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Neurobiology of Disease Mar 2024Depression frequently occurs in patients with liver cirrhosis, yet the reasons for this correlation are not fully understood. Dysbiosis of gut microbiota has been...
Depression frequently occurs in patients with liver cirrhosis, yet the reasons for this correlation are not fully understood. Dysbiosis of gut microbiota has been implicated in depression through the gut-brain axis via the vagus nerve. This study explored the potential role of the gut-liver-brain axis via the vagus nerve in depression-like phenotypes in mice with liver cirrhosis. These mice underwent common bile duct ligation (CBDL), a method used to stimulate liver cirrhosis. To assess depression-like behaviors, behavioral tests were conducted 10 days following either sham or CBDL surgeries. The mice with CBDL displayed symptoms such as splenomegaly, elevated plasma levels of interleukin-6 and tumor necrosis factor-α, depression-like behaviors, decreased levels of synaptic proteins in the prefrontal cortex (PFC), disrupted gut microbiota balance, and changes in blood metabolites (or lipids). Additionally, there were positive or negative correlations between the relative abundance of microbiome and behavioral data or blood metabolites (or lipids). Significantly, these changes were reversed in CBDL mice by performing a subdiaphragmatic vagotomy. Intriguingly, depression-like phenotypes in mice with CBDL were improved after a single injection of arketamine, a new antidepressant. These results suggest that CBDL-induced depression-like phenotypes in mice are mediated through the gut-liver-brain axis via the subdiaphragmatic vagus nerve, and that arketamine might offer a new treatment approach for depression in liver cirrhosis patients.
Topics: Mice; Humans; Animals; Brain-Gut Axis; Depression; Common Bile Duct; Liver Cirrhosis; Vagus Nerve; Ligation; Brain; Lipids
PubMed: 38331354
DOI: 10.1016/j.nbd.2024.106433 -
Pharmaceuticals (Basel, Switzerland) Dec 2023Purine nucleosides (adenosine) and nucleotides such as adenosine mono/di/triphosphate (AMP/ADP/ATP) may produce complex cardiovascular responses. For example,...
Purine nucleosides (adenosine) and nucleotides such as adenosine mono/di/triphosphate (AMP/ADP/ATP) may produce complex cardiovascular responses. For example, adenosine-5'-(β-thio)-diphosphate (ADPβS; a stable synthetic analogue of ADP) can induce vasodilatation/vasodepressor responses by endothelium-dependent and independent mechanisms involving purinergic P2Y receptors; however, the specific subtypes participating in these responses remain unknown. Therefore, this study investigated the receptor subtypes mediating the blood pressure changes induced by intravenous bolus of ADPβS in male Wistar rats in the absence and presence of central mechanisms with the antagonists MRS2500 (P2Y), PSB0739 (P2Y), and MRS2211 (P2Y). For this purpose, 120 rats were divided into 60 anaesthetised rats and 60 pithed rats, and further subdivided into four groups ( = 30 each), namely: (a) anaesthetised rats, (b) anaesthetised rats with bilateral vagotomy, (c) pithed rats, and (d) pithed rats continuously infused (intravenously) with methoxamine (an α-adrenergic agonist that restores systemic vascular tone). We observed, in all four groups, that the immediate decreases in diastolic blood pressure produced by ADPβS were exclusively mediated by peripheral activation of P2Y receptors. Nevertheless, the subsequent increases in systolic blood pressure elicited by ADPβS in pithed rats infused with methoxamine probably involved peripheral activation of P2Y, P2Y, and P2Y receptors.
PubMed: 38139810
DOI: 10.3390/ph16121683 -
The Journal of International Medical... Oct 2023To compare clinical and operative results between laparoscopic primary repair (LPR) alone and LPR with highly selective vagotomy (LPR-HSV) in patients with duodenal...
OBJECTIVE
To compare clinical and operative results between laparoscopic primary repair (LPR) alone and LPR with highly selective vagotomy (LPR-HSV) in patients with duodenal ulcer perforation.
METHODS
Clinical data from patients who underwent either LPR or LPR-HSV by resecting both sides of the neurovascular bundle using an ultrasonic or bipolar electrosurgical device for duodenal ulcer perforations, between 2010 and 2020, were retrospectively collected. Between-group differences in continuous and categorical variables were statistically analysed.
RESULTS
Data from 184 patients (mean age, 49.6 years), who underwent either LPR ( = 132) or LPR-HSV ( = 52) were included. The mean operation time was significantly longer in the LPR-HSV group (116.5 ± 39.8 min) than in the LPR group (91.2 ± 33.3 min). Hospital stay was significantly shorter in the LPR-HSV group (8.6 ± 2.6 days) versus the LPR group (11.3 ± 7.1 days). The mean postoperative day of starting soft fluid diet was also significantly shorter in the LPR-HSV group (4.5 ± 1.4 days) than in the LPR group (5.6 ± 4 days). No between-group difference in morbidity rate was observed. The learning curve of the HSV procedure showed a stable procedure time after 10 operations.
CONCLUSIONS
LPR with HSV may be a safe and feasible procedure for selective cases who are at high risk for ulcer recurrence.
Topics: Humans; Middle Aged; Duodenal Ulcer; Vagotomy, Proximal Gastric; Retrospective Studies; Peptic Ulcer Perforation; Laparoscopy; Recurrence; Postoperative Complications
PubMed: 37890147
DOI: 10.1177/03000605231206319 -
Frontiers in Physiology 2024The influence of vagus nerve stimulation (VNS) parameters on provoked cardiac effects in different levels of cardiac innervation is not well understood yet. This study...
INTRODUCTION
The influence of vagus nerve stimulation (VNS) parameters on provoked cardiac effects in different levels of cardiac innervation is not well understood yet. This study examines the effects of VNS on heart rate (HR) modulation across a spectrum of cardiac innervation states, providing data for the potential optimization of VNS in cardiac therapies.
MATERIALS AND METHODS
Utilizing previously published data from VNS experiments on six sheep with intact innervation, and data of additional experiments in five rabbits post bilateral rostral vagotomy, and four isolated rabbit hearts with additionally removed sympathetic influences, the study explored the impact of diverse VNS parameters on HR.
RESULTS
Significant differences in physiological threshold charges were identified across groups: 0.09 ± 0.06 μC for intact, 0.20 ± 0.04 μC for vagotomized, and 9.00 ± 0.75 μC for isolated hearts. Charge was a key determinant of HR reduction across all innervation states, with diminishing correlations from intact ( = 0.7) to isolated hearts ( = 0.44). An inverse relationship was observed for the number of pulses, with its influence growing in conditions of reduced innervation (intact = 0.11, isolated = 0.37). Frequency and stimulation delay showed minimal correlations ( < 0.17) in all conditions.
CONCLUSION
Our study highlights for the first time that VNS parameters, including stimulation intensity, pulse width, and pulse number, crucially modulate heart rate across different cardiac innervation states. Intensity and pulse width significantly influence heart rate in innervated states, while pulse number is key in denervated states. Frequency and delay have less impact impact across all innervation states. These findings suggest the importance of customizing VNS therapy based on innervation status, offering insights for optimizing cardiac neuromodulation.
PubMed: 38835728
DOI: 10.3389/fphys.2024.1379936 -
Biology Jan 2024Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while...
BACKGROUND
Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype.
METHODS
Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3-54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages' CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR).
RESULTS
Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations.
CONCLUSIONS
The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.
PubMed: 38248469
DOI: 10.3390/biology13010038 -
Osteoarthritis and Cartilage Open Jun 2024Low vagal tone is common in osteoarthritis (OA) comorbidities and results in greater peripheral inflammation. Characterizing vagal tone's role in OA pathogenesis may...
OBJECTIVE
Low vagal tone is common in osteoarthritis (OA) comorbidities and results in greater peripheral inflammation. Characterizing vagal tone's role in OA pathogenesis may offer insights into OA's influences beyond the articular joint. We hypothesized that low vagal tone would accelerate onset of OA-related gait changes and worsen joint damage in a rat knee OA model.
METHODS
Knee OA was induced in male Sprague Dawley rats by transecting the medial collateral ligament and medial meniscus. Then, left cervical vagus nerve transection (VGX, n = 9) or sham VGX (non-VGX, n = 6) was performed. Gait and tactile sensitivity were assessed at baseline and across 12 weeks, with histology and systemic inflammation evaluated at endpoint.
RESULTS
At week 4, VGX animals showed limping gait characteristics through shifted stance times from their OA to non-OA limb (p = 0.055; stance time imbalance = 1.6 ± 1.6%) and shifted foot strike locations (p < 0.001; spatial symmetry = 48.4 ± 0.835%), while non-VGX animals walked with a balanced and symmetric gait. Also at week 4, while VGX animals had a mechanical sensitivity (50% withdrawal threshold) of 13.97 ± 7.70 compared to the non-VGX animal sensitivity of 29.74 ± 9.43, this difference was not statistically significant. Histologically, VGX animals showed thinner tibial cartilage and greater subchondral bone area than non-VGX animals (p = 0.076; VGX: 0.80 ± 0.036 mm; non-VGX: 0.736 ± 0.066 mm). No group differences in systemic inflammation were observed at endpoint.
CONCLUSIONS
VGX resulted in quicker onset of OA-related symptoms but remained unchanged at later timepoints. VGX also had thinner cartilage and abnormal bone remodeling than non-VGX. Overall, low vagal tone had mild effects on OA symptoms and joint remodeling, and not at the level seen in common OA comorbidities.
PubMed: 38655014
DOI: 10.1016/j.ocarto.2024.100467 -
Neurobiology of Disease Jun 2024Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to...
Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS model. We found that splenectomy significantly inhibited arketamine's antidepressant-like effects in CSDS-susceptible mice. RNA-sequencing analysis identified the oxidative phosphorylation (OXPHOS) pathway in the prefrontal cortex (PFC) as a key mediator of splenectomy's impact on arketamine's effects. Furthermore, oligomycin A, an inhibitor of the OXPHOS pathway, reversed the suppressive effects of splenectomy on arketamine's antidepressant-like effects. Specific genes within the OXPHOS pathways, such as COX11, UQCR11 and ATP5e, may contribute to these inhibitory effects. Notably, transforming growth factor (TGF)-β1, along with COX11, appears to modulate the suppressive effects of splenectomy and contribute to arketamine's antidepressant-like effects. Additionally, SRI-01138, an agonist of the TGF-β1 receptor, alleviated the inhibitory effects of splenectomy on arketamine's antidepressant-like effects. Subdiaphragmatic vagotomy also counteracted the inhibitory effects of splenectomy on arketamine's antidepressant-like effects in CSDS-susceptible mice. These findings suggest that the OXPHOS pathway and TGF-β1 in the PFC play significant roles in the antidepressant-like effects of arketamine, mediated through the spleen-brain axis via the vagus nerve.
PubMed: 38901783
DOI: 10.1016/j.nbd.2024.106573 -
Heliyon Apr 2024The use of proton pump inhibitors in the acute phase of cerebral infarction may lead to adverse long-term outcomes, this study aims to explore the potential of...
BACKGROUND
The use of proton pump inhibitors in the acute phase of cerebral infarction may lead to adverse long-term outcomes, this study aims to explore the potential of electroacupuncture (EA) in replacing omeprazole in exerting post-stroke gastrointestinal protection.
METHODS
A permanent middle cerebral artery infarction model was established using the modified Longa thread occlusion technique. Gastrointestinal motility, gastrointestinal mucosal damage, cerebral infarct volume, and alterations in choline acetyltransferase (ChAT)-positive neurons within the dorsal motor nucleus of the vagus nerve (DMV) were assessed after 7 days of EA at Zusanli (ST36) or omeprazole intervention. To evaluate the role of the vagal nerve in mitigating post-stroke gastrointestinal dysfunction, we employed subdiaphragmatic vagotomy and the ChAT-specific inhibitor α-NETA. Additionally, we utilized methyllycaconitine (MLA), a selective inhibitor of the α7-type nicotinic acetylcholine receptor (α7nAChR), and PNU282987, an agonist, to identify the target of EA.
RESULTS
EA restored ChAT neurons lost in the DMV, activated the vagus nerve and conferred cerebroprotection while ameliorating gastrointestinal mucosal injury and gastrointestinal motility disorders. In addition, following the administration of the α7nAChR antagonist, the attenuation of gastric mucosal injury and inflammatory factors induced by EA was hindered, although gastrointestinal motility still exhibited improvement.
CONCLUSION
EA at ST36 promotes the restoration of cholinergic signaling in the DMV of stroke-afflicted rats, and its excitation of the vagal nerve inhibits gastrointestinal inflammation after stroke via α7nAChR, while improvement in gastrointestinal motility could be mediated by other acetylcholine receptors.
PubMed: 38638995
DOI: 10.1016/j.heliyon.2024.e29426 -
Scientific Reports Apr 2024The vagus nerve is the only pathway for transmitting parasympathetic signals between the brain and thoracoabdominal organs, thereby exhibiting anti-inflammatory...
The vagus nerve is the only pathway for transmitting parasympathetic signals between the brain and thoracoabdominal organs, thereby exhibiting anti-inflammatory functions through the cholinergic anti-inflammatory pathway. Despite often being resected during lymph node dissection in upper gastrointestinal cancer surgery, the impact of vagotomy on postoperative outcomes in gastric cancer patients remains unclear. Sub-diaphragmatic vagotomy was performed on C57BL/6 mice. Three weeks later, syngeneic murine gastric cancer cell line YTN16P was injected into the peritoneal cavity, and the number of peritoneal metastases (PM) on the mesentery and omentum compared with control mice. The phenotypes of immune cells in peritoneal lavage and omental milky spots one day after tumor inoculation were analyzed using flow cytometry and immunohistochemistry. Intraperitoneal transfer of 3 × 10 YTN16P significantly increased the number of metastatic nodules on the mesentery in the vagotomy group compared to the control group. The omental metastasis grade was also significantly higher in the vagotomy group. Phenotypic analysis of immune cells in peritoneal lavage did not reveal significant differences after vagotomy. However, vagotomized mice exhibited a notable increase in milky spot area, with a higher presence of cytokeratin(+) tumor cells, F4/80(+) macrophages, and CD3(+) T cells. Vagus nerve signaling appears to regulate the immune response dynamics within milky spots against disseminated tumor cells and inhibits the development of PM. Preserving the vagus nerve may offer advantages in advanced gastric cancer surgery to reduce peritoneal recurrence.
Topics: Humans; Mice; Animals; Peritoneal Neoplasms; Stomach Neoplasms; Mice, Inbred C57BL; Omentum; Vagus Nerve
PubMed: 38570542
DOI: 10.1038/s41598-024-58440-w