Curcumin attenuates collagen-induced inflammatory response through the "gut-brain axis".

BACKGROUND: Previous studies have demonstrated that oral administration of curcumin exhibited an anti-arthritic effect despite its poor bioavailability. The present study aimed to explore whether the gut-brain axis is involved in the therapeutic effect of curcumin. METHODS: The collagen-induced arthritis (CIA) rat model was induced by immunization with an emulsion of collagen II and complete Freund's adjuvant. Sympathetic and parasympathetic tones were measured by electrocardiographic recordings. Unilateral cervical vagotomy (VGX) was performed before the induction of CIA. The ChAT, AChE activities, and serum cytokine levels were determined by ELISA. The expression of the high-affinity choline transporter 1 (CHT1), ChAT, and vesicular acetylcholine transporter (VAChT) were determined by real-time PCR and immunohistochemical staining. The neuronal excitability of the vagus nerve was determined by whole-cell patch clamp recording. RESULTS: Oral administration of curcumin restored the imbalance between the sympathetic and parasympathetic tones in CIA rats and increased ChAT activity and expression of ChAT and VAChT in the gut, brain, and synovium. Additionally, VGX eliminated the effects of curcumin on arthritis and ACh biosynthesis and transport. Electrophysiological data showed that curcumin markedly increased neuronal excitability of the vagus nerve. Furthermore, selective α7 nAChR antagonists abolished the effects of curcumin on CIA. CONCLUSIONS: Our results demonstrate that curcumin attenuates CIA through the "gut-brain axis" by modulating the function of the cholinergic system. These findings provide a novel approach for mechanistic studies of anti-arthritic compounds with low oral absorption and bioavailability.

Two-Year Outcomes of Vagal Nerve Blocking (vBloc) for the Treatment of Obesity in the ReCharge Trial.

BACKGROUND: The ReCharge Trial demonstrated that a vagal blocking device (vBloc) is a safe and effective treatment for moderate to severe obesity. This report summarizes 24-month outcomes. METHODS: Participants with body mass index (BMI) 40 to 45 kg/m2, or 35 to 40 kg/m2 with at least one comorbid condition were randomized to either vBloc therapy or sham intervention for 12 months. After 12 months, participants randomized to vBloc continued open-label vBloc therapy and are the focus of this report. Weight loss, adverse events, comorbid risk factors, and quality of life (QOL) will be assessed for 5 years. RESULTS: At 24 months, 123 (76 %) vBloc participants remained in the trial. Participants who presented at 24 months (n = 103) had a mean excess weight loss (EWL) of 21 % (8 % total weight loss [TWL]); 58 % of participants had ≥5 % TWL and 34 % had ≥10 % TWL. Among the subset of participants with abnormal preoperative values, significant improvements were observed in mean LDL (-16 mg/dL) and HDL cholesterol (+4 mg/dL), triglycerides (-46 mg/dL), HbA1c (-0.3 %), and systolic (-11 mmHg) and diastolic blood pressures (-10 mmHg). QOL measures were significantly improved. Heartburn/dyspepsia and implant site pain were the most frequently reported adverse events. The primary related serious adverse event rate was 4.3 %. CONCLUSIONS: vBloc therapy continues to result in medically meaningful weight loss with a favorable safety profile through 2 years. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01327976.

α-Terpineol Induces Gastric Retention of Liquids by Inhibiting Vagal Parasympathetic Pathways in Rats.

α-Terpineol is a monoterpene with smooth muscle relaxant properties. In this study, its effects on the gastric emptying rate of awake rats were evaluated with emphasis on the mode by which it induces gastrointestinal actions. Administered by gavage, α-terpineol (50 mg/kg) delayed gastric emptying of a liquid test meal at 10 min postprandial. Hexamethonium or guanethidine did not interfere with the retarding effect induced by α-terpineol, but atropine and L-NG-nitroarginine methyl ester abolished it. In vagotomized rats, α-terpineol did not delay gastric emptying. In isolated strips of gastric fundus, concentration-effect curves in response to carbamylcholine were higher in magnitude after treatment with the monoterpene. α-Terpineol (1 to 2000 µM) relaxed sustained contractions induced by carbamylcholine or a high K+ concentration in a concentration-dependent manner. This relaxing effect was not affected by the presence of L-NG-nitroarginine methyl ester, 1 H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, tetraethylammonium, or atropine. Smooth muscle contractions induced by electrical field stimulation were inhibited by α-terpineol. In conclusion, α-terpineol induced gastric retention in awake rats through mechanisms that depended on intact vagal innervation to the stomach, which involved cholinergic/nitrergic signalling. Such a retarding effect induced by α-terpineol appears not to result from a direct action of the monoterpene on gastric smooth muscle cells.

A Randomized Controlled Trial of Vagus Nerve-preserving Distal Gastrectomy Versus Conventional Distal Gastrectomy for Postoperative Quality of Life in Early Stage Gastric Cancer Patients.

OBJECTIVE: To compare the postoperative quality of life of vagus nerve preserving distal gastrectomy (VPG) vs conventional distal gastrectomy (CG) in patients with early-stage gastric cancer. DESIGN: Randomized controlled clinical trial. SETTING: Large tertiary comprehensive cancer center in Korea. PARTICIPANTS: One hundred sixty-three patients with early gastric cancer 18 years of age or older expected to undergo curative gastric resection. INTERVENTION: Patients were randomized 1:1 to VPG (n = 85) or CG (n = 78). MAIN OUTCOME MEASURES: European Organization for Research and Treatment of Cancer (EORTC) gastric module (STO22). RESULTS: Patients assigned to VPG showed less diarrhea 3 and 12 months after surgery (P = 0.040 and 0.048, respectively) and less appetite loss at 12 months (P = 0.011) compared with those assigned to CG. In both groups, fatigue, anxiety, eating restriction, and body image deteriorated at 3 months after surgery and did not regain baseline levels 12 months after surgery. There were no significant differences between the 2 groups in cancer recurrence and death over 5 years of follow-up. CONCLUSIONS: Early gastric cancer patients undergoing VPG reported significantly less diarrhea and appetite loss at 12 months postsurgery compared with those undergoing CG, with no differences in long-term clinical outcomes. VPG may improve the quality of life after gastrectomy in early gastric cancer patients compared with CG.

Selective atrial vagal denervation guided by spectral mapping to treat advanced atrioventricular block.

AIMS: Asymptomatic nocturnal long ventricular pauses are usually detected accidentally and it has been suggested that they may lead to sudden death. Identification of predisposing factors could prevent cardiovascular events. METHODS AND RESULTS: We report the case of a patient with frequent asymptomatic nocturnal ventricular pauses of 3-11 s, characteristic of a vagally mediated atrioventricular (AV) block. Echocardiography, treadmill test, thyroid function test levels, and polysomnogram were normal. In an attempt to reduce the risk, it was decided that an atrial vagal denervation induced by radiofrequency (RF) ablation (cardioneuroablation) could be useful. Spectral mapping was used to localize endocardial vagal innervation in the right and left aspects of the inter-atrial septum, responsible for the sinus node and AV node modulation, and RF pulses were applied in those sites only. After finishing the procedure, significant changes were observed in the heart rate (66-90 b.p.m.), atrial-His interval (115-74 ms), Wenckebach cycle length (820-570 ms), and sinus node recovery time (1100-760 ms). Follow-up Holter recording demonstrated that the number of ventricular pauses had reduced from 438 to 0. Heart rate and time domain characteristics were compatible with vagal denervation. CONCLUSION: Ablation of the endocardial vagal innervation sites seems to be safe and efficient in reducing the frequency and the length of the ventricular pauses. It was possible by identifying certain spectral components of the atrial electrogram, resulting in a conservative approach.

Experience with a Low Single Cervical Incision for Implantation of a Vagus Nerve Stimulator: Technique and Advantages.

OBJECTIVE: This report describes the technique for implanting a vagus nerve stimulator via a single low anterior cervical incision and discusses the advantages of this technique over that of the more commonly used 2-incision technique. METHODS: The authors performed a retrospective review of all patients who underwent implantation of a vagus nerve stimulator by the senior author over a 10-year period. RESULTS: One hundred thirty-one patients underwent implantation of vagus nerve stimulators via the single-incision technique. There were no instances of vagus nerve injury, postoperative hematoma, or wound infection, and cosmesis was excellent. CONCLUSION: The single-incision technique described here for implantation of vagus nerve stimulators is technically straightforward and safe, and has significant advantages over the 2-incision technique.

Blood lipids affect rat islet blood flow regulation through ß3-adrenoceptors.

Pancreatic islet blood perfusion varies according to the needs for insulin secretion. We examined the effects of blood lipids on pancreatic islet blood flow in anesthetized rats. Acute administration of Intralipid to anesthetized rats increased both triglycerides and free fatty acids, associated with a simultaneous increase in total pancreatic and islet blood flow. A preceding abdominal vagotomy markedly potentiated this and led acutely to a 10-fold increase in islet blood flow associated with a similar increase in serum insulin concentrations. The islet blood flow and serum insulin response could be largely prevented by pretreatment with propranolol and the selective ß3-adrenergic inhibitor SR-59230A. The nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester prevented the blood flow increase but was less effective in reducing serum insulin. Increased islet blood flow after Intralipid administration was also seen in islet and whole pancreas transplanted rats, i.e., models with different degrees of chronic islet denervation, but the effect was not as pronounced. In isolated vascularly perfused single islets Intralipid dilated islet arterioles, but this was not affected by SR-59230A. Both the sympathetic and parasympathetic nervous system are important for the coordination of islet blood flow and insulin release during hyperlipidemia, with a previously unknown role for ß3-adrenoceptors.

Electroacupuncture improves gut barrier dysfunction in prolonged hemorrhagic shock rats through vagus anti-inflammatory mechanism.

AIM: To investigate whether electroacupuncture (EA) at Zusanli (ST36) prevents intestinal barrier and remote organ dysfunction following prolonged hemorrhagic shock through a vagus anti-inflammatory mechanism. METHODS: Sprague-Dawley rats were subjected to about 45% of total blood volume loss followed by delayed fluid replacement (DFR) with Ringer lactate 3h after hemorrhage. In a first study, rats were randomly divided into six groups: (1) EAN: EA at non-channel acupoints followed by DFR; (2) EA: EA at ST36 after hemorrhage followed by DFR; (3) VGX/EA: vagotomy (VGX) before EA at ST36 and DFR; (4) VGX/EAN: VGX before EAN and DFR; (5) α-bungarotoxin (α-BGT)/EA: intraperitoneal injection of α-BGT before hemorrhage, followed by EA at ST36 and DFR; and (6) α-BGT/EAN group: α-BGT injection before hemorrhage followed by EAN and DFR. Survival and mean arterial pressure (MAP) were monitored over the next 12 h. In a second study, with the same grouping and treatment, cytokine levels in plasma and intestine, organ parameters, gut injury score, gut permeability to 4 kDa FITC-dextran, and expression and distribution of tight junction protein ZO-1 were evaluated. RESULTS: MAP was significantly lowered after blood loss; EA at ST36 improved the blood pressure at corresponding time points 3 and 12 h after hemorrhage. EA at ST36 reduced tumor necrosis factor-α and interleukin (IL)-6 levels in both plasma and intestine homogenates after blood loss and DFR, while vagotomy or intraperitoneal injection of α-BGT before EA at ST36 reversed its anti-inflammatory effects, and EA at ST36 did not influence IL-10 levels in plasma and intestine. EA at ST36 alleviated the injury of intestinal villus, the gut injury score being significantly lower than that of EAN group (1.85 ± 0.33 vs 3.78 ± 0.59, P < 0.05). EA at ST36 decreased intestinal permeability to FITC-dextran compared with EAN group (856.95 ng/mL ± 90.65 ng/mL vs 2305.62 ng/mL ± 278.32 ng/mL, P < 0.05). EA at ST36 significantly preserved ZO-1 protein expression and localization at 12 h after hemorrhage. However, EA at non-channel acupoints had no such effect, and abdominal vagotomy and α-BGT treatment could weaken or eliminate the effects of EA at ST36. Besides, EA at ST36 decreased blood aminotransferase, MB isoenzyme of creatine kinase and creatinine vs EAN group at corresponding time points. At the end of 12-h experiment, the survival rate of the EA group was significantly higher than that of the other groups. CONCLUSION: EA at ST36 attenuates the systemic inflammatory response, protects intestinal barrier integrity, improves organ function and survival rate after hemorrhagic shock via activating the cholinergic anti-inflammatory mechanism.

Bilateral atrial ganglionated plexus involvement in atrial responses to left-sided plexus stimulation in canines.

AIMS: Given the clinical interest concerning 'reflex vagal' responses to identify left atrial (LA) targets for ablative therapy of atrial fibrillation, we investigated whether vagal and bilateral atrial neural pathways may be involved in chronotropic and atrial repolarization responses to LA ganglionated plexus (GP) stimulation. METHODS AND RESULTS: Unipolar electrograms were recorded from 191 right atrial (RA) and LA sites in anaesthetized canines prior to and during electrical stimulation of the right vagus nerve (VgN), left VgN, or LAGP at baseline and following (i) bilateral VgN decentralization, and radiofrequency ablation of (ii) periaortic/superior vena cava (Ao/SVC) and (iii) RAGP in 14 animals (anterograde group), and in the reverse order in 7 (retrograde). Repolarization changes were also measured in similar preparations during Ao/SVC (n = 8) and RAGP stimulation (n = 23). Sinus cycle length (SCL) prolongation, and RA and LA repolarization changes (affected atrial surface area) were induced during LAGP stimulation. SCL prolongation and RA repolarization changes were unaffected by VgN decentralization but reduced following Ao/SVC and RAGP ablation in the anterograde group. In the retrograde group, chronotropic and RA repolarization changes were reduced following RAGP and abolished following Ao/SVC ablation. In contrast, LA repolarization responses to LAGP stimulation were reduced following VgN decentralization and each subsequent ablation step, with small residual responses after completing the anterograde protocol. Ao/SVC and RAGP stimulation exerted predominant influences in adjacent regions as well as demonstrating LA extensions. CONCLUSION: Vagal as well as bilateral atrial neural pathways are involved in mediating chronotropic and LA repolarization responses to LAGP stimulation.

Intestinal fatty acid infusion modulates food preference as well as calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways in rats.

The intestine plays important roles in the regulation of feeding behavior by sensing macronutrients. Intestinal fatty acids strongly suppress food intake, but little is known about whether intestinal fatty acids affect food preference. We investigated the effects of jejunal fatty acids infusion on food preference by conducting two-diet choice experiments in rats fed a high-fat diet (HFD) and a high-carbohydrate diet (HCD). Jejunal linoleic acid (18:2) infusion reduced HFD intake dose-dependently, while HCD intake increased with the middle dose of the infusion we examined (100 µL/h) and reduced to the control level with the higher doses (150 and 200 µL/h). α-Linolenic acid (18:3), but not caprylic acid (8:0), altered the food preference and total calorie intake in the same manner as linoleic acid. Linoleic acid infusion dose-dependently increased plasma glucagon-like peptide-1, peptide YY and cholecystokinin levels, but not ghrelin levels. Subdiaphragmatic vagotomy or midbrain transection prevented the change in food preference and total calorie intake by linoleic acid infusion. Jejunal linoleic acid infusion increased norepinephrine turnover in the paraventricular hypothalamic nucleus, while intracerebroventricular injection of idazoxan, an α2-adrenergic receptor (AR) antagonist, suppressed the increased HCD intake, but did not affect the decreased HFD intake. These findings indicated that intestinal long-chain fatty acids modulated food preference as well as total calorie intake via the vagal nerve and midbrain-hypothalamic neural pathways. The effects of the α2-AR antagonist in the brain suggested that the brain distinctly controlled HCD and HFD intake in response to jejunal linoleic acid infusion.

Relative contributions of afferent vagal fibers to resistance to diet-induced obesity.

BACKGROUND: We previously demonstrated vagal neural pathways, specifically subdiaphragmatic afferent fibers, regulate expression of the intestinal sodium-glucose cotransporter SGLT1, the intestinal transporter responsible for absorption of dietary glucose. We hypothesized targeting this pathway could be a novel therapy for obesity. We therefore tested the impact of disrupting vagal signaling by total vagotomy or selective vagal de-afferentation on weight gain and fat content in diet-induced obese rats. METHODS: Male Sprague-Dawley rats (n = 5-8) underwent truncal vagotomy, selective vagal de-afferentation with capsaicin, or sham procedure. Animals were maintained for 11 months on a high-caloric Western diet. Abdominal visceral fat content was assessed by magnetic resonance imaging together with weight of fat pads at harvest. Glucose homeostasis was assessed by fasting blood glucose and HbA1C. Jejunal SGLT1 gene expression was assessed by qPCR and immunoblotting and function by glucose uptake in everted jejunal sleeves. RESULTS: At 11-months, vagotomized rats weighed 19% less (P = 0.003) and de-afferented rats 7% less (P = 0.19) than shams. Vagotomized and de-afferented animals had 52% (P < 0.0001) and 18% reduction (P = 0.039) in visceral abdominal fat, respectively. There were no changes in blood glucose or glycemic indexes. SGLT1 mRNA, protein and function were unchanged across all cohorts at 11-months postoperatively. CONCLUSIONS: Truncal vagotomy led to significant reductions in both diet-induced weight gain and visceral abdominal fat deposition. Vagal de-afferentation led to a more modest, but clinically and statistically significant, reduction in visceral abdominal fat. As increased visceral abdominal fat is associated with excess morbidity and mortality, vagal de-afferentation may be a useful adjunct in bariatric surgery.

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4.

The aim of our study was to investigate the anorectic and brain stimulatory effects of various doses of exendin-4 (Ex-4) and to investigate the role of the vagus nerve in Ex-4-induced brain activation. A dose-related increase in c-fos mRNA expression was observed following Ex-4 administration (0.155-15.5 µg/kg). Doses of Ex-4 that caused anorexia without aversive effects (0.155, 0.775 µg/kg) induced c-fos expression in the hypothalamic arcuate and paraventricular (PVH; parvocellular) nuclei as well as in the limbic and brainstem structures. Doses of Ex-4 that caused aversion (1.55, 15.5 µg/kg) stimulated the same regions (in a more intense way) and additionally activated the magnocellular hypothalamic structures (supraoptic nucleus and PVH magnocellular). The brain c-fos pattern induced by Ex-4 showed both similarities and differences with that induced by refeeding. Subdiaphragmatic vagotomy significantly blunted the stimulation of c-fos mRNA expression induced by Ex-4 in the nodose ganglion, the medial part of nucleus of the solitary tract, and the parvocellular division of the PVH. Pretreatment with Ex-9-39 (330 µg/kg ip) impaired the neuronal activation evoked by Ex-4 in all brain regions and in the nodose ganglion. Effects of Ex-4 on hypothalamic-pituitary-adrenal axis activity were not altered by vagotomy. Results of this study demonstrate and relate the anorectic and brain stimulatory effects of aversive and nonaversive doses of Ex-4 and indicate that the activation of specific central regions induced by the peripheral administration of Ex-4 is, at least in part, dependent on the integrity of the vagus nerve.

Complex fractionated electrograms and AF nests in vagally mediated atrial fibrillation.

BACKGROUND: Catheter ablation targeting of complex fractionated atrial electrograms (CFAEs) is one of the techniques used for atrial fibrillation (AF) ablation. The ablation of sites showing a high-frequency spectral component (HFC) during sinus rhythm, known as AF nests, has been introduced as an adjunct to conventional ablation. Known locations of some AF nests are similar to CFAE sites. However, it has not been systematically evaluated whether these two targets represent the same foci. The purpose of this study was to compare the anatomical locations of these sites using an animal model of vagally mediated AF. METHODS: Five anesthetized open-chest dogs were evaluated. Atrial electrograms were obtained epicardially. AF was induced by burst atrial pacing with 20 Hz during vagal stimulation. A total of 15 sites (eight sites in right atrium and seven sites in left atrium) were evaluated in each animal. The CFAE was determined during AF according to the electrogram patterns. After sinus conversion, real-time spectrum analysis was used for AF nest assessment at the same location. RESULTS: The CFAE was observed at the high and mid sulcus terminalis areas, pulmonary vein antrum, and mid portion of the coronary sinus. Among them, only 60% of the CFAE sites showed HFC during sinus rhythm. In addition, some of the non-CFAE sites (22%) showed HFC during sinus rhythm. CONCLUSION: The CFAE sites were not the same as the AF nests in this animal model of vagally mediated AF. Therefore, these two types of ablation methods appear to target different substrates of AF.

1-Nitro-2-phenylethane, the main constituent of the essential oil of Aniba canelilla, elicits a vago-vagal bradycardiac and depressor reflex in normotensive rats.

Previously, it was shown that intravenous (i.v.) treatment with the essential oil of Aniba canelilla (EOAC) elicited a hypotensive response that is due to active vascular relaxation rather than to the withdrawal of sympathetic tone. The present study investigated mechanisms underlying the cardiovascular responses to 1-nitro-2-phenylethane, the main constituent of the EOAC. In pentobarbital-anesthetized normotensive rats, 1-nitro-2-phenylethane (1-10mg/kg, i.v.) elicited dose-dependent hypotensive and bradycardiac effects which were characterized in two periods (phases 1 and 2). The first rapid component (phase 1) evoked by 1-nitro-2-phenylethane (10mg/kg) was fully abolished by bilateral vagotomy, perineural treatment of both cervical vagus nerves with capsaicin (250 microg/ml) and was absent after left ventricle injection. However, pretreatment with capsazepine (1mg/kg, i.v.) or ondansetron (30 microg/kg, i.v.) did not alter phase 1 of the cardiovascular responses to 1-nitro-2-phenylethane (10mg/kg, i.v.). In conscious rats, 1-nitro-2-phenylethane (1-10mg/kg, i.v.) evoked rapid hypotensive and bradycardiac (phase 1) effects that were fully abolished by methylatropine (1mg/kg, i.v.). It is concluded that 1-nitro-2-phenylethane induces a vago-vagal bradycardiac and depressor reflex (phase 1) that apparently results from the stimulation of vagal pulmonary rather than cardiac C-fiber afferents. The transduction mechanism of the 1-nitro-2-phenylethane excitation of C-fiber endings is not fully understood and does not appear to involve activation of either Vanilloid TPRV(1) or 5-HT(3) receptors. The phase 2 hypotensive response to 1-nitro-2-phenylethane seems to result, at least in part, from a direct vasodilatory effect since 1-nitro-2-phenylethane (1-300 microg/ml) induced a concentration-dependent reduction of phenylephrine-induced contraction in rat endothelium-containing aorta preparations.

Combination of bypassing stomach and vagus dissection in high-fat diet-induced obese rats-a long-term investigation.

BACKGROUND: Gastric bypass is the most popular technique in obesity therapy. We hypothesize that bypass surgery can help to control the body weight in morbid obesity, and this effect can be enhanced by vagus dissection. METHODS: Thirty-six Wistar rats were used in this investigation. They were randomly allocated into six groups. Rats in the gastric bypass group (GB1 and GB2) and the bypass with vagus dissection group (VD1 and VD2) received surgery. Rats in the control group (CO1 and CO2) received sham operation. Twenty days later, rats in the CO1, GB1, and VD1 groups were killed and data on body weights, food intakes, fasting glucose, plasma ghrelin and leptin levels, and GHS-R1a and leptin receptor protein expression in the hypothalamus were collected and summarized. One hundred days later, rats in the CO2, GB2, and VD2 groups were also killed and the same experiments were repeated. RESULTS: Body weights of rats were 258 +/- 4.2 and 232 +/- 2.4 g in the GB1 and VD1 groups, respectively, much lower than the CO1 group (303 +/- 6.9 g). Body weights of rats were 316 +/- 12.3 and 315 +/- 10.3 g in the GB2 and VD2 groups, respectively, much lower than the CO2 group. Food intake in the VD1 group was lower than in the GB1 group, while there were no statistical differences between the VD2 and GB2 groups. Fasting glucose in the GB1 and GB2 groups was much lower than the CO1 and CO2 groups. Plasma ghrelin concentrations were much lower in the GB1 and VD1 groups compared to the CO1 group. One hundred days after surgery, the ghrelin concentrations in the GB2 and VD2 groups were also much lower than the CO2 group. Leptin concentrations decreased significantly with weight loss after bypass surgery. GHS-R1a protein expression in the hypothalamus was much lower in the GB1 and VD1 groups compared to the CO1 group. GHS-R1a protein expressions in the GB2 and VD2 groups were lower than the CO2 group. There were no statistical differences in leptin receptor expression in the hypothalamus (not shown). CONCLUSION: Vagus nerve dissection is effective on body weight control in the early stage, but not in the long term. The hypothalamus is important in weight control by modulating ghrelin and leptin expressions. Bypass surgery can modulate the expression of ghrelin and its receptor. Leptin is also modulated by bypass surgery.

Low-level vagosympathetic stimulation: a paradox and potential new modality for the treatment of focal atrial fibrillation.

BACKGROUND: We used high-frequency stimulation delivered during the refractory period of the atrium and pulmonary veins (PVs) to induce focal firing and atrial fibrillation (AF). This study was designed to demonstrate that bilateral low-level vagosympathetic nerve stimulation (LL-VNS) could suppress high-frequency stimulation-induced focal AF at atrial and PV sites. METHODS AND RESULTS: In 23 dogs anesthetized with Na-pentobarbital, electrodes in the vagosympathetic trunks allowed LL-VNS at 1 V below that which slowed the sinus rate or atrioventricular conduction. Multielectrode catheters were fixed at the right and left superior and inferior PVs and both atrial appendages. LL-VNS continued for 3 hours. At the end of each hour, the high-frequency stimulation algorithm consisting of a 40-ms train of stimuli (200 Hz; stimulus duration, 0.1 to 1.0 ms) was delivered 2 ms after the atrial pacing stimulus during the refractory period at each PV and atrial appendages site. The lowest voltage of high-frequency stimulation that induced AF was defined as the AF threshold. Five dogs without LL-VNS served as sham controls. Six dogs underwent LL-VNS after transection of bilateral vagosympathetic trunks. LL-VNS induced a progressive increase in AF threshold at all PV and atrial appendages sites, particularly significant (P<0.05) at the right superior PV, right inferior PV, left superior PV, and right atrial appendage. Bilateral vagosympathetic transection did not significantly alter the previous findings, and the 5 sham control dogs did not show changes in AF threshold at any site over a period of 3 hours. CONCLUSIONS: LL-VNS may prevent episodic AF caused by rapid PV and non-PV firing.

Cluster headache and TACs: rationale for central and peripheral neuromodulation.

Cluster headache, the most severe of primary headache conditions for functional and social impairment it provokes, has been recently the object of a great amount of clinical, physiopathological, surgical and functional neuroradiological studies aimed to uncover the real mechanisms which underlie its disabling manifestations. Refinement of methodological and systematic features of multidisciplinary researches in this field has been allowing for more and more precise delineations of the role of both peripheral and central nervous system's contribution in pathophysiology of the disease. Aim of this manuscript is the report of the present knowledge in the role of the different surgical options in the treatment of drug-resistant cluster headache and Short-lasting Unilateral neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT), which take into account their different hypothesized pathological mechanisms and which comprise central nervous system's approach (Deep Brain Stimulation [DBS] and peripheral approach, namely Occipital Nerve Stimulation (ONS) and Vagal Nerve Stimulation (VNS).

Horner's syndrome: a complication of experimental carotid artery surgery in rats.

PURPOSE: To report on the occurrence of iatrogenic Horner's syndrome (HS) in epileptic rats after implantation of an electrode for vagus nerve stimulation and to describe the possible consequences of this new complication of carotid artery surgery in rats. METHODS: A bipolar circular electrode was placed around the left carotid artery and vagus nerve of 31 rats. The incidence of HS was evaluated by visual inspection within 24 h after surgery. RESULTS: 68% of rats suffered from HS immediately after surgery. This complication did not affect epileptogenesis. CONCLUSION: The occurrence of HS in the rat is a frequent complication of vagus nerve electrode implantation, which does not affect epileptogenesis in this study. However, rats affected by HS may suffer from damage to the sympathetic innervation of the gut, due to rat-specific neuroanatomy. Therefore, caution towards other research questions is warranted.

Selection of electrical algorithms to treat obesity with intermittent vagal block using an implantable medical device.

BACKGROUND: A laparoscopically implantable electrical device that intermittently blocks both vagi near the esophagogastric junction led to significant excess weight loss (EWL) in an initial clinical trial in obese patients. The study objective was to optimize therapy algorithms and determine the EWL achieved with a second-generation device at university hospitals in Australia, Norway, and Switzerland. METHODS: Data acquired during the initial clinical trial were analyzed and subsequently used to select alternative electrical algorithms. In the second trial, vagal blocking using one selected therapy algorithm was initiated 2 weeks after implanting the second-generation device. The patients were followed up for 6 months to assess the EWL and safety, including adverse events. RESULTS: In the initial clinical trial, vagal blocking algorithm durations of 90-150 s were associated with greater EWL compared with either shorter or longer algorithm durations (P<.01). The second trial enrolled 27 patients (mean body mass index 39.3+/-.8 kg/m2) to evaluate a 120-s blocking algorithm. At 6 months, greater EWL was achieved (22.7%+/-3.1%, n=24) compared with the initial study and first-generation device (14.2%+/-2.2%, n=29, P=.03). In both trials, an association was found between the number of 90-150-s algorithms delivered daily and greater EWL (P=.03). No deaths, unanticipated device-related adverse events, or medically serious adverse events were associated with the device. CONCLUSION: This second-generation vagal blocking device, using a therapy algorithm of 120-s duration, resulted in a clinically acceptable safety profile and significantly greater EWL compared with the first-generation device delivering a wider range of therapy algorithm durations.

The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via alpha7 nicotinic acetylcholine receptor.

BACKGROUND & AIMS: Although accumulating evidence has recently shown that the efferent vagus nerve attenuates systemic inflammation, it remains unclear whether or not the vagus nerve can affect Fas-induced liver apoptosis. We investigated the effect of the vagus nerve by using a selective hepatic vagotomy. METHODS: We assessed the mortality and apoptosis in Fas-induced fulminant hepatitis in sham-operated and vagotomized male C57BL/6 mice. To determine how the nerve influences hepatocyte apoptosis, hepatitis was preceded by pretreatment with nicotine; PNU-282987, an alpha7 nicotinic acetylcholine receptor (AChR) agonist; liposome-encapsulated dichloromethylene diphosphonate (lipo-Cl(2)MDP), a macrophage eliminator; and Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP), an oxidative inhibitor. RESULTS: Mortality in the vagotomized mice was significantly higher than that in the sham-operated mice following intravenous administration with the anti-Fas antibody Jo-2. This result was also supported by the data from both terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling and caspase-3 assay, in which vagotomized livers showed a significant elevation in the number of apoptotic hepatocytes and increased caspase-3 activity following Jo-2 treatment compared with the sham-operated livers. Supplementation with nicotine and PNU-282987 dose dependently inhibited this detrimental effect of the vagotomy. Moreover, the vagotomy-triggered exacerbation of Fas-induced hepatitis was completely blocked by lipo-Cl(2)MDP. Similarly, pretreatment with MnTBAP also completely suppressed the vagotomy-triggered exacerbation. CONCLUSIONS: The hepatic vagus nerve appears to play an important role in attenuating Fas-induced hepatocyte apoptosis through alpha7 nicotinic AChR, perhaps by causing the Kupffer cells to reduce their generation of an excessive amount of reactive oxygen species.