Ketamine and its enantiomers for depression: a bibliometric analysis from 2000 to 2023.

Ketamine has demonstrated rapid and sustained antidepressant effects, marking its emergence as an innovative treatment of depression. Despite the growing number of preclinical and clinical studies exploring the antidepressant effects of ketamine and its enantiomers, a comprehensive bibliometric analysis in this field has yet to be conducted. This study employs bibliometric methods and visualization tools to examine the literature and identify key topics related to the antidepressant effects of ketamine and its enantiomers. We sourced publications on the antidepressant effects of ketamine and its enantiomers from the Web of Science Core Collection (WOSCC) database, covering the period from 2000 to 2023. Tools such as VOSviewer, CiteSpace and the R package "bibliometrix" were utilized for visual analysis. The study included 4,274 publications, with a notable increase in publications peaking in 2022. Co-occurrence analysis highlighted two primary research focal points: the efficacy and safety of ketamine and its enantiomers in treating depression, and the mechanisms behind their antidepressant effects. In conclusion, this analysis revealed a significant increase in research on the antidepressant effects of ketamine and its enantiomers over the past two decades, leading to the approval of esketamine nasal spray for treatment-resistant depression. The rapid antidepressant effects of ketamine have spurred further studies into its mechanisms of action and the search for new antidepressants with fewer side effects.

Hairless (Hr) Deficiency Mitigates High-Fat Diet-Induced Obesity and Insulin Resistance in Mice.

Obesity is a significant global health concern linked to excessive dietary energy intake. This research focuses on the mammalian hairless protein (HR), known for its role in skin and hair function, and its impact on metabolism. Examining male wild-type (Hr+/+) and Hr null (Hr-/-) mice over a 14-week normal chow diet (NCD) or high-fat diet (HFD) intervention. This study reveals that HR deficiency exhibited a protective effect against HFD-induced obesity and insulin resistance. This protective effect is attributed to increased energy expenditure in Hr-/- mice. Moreover, the brown adipose tissue (BAT) of Hr-/- mice displays elevated levels of the thermogenic protein, uncoupling protein 1 (Ucp1), and its key transcriptional regulators (PPARγ and PGC1α), compared to Hr+/+ mice. In summary, the findings underscore the protective role of HR deficiency in countering HFD-induced adiposity by enhancing insulin sensitivity, raising energy expenditure, and augmenting thermogenic factors in BAT. Further exploration of HR metabolic regulation holds promise for potential therapeutic targets in addressing obesity-related metabolic disorders.

Efficacy and safety of esketamine for perioperative depression in patients undergoing elective surgery: A meta-analysis of randomized controlled trials.

BACKGROUND: Depression is a prevalent mood disorder during the perioperative period, with both preoperative concurrent depression and new-onset postoperative depression impacting postoperative recovery. Recent studies have indicated that the dissociative anesthetic esketamine may alleviate perioperative depressive symptoms. OBJECTIVE: This meta-analysis aimed to assess the efficacy and safety of esketamine in treating perioperative depression. METHODS: We selected randomized controlled trials comparing esketamine to placebo in terms of postoperative depressive symptoms. The primary outcome was postoperative depression scores, with secondary outcomes including the prevalence of postoperative depression, pain scores using the Visual Analogue Scale or Numeric Rating Scale, and incidences of adverse reactions such as nausea/vomiting, dizziness, dreams/nightmares, hallucinations. RESULTS: We enrolled a total of 17 studies involving 2462 patients. The esketamine group demonstrated a significant reduction in postoperative depression scores within one week after surgery (SMD -0.47, 95% CI (-0.66, -0.27), P < 0.001) and over the long term (SMD -0.44, 95% CI (-0.79, -0.09), P = 0.01). Furthermore, esketamine significantly decreased the prevalence of postoperative depression both within one week (RR 0.46, 95% CI (0.33, 0.63), P < 0.001) and over the long term (RR 0.50, 95% CI (0.36, 0.70), P < 0.001). Additionally, esketamine effectively relieved pain on the first postoperative day compared to control. However, it also increased the risks of dizziness and hallucinations for a short time. CONCLUSION: This meta-analysis suggests that the intraoperative or postoperative application of esketamine could be a potentially effective treatment for perioperative depression, although the increased risk of adverse reactions should be considered.

Artificial intelligence algorithms for predicting post-operative ileus after laparoscopic surgery.

Objective: By constructing a predictive model using machine learning and deep learning technologies, we aim to understand the risk factors for postoperative intestinal obstruction in laparoscopic colorectal cancer patients, and establish an effective artificial intelligence-based predictive model to guide individualized prevention and treatment, thus improving patient outcomes. Methods: We constructed a model of the artificial intelligence algorithm in Python. Subjects were randomly assigned to either a training set for variable identification and model construction, or a test set for testing model performance, at a ratio of 7:3. The model was trained with ten algorithms. We used the AUC values of the ROC curves, as well as accuracy, precision, recall rate and F1 scores. Results: The results of feature engineering composited with the GBDT algorithm showed that opioid use, anesthesia duration, and body weight were the top three factors in the development of POI. We used ten machine learning and deep learning algorithms to validate the model, and the results were as follows: the three algorithms with best accuracy were XGB (0.807), Decision Tree (0.807) and Neural DecisionTree (0.807); the two algorithms with best precision were XGB (0.500) and Decision Tree (0.500); the two algorithms with best recall rate were adab (0.243) and Decision Tree (0.135); the two algorithms with highest F1 score were adab (0.290) and Decision Tree (0.213); and the three algorithms with best AUC were Gradient Boosting (0.678), XGB (0.638) and LinearSVC (0.633). Conclusion: This study shows that XGB and Decision Tree are the two best algorithms for predicting the risk of developing ileus after laparoscopic colon cancer surgery. It provides new insight and approaches to the field of postoperative intestinal obstruction in colorectal cancer through the application of machine learning techniques, thereby improving our understanding of the disease and offering strong support for clinical decision-making.

A predictive model for post-thoracoscopic surgery pulmonary complications based on the PBNN algorithm.

We constructed an early prediction model for postoperative pulmonary complications after thoracoscopic surgery using machine learning and deep learning algorithms. The artificial intelligence prediction models were built in Python, primarily using artificial intelligencealgorithms including both machine learning and deep learning algorithms. Correlation analysis showed that postoperative pulmonary complications were positively correlated with age and surgery duration, and negatively correlated with serum albumin. Using the light gradient boosting machine(LGBM) algorithm, weighted feature engineering revealed that single lung ventilation duration, history of smoking, surgery duration, ASA score, and blood glucose were the main factors associated with postoperative pulmonary complications. Results of artificial intelligence algorithms for predicting pulmonary complications after thoracoscopy in the test group: In terms of accuracy, the two best algorithms were Logistic Regression (0.831) and light gradient boosting machine(0.827); in terms of precision, the two best algorithms were Gradient Boosting (0.75) and light gradient boosting machine (0.742); in terms of recall, the three best algorithms were gaussian naive bayes (0.581), Logistic Regression (0.532), and pruning Bayesian neural network (0.516); in terms of F1 score, the two best algorithms were LogisticRegression (0.589) and pruning Bayesian neural network (0.566); and in terms of Area Under Curve(AUC), the two best algorithms were light gradient boosting machine(0.873) and pruning Bayesian neural network (0.869). The results of this study suggest that pruning Bayesian neural network (PBNN) can be used to assess the possibility of pulmonary complications after thoracoscopy, and to identify high-risk groups prior to surgery.

Causal association between genetically predicted circulating immune cell counts and frailty: a two-sample Mendelian randomization study.

Background: Despite the recognized link between immune responses and frailty, the association between immune cell counts and frailty based on previous observational studies remains disputed, with uncertain causal nexus. This study aimed to elucidate causal association between genetically predicted circulating immune cell counts and frailty. Methods: We conducted the two-sample Mendelian randomization (MR) study with independent genetic variants associated with six immune cell subtype counts from genome-wide association studies in 563,946 European individuals. Frailty summary data, assessed via frailty index (FI), was obtained from study comprising 175,226 subjects. Univariate MR, reverse MR and multivariate MR were conducted to comprehensive investigate the association between immune cell counts and FI, with two-step MR analysis for mediation analysis. Results: Univariate MR evidence indicated that among six leukocyte subtype counts, only elevated eosinophil count was significantly correlated with higher FI (ß = 0.059, 95% confidence interval [CI], 0.042-0.078, P=5.63E-11), with no reverse causal relationship identified in reverse MR. In multivariate MR, the causal effect of eosinophil count retained statistical significance (ß = 0.063, 95% CI, 0.021-0.104, P = 0.003). Ultimately, the two-step MR analysis demonstrated two mediators in this causal pathway: asthma (ß= 0.019, 95% CI, 0.013-0.025, P = 35.84E-10, mediated proportion, 31.732%) and rheumatoid arthritis (ß= 0.004, 95% CI, 0.001-0.006, P=1.75E-03, mediated proportion, 6.411%). Conclusions: Within immune cell subtypes, MR evidence indicated only genetically predicted circulating eosinophil count had irreversible and independent causal effect on frailty, with asthma and rheumatoid arthritis possibly serving as partial mediators. The finding stressed the need for further exploring physiological functions of eosinophils in order to develop effective strategies against frailty.

Repeated (S)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota-brain axis.

Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (S)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (S)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (S)-ketamine treatments improved the abnormal composition of the gut microbiome (ß-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut - brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (S)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated (S)-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (S)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota - brain axis, primarily through the enhancement of hippocampal BDNF - TrkB signaling by butyrate.

Rbfox1 regulates alternative splicing of Nrcam in primary sensory neurons to mediate peripheral nerve injury-induced neuropathic pain.

The primary sensory neurons of the dorsal root ganglia (DRG) are subject to transcriptional alterations following peripheral nerve injury. These alterations are believed to play a pivotal role in the genesis of neuropathic pain. Alternative RNA splicing is a process that generates multiple transcript variants from a single gene, significantly contributing to the complexity of the transcriptome. However, little is known about the functional significance and control of alternative RNA splicing in injured DRG after spinal nerve ligation (SNL). In our study, we conducted a comprehensive transcriptome profiling and bioinformatic analysis to approach and identified a neuron-specific isoform of an RNA splicing regulator, RNA-binding Fox1 (Rbfox1, also known as A2BP1), as a crucial regulator of alternative RNA splicing in injured DRG after SNL. Notably, Rbfox1 expression is markedly reduced in injured DRG following peripheral nerve injury. Restoring this reduction effectively mitigates nociceptive hypersensitivity. Conversely, mimicking the downregulation of Rbfox1 expression generates neuropathic pain symptoms. Mechanistically, we uncovered that Rbfox1 may be a key factor influencing alternative RNA splicing of neuron-glial related cell adhesion molecule (NrCAM), a key neuronal cell adhesion molecule. In injured DRG after SNL, the downregulation of Rbfox1amplifies the insertion of exon 10 in Nrcam transcripts, leading to an increase in long Nrcam variants (L-Nrcam) and a corresponding decrease in short Nrcam variants (S-Nrcam) within injured DRG. In summary, our study supports the essential role of Rbfox1 in neuropathic pain within DRG, probably via the regulation of Nrcam splicing. These findings suggest that Rbfox1 could be a potential target for neuropathic pain therapy.

Clinical variables and genetic variants associated with perioperative anaphylaxis in Chinese Han population: A pilot study.

Background: Perioperative anaphylaxis (POA) can lead to severe consequences. Identifying clinical risk factors and genetic loci associated with POA through pre-prescription screening may help reduce its incidence. Methods: Using univariate regression and covariate-adjusted multivariate regression, we retrospectively analyzed the association between clinical characteristics and POA in 72 POA patients and 72 non-POA individuals. The discovery study of whole-exome association relied on whole-exome sequencing of 73 POA cases and 1339 healthy individuals. A replication study involving an independent set of 16 POA cases and 1339 healthy individuals confirmed this association. The accurate typing of human leucocyte antigen through exome sequencing (ATHLATES) algorithm and the whole-exome sequencing data were used for genotyping the human leucocyte antigen G (HLA-G) of 73 POA patients. The HLA-G of 16 POA cases and 122 non-POA patients were genotyped through Sanger sequencing. We used Fisher's exact probability method to compare the allele and carrier frequencies between POA patients and healthy individuals or non-POA patients. A Pc (P/Bonferroni correction coefficient) < 0.05 represents statistical significance. Results: Regression analysis identified female sex, an unconfirmed food allergy label, and a history of prior surgery as clinical variables associated with POA. The whole-exome association discovery study identified a strong signal in the major histocompatibility complex region on chromosome 6, with the rs1130356 being the most significant locus (P = 1.5E-10, OR = 3.4, 95% CI = 2.4-4.9). The replication study verified the association between the rs1130356-T allele and POA cases (P = 1.0E-6, OR = 6.3, 95% CI = 3.1-12.7). Compared with non-POA patients, HLA-G∗01:01 (Pc = 2.4E-4, OR = 2.4, 95% CI = 1.6-3.6) was significantly enriched, while HLA-G∗01:04 (Pc = 1.2E-6, OR = 0.3, 95% CI = 0.2-0.5) was lessened in POA patients. Conclusion: Our study suggested an association between POA and the risk factors of female sex, an unconfirmed food allergy label, and prior surgery. HLA-G, located in the human leucocyte antigen (HLA) region, may act as a surrogate genetic marker for POA. This suggests a causal relationship between this specific genomic region and POA. Our findings shed light on the contribution of human exome genetic variants to the susceptibility to POA.

TMEM63B channel is the osmosensor required for thirst drive of interoceptive neurons.

Thirst plays a vital role in the regulation of body fluid homeostasis and if deregulated can be life-threatening. Interoceptive neurons in the subfornical organ (SFO) are intrinsically osmosensitive and their activation by hyperosmolarity is necessary and sufficient for generating thirst. However, the primary molecules sensing systemic osmolarity in these neurons remain elusive. Here we show that the mechanosensitive TMEM63B cation channel is the osmosensor required for the interoceptive neurons to drive thirst. TMEM63B channel is highly expressed in the excitatory SFO thirst neurons. TMEM63B deletion in these neurons impaired hyperosmolarity-induced drinking behavior, while re-expressing TMEM63B in SFO restored water appetite in TMEM63B-deficient mice. Remarkably, hyperosmolarity activates TMEM63B channels, leading to depolarization and increased firing rate of the interoceptive neurons, which drives drinking behavior. Furthermore, TMEM63B deletion did not affect sensitivities of the SFO neurons to angiotensin II or hypoosmolarity, suggesting that TMEM63B plays a specialized role in detecting hyperosmolarity in SFO neurons. Thus, our results reveal a critical osmosensor molecule for the generation of thirst perception.

Clemastine-induced enhancement of hippocampal myelination alleviates memory impairment in mice with chronic pain.

Patients with chronic pain often experience memory impairment, but the underlying mechanisms remain elusive. The myelin sheath is crucial for rapid and accurate action potential conduction, playing a pivotal role in the development of cognitive abilities in the central nervous system. The study reveals that myelin degradation occurs in the hippocampus of chronic constriction injury (CCI) mice, which display both chronic pain and memory impairment. Using fiber photometry, we observed diminished task-related neuronal activity in the hippocampus of CCI mice. Interestingly, the repeated administration with clemastine, which promotes myelination, counteracts the CCI-induced myelin loss and reduced neuronal activity. Notably, clemastine specifically ameliorates the impaired memory without affecting chronic pain in CCI mice. Overall, our findings highlight the significant role of myelin abnormalities in CCI-induced memory impairment, suggesting a potential therapeutic approach for treating memory impairments associated with neuropathic pain.

Liraglutide ameliorates delirium-like behaviors of aged mice undergoing cardiac surgery by mitigating microglia activation via promoting mitophagy.

OBJECTIVE: Postoperative delirium (POD) is a prevalent complication in cardiac surgery patients, particularly the elderly, with neuroinflammation posited as a crucial contributing factor. We investigated the prophylactic effects of liraglutide, a GLP-1 analog, on delirium-like behaviors in aged mice undergoing cardiac surgery and explored the underlying mechanisms focusing on neuroinflammation, mitochondrial dysfunction, and synaptic plasticity. METHODS: Using a cardiac ischemia-reperfusion animal model to mimic cardiac surgery, we assessed delirium-like behaviors, microglial activation, NLRP3 inflammasome activation, mitophagy, synaptic engulfment, and synaptic plasticity. RESULTS: Cardiac surgery triggered delirium-like behaviors, concomitant with heightened microglial and NLRP3 inflammasome activation and impaired mitochondrial function and synaptic plasticity. Pretreatment with liraglutide ameliorated these adverse outcomes. Mechanistically, liraglutide enhanced mitophagy, thereby inhibiting NLRP3 inflammasome activation and subsequent microglial activation. Furthermore, liraglutide counteracted surgery-induced synaptic loss and impairment of synaptic plasticity. CONCLUSION: Liraglutide exerts protective effects against delirium-like behaviors in aged mice post-cardiac surgery, potentially through bolstering microglia mitophagy, curtailing neuroinflammation, and preserving synaptic integrity. This highlights the potential of liraglutide as a promising perioperative strategy for delirium prevention in cardiac surgery patients.

SynCAM1 deficiency in the hippocampal parvalbumin interneurons contributes to sevoflurane-induced cognitive impairment in neonatal rats.

AIMS: Sevoflurane is widely used for general anesthesia in children. Previous studies reported that multiple neonatal exposures to sevoflurane can induce long-term cognitive impairment in adolescent rats, but the underlying mechanisms were not defined. METHODS: Postnatal day 6 (P6) to P8 rat pups were exposed to 30% oxygen with or without 3% sevoflurane balanced with air. The Y maze test (YMT) and Morris water maze (MWM) tests were performed in some cohorts from age P35 to assess cognitive functions, and their brain samples were harvested at age P14, 21, 28, 35, and 42 for measurements of various molecular entities and in vivo electrophysiology experiments at age P35. RESULTS: Sevoflurane exposure resulted in cognitive impairment that was associated with decreased synCAM1 expression in parvalbumin (PV) interneurons, a reduction of PV phenotype, disturbed gamma oscillations, and dendritic spine loss in the hippocampal CA3 region. Enriched environment (EE) increased synCAM1 expression in the PV interneurons and attenuated sevoflurane-induced cognitive impairment. The synCAM1 overexpression by the adeno-associated virus vector in the hippocampal CA3 region restored sevoflurane-induced cognitive impairment, PV phenotype loss, gamma oscillations decrease, and dendritic spine loss. CONCLUSION: Our data suggested that neonatal sevoflurane exposure results in cognitive impairment through decreased synCAM1 expression in PV interneurons in the hippocampus.

Myelin-associated oligodendrocytic basic protein-dependent myelin repair confers the long-lasting antidepressant effect of ketamine.

Ketamine exhibits rapid and sustained antidepressant effects. As decreased myelination has been linked to depression pathology, changes in myelination may be a pivotal mechanism underlying ketamine's long-lasting antidepressant effects. Although ketamine has a long-lasting facilitating effect on myelination, the precise roles of myelination in ketamine's sustained antidepressant effects remain unknown. In this study, we employed spatial transcriptomics (ST) to examine ketamine's lasting effects in the medial prefrontal cortex (mPFC) and hippocampus of mice subjected to chronic social defeat stress and identified several differentially expressed myelin-related genes. Ketamine's ability to restore impaired myelination in the brain by promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes was demonstrated. Moreover, we showed that inhibiting the expression of myelin-associated oligodendrocytic basic protein (Mobp) blocked ketamine's long-lasting antidepressant effects. We also illustrated that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signaling mediated ketamine's facilitation on myelination. In addition, we found that the (R)-stereoisomer of ketamine showed stronger effects on myelination than (S)-ketamine, which may explain its longer-lasting antidepressant effects. These findings reveal novel mechanisms underlying the sustained antidepressant effects of ketamine and the differences in antidepressant effects between (R)-ketamine and (S)-ketamine, providing new insights into the role of myelination in antidepressant mechanisms.

Plasma Aß level alterations after sleep deprivation correspond to brain structural remodeling in medical night shift workers.

The relationship between brain structure alteration and metabolic product clearance after night shift work with total sleep deprivation (SD) remains unclear. Twenty-two intensive care unit staff on regularly rotating shift work were implemented with structural and diffusion MRI under both rest wakefulness (RW) and SD conditions. Peripheral blood samples were collected for the measurement of cerebral metabolites. Voxel-based morphometry and diffusion tensor imaging analysis were used to investigate the alterations in the gray matter density (GMD) and mean diffusivity (MD) within the participants. Furthermore, correlation analysis was performed to investigate the relationship between the neuroimaging metrics and hematological parameters. A significant increase in the GMD values was observed in the anterior and peripheral areas of the brain under SD. In contrast, a decrease in the values was observed in the posterior regions, such as the bilateral cerebellum and thalamus. In addition, a significant reduction in the total cerebrospinal fluid volume was observed under SD. The Aß42/Aß40 levels in participants under SD were significantly lower than those under RW. The mean MD increment values extracted from the region of interest (ROI) of the anterior brain were negatively correlated with the increment of plasma Aß42/Aß40 levels (r = -0.658, P = 0.008). The mean GMD decrement values extracted from the posterior ROI were positively correlated with the increment of plasma Aß-40 levels (r = 0.601, P = 0.023). The findings of this study suggest that one night of shift work under SD induces extensive and direction-specific structural alterations of the brain, which are associated with aberrant brain metabolic waste clearance.

The role of the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve in chronic inflammatory pain and comorbid spatial working memory impairment in complete Freund's adjuvant mice.

Chronic inflammatory pain (CIP) is a common public medical problem, often accompanied by memory impairment. However, the mechanisms underlying CIP and comorbid memory impairment remain elusive. This study aimed to examine the role of the gut-microbiota-brain axis in CIP and comorbid memory impairment in mice treated with complete Freund's adjuvant (CFA). 16S rRNA analysis showed the altered diversity of gut microbiota from day 1 to day 14 after CFA injection. Interestingly, fecal microbiota transplantation (FMT) from healthy naive mice ameliorated comorbidities, such as mechanical allodynia, thermal hyperalgesia, spatial working memory impairment, neuroinflammation, and abnormal composition of gut microbiota in the CFA mice. Additionally, subdiaphragmatic vagotomy (SDV) blocked the onset of these comorbidities. Interestingly, the relative abundance of the bacterial genus or species was also correlated with these comorbidities after FMT or SDV. Therefore, our results suggest that the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve is crucial for the development of CIP and comorbid spatial working memory impairment in CFA mice.

Peroxisome proliferator-activated receptor gamma agonist pioglitazone alleviates hemorrhage-induced thalamic pain and neuroinflammation.

BACKGROUND: Thalamic pain frequently occurs after stroke and is a challenging clinical issue. However, the mechanisms underlying thalamic pain remain unclear. Neuroinflammation is a key determining factor in the occurrence and maintenance of hemorrhage-induced thalamic pain. Pioglitazone is an agonist of peroxisome proliferator-activated receptor gamma (PPARγ) and shows anti-inflammatory effects in multiple diseases. The present work focused on exploring whether PPARγ is related to hemorrhage-induced thalamic pain. METHODS: Immunostaining was conducted to analyze the cellular localization of PPARγ and co-localization was evaluated with NeuN, ionized calcium-binding adapter molecular 1 (IBA1), and glia fibrillary acidic protein (GFAP). Western blot analyses were used to evaluate MyD88, pNF-κB/NF-κB, pSTAT6/STAT6, IL-1ß, TNF-α, iNOS, Arg-1, IL-4, IL-6, and IL-10 expression. Behavioral tests in mice were conducted to evaluate continuous pain hypersensitivity. RESULTS: We found that pioglitazone appeared to mitigate the contralateral hemorrhage-induced thalamic pain while inhibiting inflammatory responses. Additionally, Pioglitazone induced phosphorylation of STAT6 and suppressed the phosphorylation NF-κB in our model of thalamic pain. These effects could be partially reversed with the PPARγ antagonist GW9662. CONCLUSION: The PPARγ agonist pioglitazone can mitigate mechanical allodynia by suppressing the NF-κB inflammasome while activating the STAT6 signal pathway, which are well-known to be associated with inflammation.

Human umbilical cord-derived mesenchymal stem cells ameliorate perioperative neurocognitive disorder by inhibiting inflammatory responses and activating BDNF/TrkB/CREB signaling pathway in aged mice.

BACKGROUND: Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice. METHODS: hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in eighteen-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, systemic and neuroinflammatory responses, neuroplasticity, endogenous neurogenesis, and brain-derived neurotrophic factor (BDNF) were assessed. To determine the brain mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated. RESULTS: hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of systemic and hippocampal inflammation and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND. CONCLUSIONS: Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.