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Frontiers in Cardiovascular Medicine 2022Following acute myocardial infarction (MI), irreversible damage to the myocardium can only be reduced by shortening the duration between symptom onset and...
BACKGROUND
Following acute myocardial infarction (MI), irreversible damage to the myocardium can only be reduced by shortening the duration between symptom onset and revascularization. While systemic hypothermia has shown promising results in slowing pre-revascularization myocardial damage, it is resource intensive and not conducive to prehospital initiation. We hypothesized that topical neck cooling (NC), an easily implemented therapy for en route transfer to definitive therapy, could similarly attenuate myocardial ischemia-reperfusion injury (IRI).
METHODS
Using an mouse model of myocardial IRI, moderate systemic hypothermia or NC was applied following left coronary artery (LCA) occlusion and subsequent reperfusion, at early, late, and post-reperfusion intervals. Vagotomy was performed after late NC in an additional group. Hearts were harvested to measure infarct size.
RESULTS
Both hypothermia treatments equally attenuated myocardial infarct size by 60% compared to control. The infarct-sparing effect of NC was temperature-dependent and timing-dependent. Vagotomy at the gastroesophageal junction abolished the infarct-sparing effect of late NC. Cardiac perfusate isolated following ischemia had significantly reduced cardiac troponin T, HMGB1, cell-free DNA, and interferon α and β levels after NC.
CONCLUSIONS
Topical neck cooling attenuates myocardial IRI in a vagus nerve-dependent manner, with an effect comparable to that of systemic hypothermia. NC attenuated infarct size when applied during ischemia, with earlier initiation resulting in superior infarct sparing. This novel therapy exerts a cardioprotective effect without requiring significant change in core temperature and may be a promising practical strategy to attenuate myocardial damage while patients await definitive revascularization.
PubMed: 35837603
DOI: 10.3389/fcvm.2022.893837 -
Nutrients Jun 2022Gamma-aminobutyric acid (GABA) is present in the mammalian brain as the main inhibitory neurotransmitter and in foods. It is widely used as a supplement that regulates...
Gamma-aminobutyric acid (GABA) is present in the mammalian brain as the main inhibitory neurotransmitter and in foods. It is widely used as a supplement that regulates brain function through stress-reducing and sleep-enhancing effects. However, its underlying mechanisms remain poorly understood, as it is reportedly unable to cross the blood-brain barrier. Here, we explored whether a single peroral administration of GABA affects feeding behavior as an evaluation of brain function and the involvement of vagal afferent nerves. Peroral GABA at 20 and 200 mg/kg immediately before refeeding suppressed short-term food intake without aversive behaviors in mice. However, GABA administration 30 min before refeeding demonstrated no effects. A rise in circulating GABA concentrations by the peroral administration of 200 mg/kg GABA was similar to that by the intraperitoneal injection of 20 mg/kg GABA, which did not alter feeding. The feeding suppression by peroral GABA was blunted by the denervation of vagal afferents. Unexpectedly, peroral GABA alone did not alter vagal afferent activities histologically. The coadministration of a liquid diet and GABA potentiated the postprandial activation of vagal afferents, thereby enhancing postprandial satiation. In conclusion, dietary GABA activates vagal afferents in collaboration with meals or meal-evoked factors and regulates brain function including feeding behavior.
Topics: Animals; Diet; Eating; Mammals; Mice; Satiation; Vagus Nerve; gamma-Aminobutyric Acid
PubMed: 35745222
DOI: 10.3390/nu14122492 -
Nutrients May 2022(1) Background: A tryptic hydrolysate of bovine α-casein (CH) exerts anxiolytic-like properties in many species, including humans. This is mainly related to the...
The Anxiolytic-like Properties of a Tryptic Hydrolysate of Bovine α Casein Containing α-Casozepine Rely on GABA Receptor Benzodiazepine Binding Sites but Not the Vagus Nerve.
(1) Background: A tryptic hydrolysate of bovine α-casein (CH) exerts anxiolytic-like properties in many species, including humans. This is mainly related to the presence of α-casozepine (α-CZP), which yields these properties in rodents. This study evaluates, in a rat model, the roles of the vagus nerve and the benzodiazepine binding site of GABA receptors in the mode of action of CH. (2) Methods: The conditioned defensive burying test was used to evaluate anxiety. (3) Results: Participation of the vagus nerve in the mode of action of CH was excluded, as the global anxiety score in vagotomised rats was not significantly different from that of non-vagotomised animals. The blocking of the binding sites of benzodiazepines with flumazenil antagonised CH anxiolytic-like properties. (4) Conclusions: The vagus nerve does not play a role in the anxiolytic-like properties of CH. On the other hand, this anxiolytic-like activity relies on the benzodiazepine binding site of the GABA receptors. This result is consistent with previous in vitro studies and, more specifically with the discovery of α-CZP, the peptide responsible for the anxiolytic-like properties of CH.
Topics: Animals; Anti-Anxiety Agents; Anxiety; Benzodiazepines; Binding Sites; Caseins; Cattle; Peptide Fragments; Rats; Receptors, GABA-A; Vagus Nerve; gamma-Aminobutyric Acid
PubMed: 35684011
DOI: 10.3390/nu14112212 -
Reproductive Biology and Endocrinology... Jun 2022Women with endometriosis have been shown to have a reduced vagal tone as compared with controls and vagotomy promoted while vagus nerve stimulation (VNS) decelerated the...
BACKGROUND
Women with endometriosis have been shown to have a reduced vagal tone as compared with controls and vagotomy promoted while vagus nerve stimulation (VNS) decelerated the progression of endometriosis in mice. Extensive research also has shown that the activation of the cholinergic anti-inflammatory pathway by VNS activates α7 nicotinic acetylcholine receptor (α7nAChR), potently reducing inflammation. Yet whether α7nAChR plays any role in endometriosis is unknown. We evaluated its expression in normal endometrium, ovarian and deep endometriotic lesions, and evaluated its role in the development of endometriosis.
METHODS
Immunohistochemistry analyses of α7nAChR in endometriotic lesions as well as control endometrium, and quantification of tissue fibrosis by Masson trichrome staining were performed. Mouse experiments were conducted to evaluate the impact of α7nAChR activation or suppression on lesional progression and possible therapeutic effect. Finally, in vitro experiments were conducted to evaluate the effect of activation of α7nAChR on epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), smooth muscle metaplasia (SMM) and fibrogenesis in an endometriotic epithelial cell line and primary endometriotic stromal cells derived from ovarian endometrioma tissue samples.
RESULTS
Immunostaining of α7nAChR was significantly reduced in human endometriotic epithelial cells as compared with their counterpart in normal endometrium. Lesional α7nAChR staining levels correlated negatively with lesional fibrosis and the severity of dysmenorrhea. The α7nAChR agonist significantly impeded the development of endometriotic lesions in mouse models possibly through hindrance of EMT and FMT. It also demonstrated therapeutic effects in mice with induced deep endometriosis. Treatment of endometriotic epithelial and stromal cells with an α7nAChR agonist significantly abrogated platelet-induced EMT, FMT and SMM, and suppressed cellular contractility and collagen production.
CONCLUSIONS
α7nAChR is suppressed in endometriotic lesions, and its activation by pharmacological means can impede EMT, FMT, SMM, and fibrogenesis of endometriotic lesions. As such, α7nAChR can be rightfully viewed as a potential target for therapeutic invention.
TRIAL REGISTRATION
Not applicable.
Topics: Animals; Cell Transdifferentiation; Endometriosis; Female; Fibrosis; Humans; Mice; Myofibroblasts; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 35658970
DOI: 10.1186/s12958-022-00955-w -
GeroScience Aug 2022Cognitive function progressively declines with advancing age. The aging process can be promoted by obesity and attenuated by exercise. Both conditions affect levels of...
Cognitive function progressively declines with advancing age. The aging process can be promoted by obesity and attenuated by exercise. Both conditions affect levels of the chemokine CX3CL1 in peripheral tissues; however, its role in cognitive aging is unknown. In the current study, we administered CX3CL1 into the peritoneal cavity of aged mice to investigate its impact on the aging process. In the peritoneal cavity, CX3CL1 not only reversed the age-associated accumulation of cells expressing the senescence marker p16 but also increased peritoneal phagocytic activity, indicating that CX3CL1 affected the phenotypes of peritoneal cells. In the hippocampus of aged mice, intraperitoneal administration of CX3CL1 increased the number of Type-2 neural stem cells and promoted brain-derived neurotrophic factor (BDNF) expression. This treatment, furthermore, improved novel object recognition memory impaired with advancing age. Intraperitoneal transplantation of peritoneal cells from CX3CL1-treated aged mice improved novel object recognition memory in recipient aged mice. It indicates that peritoneal cells have a critical role in the CX3CL1-induced improvement of recognition memory in aged mice. Vagotomy inhibited the CX3CL1-induced increase in BDNF expression, demonstrating that the vagus nerve is involved in the hippocampal BDNF expression induced by intraperitoneal administration of CX3CL1. Thus, our results demonstrate that a novel connection among the peritoneal cells, the vagus nerve, and the hippocampus can reverse the age-associated decline in recognition memory.
Topics: Animals; Mice; Brain-Derived Neurotrophic Factor; Chemokine CX3CL1; Recognition, Psychology; Hippocampus; Cognition
PubMed: 35593945
DOI: 10.1007/s11357-022-00579-3 -
Molecular Medicine (Cambridge, Mass.) May 2022Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and...
BACKGROUND
Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm.
METHODS
The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes.
RESULTS
Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages.
CONCLUSIONS
These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.
Topics: Animals; Anti-Inflammatory Agents; COVID-19; Cytokine Release Syndrome; Famotidine; Histamine; Histamine H2 Antagonists; Lipopolysaccharides; Mice; Reflex; Vagus Nerve; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 35578169
DOI: 10.1186/s10020-022-00483-8 -
Cancers May 2022Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate... (Review)
Review
Interactions between the immune system and the nervous system are crucial in maintaining homeostasis, and disturbances of these neuro-immune interactions may participate in carcinogenesis and metastasis. Nerve endings have been identified within solid tumors in humans and experimental animals. Although the involvement of the efferent sympathetic and parasympathetic innervation in carcinogenesis has been extensively investigated, the role of the afferent sensory neurons and the neuropeptides in tumor development, growth, and progression is recently appreciated. Similarly, current findings point to the significant role of Schwann cells as part of neuro-immune interactions. Hence, in this review, we mainly focus on local and systemic effects of sensory nerve activity as well as Schwann cells in carcinogenesis and metastasis. Specific denervation of vagal sensory nerve fibers, or vagotomy, in animal models, has been reported to markedly increase lung metastases of breast carcinoma as well as pancreatic and gastric tumor growth, with the formation of liver metastases demonstrating the protective role of vagal sensory fibers against cancer. Clinical studies have revealed that patients with gastric ulcers who have undergone a vagotomy have a greater risk of stomach, colorectal, biliary tract, and lung cancers. Protective effects of vagal activity have also been documented by epidemiological studies demonstrating that high vagal activity predicts longer survival rates in patients with colon, non-small cell lung, prostate, and breast cancers. However, several studies have reported that inhibition of sensory neuronal activity reduces the development of solid tumors, including prostate, gastric, pancreatic, head and neck, cervical, ovarian, and skin cancers. These contradictory findings are likely to be due to the post-nerve injury-induced activation of systemic sensory fibers, the level of aggressiveness of the tumor model used, and the local heterogeneity of sensory fibers. As the aggressiveness of the tumor model and the level of the inflammatory response increase, the protective role of sensory nerve fibers is apparent and might be mostly due to systemic alterations in the neuro-immune response. Hence, more insights into inductive and permissive mechanisms, such as systemic, cellular neuro-immunological mechanisms of carcinogenesis and metastasis formation, are needed to understand the role of sensory neurons in tumor growth and spread.
PubMed: 35565462
DOI: 10.3390/cancers14092333 -
Obesity Surgery Jul 2022Evidences about the gut microbiota role in weight loss after bariatric surgery (BS) are growing. The objective of this study was to observe the changes of gut microbiota...
PURPOSE
Evidences about the gut microbiota role in weight loss after bariatric surgery (BS) are growing. The objective of this study was to observe the changes of gut microbiota after sleeve gastrectomy (SG) and SG plus truncal vagotomy (SG-TV) and identify specific microbes that may contribute to the improvement of obesity after surgeries.
MATERIALS AND METHODS
Forty high-fat diet-induced obesity (DIO) mice were randomized to SG, SG-TV, or sham operation (SH) groups. Body weight (BW) and fast blood glucose (FBG) were measured before and 1, 2, 4, 8, and 12 weeks post-operatively. Fecal samples were collected before and at post-operative week 12 and profiled using 16S rRNA relative and absolute quantitative sequencing.
RESULTS
After the surgery, the SG and SG-TV surgeries significantly reduce BW and FBG levels compared with SH, and the SG-TV achieved better effects than SG. A decreasing trend in alpha diversity of gut microbiota and significant changes in taxonomic composition were observed after surgeries. Then, we identified a set of microbes and pathways significantly different in abundance after BS. The genus Parabacteroides and one pathway (polyketide sugar unit biosynthesis) increased in SG-TV group specially, which was also negatively correlated with BW and FBG.
CONCLUSION
SG and SG-TV indeed achieve effects of weight loss, but TV could enhance the efficacy of SG. The identified different microbes and pathways, like Parabacteroides, polyketide sugar unit biosynthesis, may partly mediate the beneficial effects of BS, and thus possibly contribute to the development of novel bacteria-based therapeutic approaches.
Topics: Animals; Bariatric Surgery; Gastrectomy; Mice; Obesity; Obesity, Morbid; Polyketides; RNA, Ribosomal, 16S; Sugars; Vagotomy, Truncal; Weight Loss
PubMed: 35546385
DOI: 10.1007/s11695-022-06017-9 -
Physiological Reports May 2022Vitronectin (VTN) is a glycoprotein enriched in the blood and activates integrin receptors. VTN blood levels increase only in female mice 24 h after an ischemic stroke...
Vitronectin (VTN) is a glycoprotein enriched in the blood and activates integrin receptors. VTN blood levels increase only in female mice 24 h after an ischemic stroke and exacerbate brain injury through IL-6-driven inflammation, but the VTN induction mechanism is unknown. Here, a 30 min middle cerebral artery occlusion (MCAO) in female mice induced VTN protein in the liver (normally the main source) in concert with plasma VTN. Male mice were excluded as VTN is not induced after stroke. MCAO also increased plasma VTN levels after de novo expression of VTN in the liver of VTN female mice, using a hepatocyte-specific (SERPINA1) promoter. MCAO did not affect SERPINA1 or VTN mRNA in the liver, brain, or several peripheral organs, or platelet VTN, compared to sham mice. Thus, hepatocytes are the source of stroke-induced increases in plasma VTN, which is independent of transcription. The cholinergic innervation by the parasympathetic vagus nerve is a potential source of brain-liver signaling after stroke. Right-sided vagotomy at the cervical level led to increased plasma VTN levels, suggesting that VTN release is inhibited by vagal tone. Co-culture of hepatocytes with cholinergic neurons or treatment with acetylcholine, but not noradrenaline (sympathetic transmitter), suppressed VTN expression. Hepatocytes have muscarinic receptors and the M1/M3 agonist bethanechol decreased VTN mRNA and protein release in vitro via M1 receptors. Finally, systemic bethanechol treatment blocked stroke-induced plasma VTN. Thus, VTN translation and release are inhibited by muscarinic signaling from the vagus nerve and presents a novel target for lessening detrimental VTN expression.
Topics: Animals; Bethanechol; Cholinergic Agents; Female; Infarction, Middle Cerebral Artery; Integrins; Liver; Mice; RNA, Messenger; Stroke; Vagus Nerve; Vitronectin
PubMed: 35531929
DOI: 10.14814/phy2.15301 -
Clinical Psychopharmacology and... May 2022Gut-microbiota-brain axis plays a role in the pathogenesis of Parkinson's disease (PD). The subdiaphragmatic vagus nerve serves as a major modulatory pathway between the...
OBJECTIVE
Gut-microbiota-brain axis plays a role in the pathogenesis of Parkinson's disease (PD). The subdiaphragmatic vagus nerve serves as a major modulatory pathway between the gut microbiota and the brain. However, the role of subdiaphragmatic vagus nerve in PD pathogenesis are unknown. Here, we investigated the effects of subdiaphragmatic vagotomy (SDV) on the neurotoxicity in the mouse striatum and colon after administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP).
METHODS
Sham or SVD was performed. Subsequently, saline or MPTP (10 mg/kg × 3, 2-hour interval) was administered to mice. Western blot analysis of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum and phosphorylated α-synuclein (p-α-Syn) in the colon was performed.
RESULTS
Repeated administration of MPTP significantly caused reduction of TH and DAT in the striatum and increase of p-α-Syn in the colon of mice. However, SDV did not affect the reduction of TH and DAT in the striatum and increases in p-α-Syn in the colon after repeated MPTP administration.
CONCLUSION
These data suggest that subdiaphragmatic vagus nerve doses not play a role in the MPTP-induced neurotoxicity in the brain and colon.
PubMed: 35466109
DOI: 10.9758/cpn.2022.20.2.389