared with the blank gelatin films, the resulting SBN-Gel films exhibited improved surface hydrophobicity, higher tense strength and elongation-at-break, lower Young's modulus values, greater opacity, poorer water vapour uptake properties and better anti-degradation capacity. CONCLUSION: The modified gelatin film material with advanced properties obtained in this work was safe, stable eco-friendly and biorefractory, and was an ideal choice to form packaging in the food industry. Also, the crosslinking SBN-Gel coating was effective in reducing corruption and extending the shelf life of peeled apple substantially. © 2018 Society of Chemical Industry.

Cellulose-based film modified by succinic anhydride for the controlled release of domperidone.

Succinic anhydride (SAD) modified microcrystalline cellulose (MCC) films was prepared and used for the controlled release of the drug domperidone (dom). The morphology and chemical structure of the modified materials were characterized by SEM, FTIR, XRD and TG/DSC techniques. The physical properties, such as water uptake and swelling, light barrier properties, mechanical testing, in vitro degradation behavior, have been investigated. Results showed that the modified cellulose membranes exhibited good anti-UV properties, higher water uptake values, improved mechanical capacity and anti-biodegradability. In addition, the modified MCC films (MS) as the drug carrier indicated the controlled release of domperidone and the release mechanism was proposed using Korsmeyer-Peppas equation at pH 7.4. The developed drug delivery system possessed the profound significance in improving pharmacodynamics and bioavailability of drugs.