BACKGROUND: Current inflammatory bowel disease (IBD) therapies are limited by incomplete efficacy, loss of response, side effects and high costs. Vagal nerve stimulation (VNS) is an investigational Bioelectronic Medicine therapy targeting the nervous system to treat IBD through an ‘inflammatory reflex’ that reduces systemic inflammation. Data in humans with IBD are promising but limited to two small studies using a cervically implanted VNS device in adults with Crohn disease (CD); no data exist to date using a non-invasive VNS modality in IBD. This study aimed to evaluate the efficacy and safety of transcutaneous auricular VNS (ta-VNS) in children and young adults with CD or ulcerative colitis (UC). METHODS: IBD patients 10-21 years of age with mild/moderate CD or UC who did not achieve remission with conventional therapy, and a fecal calprotectin (FC) >200 ug/g within 4 weeks of study entry were enrolled. Subjects were randomized to receive either ta-VNS using a transcutaneous electrical nerve stimulator unit targeting the cymba conchae of the external left ear, or sham stimulation of the posterior lower leg, for 5 minutes once daily for a 2-week duration followed by a switch to the alternative stimulation for an additional 2 weeks. At week 4, all subjects were assigned to receive active ta-VNS for 5 minutes twice daily until week 16 so that all received 14 weeks of active ta-VNS by the end of the study. Primary study endpoint was defined as ∆FC ≥50% reduction from baseline to week 16. Secondary endpoints included improvement in weighted Pediatric Crohn Disease Activity Index (wPCDAI) or Pediatric Ulcerative Colitis Activity Index (PUCAI). RESULTS: Twenty-two subjects were enrolled (12 UC, 10 CD; median age 14.4 years [range 10-21] 54.5% male). Median baseline FC was 587 (range 18 – 3828, SD 1074). 5 subjects (4 UC, 1 CD) had FC levels 12.5 at baseline, 3 (50%) achieved clinical remission (wPCDAI ≤ 10) at week 16. In the full UC cohort (n = 12), baseline PUCAI ranged from 0-45. In the 6 with PUCAI > 10 at baseline, 2 (33%) achieved clinical remission at week 16. There were no safety concerns. CONCLUSION: Non-invasive ta-VNS reduced FC levels and improved symptoms in a pediatric cohort with mild/moderate IBD. Further research is needed to identify optimal electrical dose and settings to achieve peak anti-inflammatory effect and to identify the mechanistic principles for this therapy.
Clusters of neuron cell bodies, termed nuclei, residing in the brainstem are the origin of cranial nerves which transmit action potentials controlling organ function. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the pancreas, liver, gastrointestinal tract and other organs. Cholinergic signaling in the vagus nerve‐mediated inflammatory reflex also controls immune system responses by inhibiting the production of cytokines in the spleen, although the function of DMN neurons in regulating pancreatic inflammation is not known. Here, we demonstrate that selective activation of cholinergic neurons in the DMN attenuates pancreatitis severity. Pancreatitis was induced with two intraperitoneal injections of the cholecystokinin analogue caerulein (50 mcg/kg), given one hour apart. A fiber‐optic cannula was inserted under stereotactic guidance into the DMN in transgenic mice expressing light‐responsive ion channel, channelrhodopsin, in cholinergic neurons under the choline acetyltransferase promoter. Animals were subjected to either optogenetic stimulation (473nm, 20 Hz, 25% duty cycle, 8‐12 mW total power) or sham stimulation (no light) for five minutes. Optogenetic stimulation but not sham stimulation of the cholinergic neurons in the DMN significantly attenuates serum amylase (4043mU/mL ± 264.4 vs. 2940mU/mL ± 170.9, p=0.0074; n=9‐11 mice/group) and pancreatic IL‐6 levels (1907pg/mg ± 879.3 vs. 1046pg/mg± 288.1, p=0.0330; n=9‐11 mice/group). The decreased severity of pancreatitis in optogenetically stimulated mice is further demonstrated by a significant improvement in pancreatic histologic severity score (6.86 ± 1.67 vs. 5.35 ± 1.44, p = 0.0462; n = 9‐11). Pharmacological blockade and surgical ablation of the vagus nerve signaling inhibit protective effects of DMN cholinergic neurons activation. Pre‐treatment with mecamylamine, a nicotinic receptor antagonist, attenuates the reduction in serum amylase following light stimulation (Sham stimulation vs. DMN vs DMN + Mecamylamine: 5047 ± 315.4 vs. 3769 ± 241.5 vs. 5620 ± 385.9, p = 0037; n = 10 mice/group). Additionally, mice with subdiaphragmatic vagotomy has no difference in serum amylase levels following optogenetic stimulation (2761mU/mL ± 787.3 vs. 2517mU/mL, p= 0.300; n=3), whereas sham surgery controls show a significant reduction in serum amylase levels (3224mU/mL ± 593.1 vs. 2087 mU/mL ± 951.2, p=0.0303; n=6 mice/group). These studies identify DMN as an important locus that regulates the severity of acute pancreatitis in vagus‐nerve‐dependent fashion, and provide new insights into the identity and central origin of the efferent vagus nerve fibers regulating acute pancreatitis.
Type 1 diabetes is characterized by autoimmune destruction of insulin-producing pancreatic β cells. The α7 nicotinic acetylcholine receptor (α7nAChR) acts as part of the “cholinergic anti-inflammatory pathway” to inhibit the production of cytokines by monocytes, macrophages, dendritic cells, and other cytokine producing cells. Administration of highly selective α7nAChR agonists in vivo have significantly reversed or prevented the inflammatory damage associated with several preclinical disease models, including collagen induced arthritis, ileus, colitis, ischemia reperfusion injury, sepsis, and autoimmune diabetes. To determine the protective effects of the cholinergic pathway in type 1 diabetes, NOD mice were treated with cholinergic pathway stimulators beginning at an early age (3-4 weeks). Blood glucose was monitored weekly to determine the onset of hyperglycemia, as determined by blood glucose >200 mg/dl. Intervention with cholinergic pathway stimulators at an early age reduced the age of onset of hyperglycemia in NOD mice and reduced the total prevalence of type 1 diabetes. This demonstrates that activation of the α7nAChR may be useful in the early prevention of type 1 diabetes.
Peripheral inflammation can be regulated by activation of brain muscarinic acetylcholine receptor (mAChR)-dependent signaling functionally associated with a vagus-nerve mediated anti-inflammatory circuit (Proc Natl Acad Sci USA, 2006, 5219; Brain Behav Immun, 2009, 23:41). Here, we studied the specific role of the M1 mAChR subtype in this regulation by utilizing BQCA, a highly specific allosteric M1 mAChR activator that crosses the blood-brain barrier. Single drug (5,10 or 20 mg/kg, i.p) administration in mice 1h prior to endotoxin (8 mg/kg, i.p.) dose-dependently reduced serum and splenic TNF levels and significantly improved survival in mice as compared to vehicle-treated controls. Pharmacological blockade of brain mAChRs significantly abolished BQCA anti-inflammatory effects. Furthermore, BQCA (20 mg/kg, i.p.) significantly reduced serum and splenic TNF levels in wild type mice, but failed to alter TNF levels in M1 KO mice. Together these results indicate the anti-inflammatory role of increased functional activity of endogenous acetylcholine on the M1 mAChR by selective allosteric receptor activation. Our findings are of interest for further development of BQCA and other centrally-acting allosteric activators of the M1 mAChR as a novel class of experimental anti-inflammatory therapeutics.
Low-grade systemic inflammation is a central event in obesity and mediates insulin resistance and other complications. Previously we discovered a role for neural cholinergic signaling in controlling inflammation (Nature, 2000, 405, 6785; Proc Natl Acad Sci USA, 2006, 5219) and demonstrated that the acetylcholinesterase inhibitor galantamine suppresses systemic lethal inflammation (Brain Behav Immun, 2009, 4; 1). Here we tested the efficacy of galantamine in alleviating obesity-associated inflammation. C57BL/6J mice with high fat-diet induced (for 8 weeks) obesity were treated with either galantamine (4 mg/kg daily, i.p.), or saline for 4 weeks while on the high-fat diet. Galantamine treatment of obese mice resulted in lower body weight and abdominal adiposity as compared to saline treatment. Galantamine significantly decreased systemic levels of characteristic pro-inflammatory cytokines/adipokines, including IL-6, MCP-1, resistin and leptin and increased adiponectin levels, accompanied by alleviated hyperglycemia, hyperinsulinemia, insulin resistance and hepatosteatosis. These results demonstrate that galantamine reduces obesity-associated inflammation and alleviates obesity-related complications and provide a rationale for further mechanistic studies and novel therapeutic implications. Translational aspects of these studies will be additionally facilitated by the fact that galantamine is a FDA approved (for the treatment of Alzheimer’s disease) cholinergic agent.
Initial exposure to an antigen, by infection or vaccination, is a critical step in developing protection against subsequent infection. Antigen injected into the dorsum of the mouse hind foot flows to the popliteal lymph node, then to the sciatic lymph node, through the lymphatics and eventually reaching the blood stream. In mice immunized to Keyhole-Limpet Hemocyanin (KLH), flow of IrDye-labeled KLH was restricted through the popliteal and sciatic lymph nodes. Imaging one hour after antigen administration revealed a significant decrease in sciatic and popliteal KLH levels in immunized mice compared to naïve animals (antigen signal in naïve 0.75 ± 0.15 vs sensitized 0.23 ± 0.11, p<0.05). Flow cytometric analysis of lymph node cellular populations revealed that antigen was associated mainly with a CD21+CD23+ mature subset of B-cells (51.9 ± 1.6% of total antigen positive cells)). Blocking neuronal activity with bupivacaine at the lymph nodes of immunized animals resulted in restoration of antigen flow, with an increase in antigen signal (control 0.27 ± 0.016 vs bupivacaine 0.38 ± 0.037, p<0.05). Conversely, direct activation of neuronal signals by noninvasive magnetic stimulation resulted in a significant decrease of antigen trafficking compared to sham controls (sham 1.39 ± 0.18 vs stimulated 0.47 ± 0.11, p<0.001). Taken together, these studies reveal a neuronal circuit that modulates antigen trafficking through a pathway involving a mature subset of B-cells.
HMGB1 is a cytokine mediator in the pathogenesis of inflammatory diseases including sepsis (Yang et al, BBA, 2009). Recently we demonstrated that haptoglobin (Hp), a naturally occurring serum protein, binds to HMGB1 and suppresses HMGB1-stimulated TNF and IL-8 release in cultured macrophages. Hp knockout mice subjected to cecal ligation and puncture (CLP)-induced sepsis had significantly higher serum HMGB1 levels and higher mortality rates compared to wild type animals (75% survival in wild type vs. 34% in Hp knockout mice; P<0.05). Wild type mice subjected to CLP and received injections of Hp were twice as likely to survive (63% survival in Hp-treated vs. 33% in vehicle control; P<0.05), suggesting the therapeutic potential of exogenous Hp in sepsis. Hp is composed of alpha and beta subunits in a polymeric form (Yueh, J. Chromat B Life Sci. 2007). Structure-functional analysis revealed that Hp beta subunit alone is sufficient to recapitulate effects of Hp to neutralize HMGB1 in vitro in macrophages. The survival advantage of Hp in CLP-induced sepsis was also fully reproduced by Hp beta. Surface plasmon resonance analysis showed that Hp beta binds HMGB1 with high affinity (Kd = 29 nM). Thus, our data reveal unexpected roles of Hp as an endogenous antagonist of HMGB1, preventing the harmful HMGB1-induced inflammation in sepsis. The essential domain of Hp maps to the beta subunit, making it a target in the design of therapeutics.
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