S -Levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure— activity relationships with regard to inhibition of angiogenesis. N-Methyllevamisole and p-bromolevamisole proved more effective than the parent compound, S -levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co-culture with normal human dermal fibroblasts.
New chemotypes exhibiting antiangiogenic effects in vitro are thus described, and further investigation of their underlying mechanism of action is warranted. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist. Lyngby, Denmark. Normal physiological angiogenesis [7,20,21].
Avastin treatment, however, is accompanied by an takes place during growth, wound healing, the menstrual cycle, increased risk of venous thromboembolism [22] and the treatment and pregnancy [1—4].
Aberrant angiogenesis has been shown to regime is expensive. This has lead to an interest in the play an important part of the pathological processes in cancer and development of peptide-based [23] and low molecular weight other diseases such as endometriosis and rheumatoid arthritis angiogenesis inhibitors.
Small molecules may be desirable in many [1,5—8]. Since the idea that inhibition of angiogenesis could have respects, including improved pharmacokinetics and half-life in the therapeutic potential in relation to cancer was first suggested about human body, a decreased risk of immune response, and 40 years ago [9,10], it has been demonstrated to be beneficial with significantly lower production costs.
Several low molecular weight respect to several types of cancer and may also have therapeutic angiogenesis inhibitors have been synthesized and investigated potential in other diseases associated with increased angiogenesis both in vitro and in vivo, as well as in clinical trials, and so far three [5—8,11—14].
Moreover, blood vessel normalization through tyrosine kinase inhibitors have gained approval by the FDA for antiangiogenic treatment has emerged as a possible complemen- cancer treatment [i. Currently, angiogenesis. Thus, in addition to the known N-alkylated analogues 7a [28].
Levamisole hydrochloride 1 , its of rheumatoid arthritis [31,32], as well as an immunostimulant racemic mixture tetramisole 2 [ 6 -levamisole], p-bromolevami- adjuvant in chemotherapy for several types of cancer [33—36], was sole 3 , and the aromatic compound 4 are commercially available recently shown to exhibit angiogenesis inhibitory activity in vitro and were tested to complement the array of derivatives obtained and tumor growth inhibition in vivo [37,38].
The in vitro through chemical synthesis Figure 3. Suramin 5 , a well- antiangiogenic effect resembled that of Avastin in several respects, documented angiogenesis inhibitor, was included in the study as but especially with regard to inhibition of network formation and well. The preparation of the N-substituted levamisole analogues induction of non-differentiated clusters of cells [38]. In addition, was accomplished by straightforward alkylation reactions Figure 4 levamisole is an alkaline phosphatase inhibitor [39,40], and recent [48,50], and the identities and purities of the synthesized structure—activity relationship studies with synthetic analogues compounds were confirmed by HPLC and NMR spectroscopy, have addressed this capacity [41,42].
Levamisole treatment, respectively. In light of the recent discovery that purification by preparative-scale reversed-phase HPLC. Thus, the effect on differentiation is revealed structures and gain structure—activity relationships related to this by HUVEC morphology and ability to form networks while the scaffold.
The cationic analogue, N-methyllevamisole, proved effect on growth is revealed by HUVEC cell number Figure 5 and particularly efficacious with respect to induction of cluster Table 1. The most efficient inhibitors were p-bromolevamisole 3 morphology and network disruption, and thus constitute an Figure 5C , the aniline-containing dihydro-analogue 4 interesting new chemotype for further investigation.
Figure 5D , and the two different N-methyllevamisole salts 7a, b Figure 5E and F , which were all more potent than S - Results and Discussion levamisole hydrochloride.
The racemic tetramisole 2 Figure 5B had the same effect as the enantiomerically pure parent compound Levamisole contains a benzene ring and a hetero-substituted 1 Figure 5A. The cluster morphology known from S - bicycle [3. Although the latter is not levamisole, was also observed for tetramisole 2 Figure 5B and an aromatic system, the presence of the thiourea moiety provides Table 1 , p-bromolevamisole 3 Figure 5C and Table 1 , and N- the ring system with some conjugation and thereby delocalization methyllevamisoles 7a, b , with the latter mentioned showing of the carbon—nitrogen double bond as well as the lone pairs at the a slightly more pronounced effect Figure 5E and F, Figure 6 A—D, bridgehead nitrogen and the sulphur atoms.
A conformational Table 1. Due to the relatively rigid nature of this molecule, morphologies containing both cords and clusters Figure 5G—M we argue that such a conformational search reflects the preferred and Table 1.
Compound 4 Figure 5D and Table 1 , on the other conformation rather well. Generation and subsequent inspection hand, inhibited the capillary network formation to give small cords of GRID calculated Molecular Interaction Fields MIFs [45] exclusively, which is reminiscent of the effect of suramin 5 clearly showed that levamisole is a hydrophobic compound with Figure 5N and Table 1 , another well-known angiogenesis only a single directional possibility for an intermolecular in- inhibitor [44,51].
The predicted pKa value of i. For protonated forms of levamisole are likely to be present, and should each of these ion pairs, identical inhibitory effects were observed, be considered equally in a structure—activity analysis.
We strongly indicating that the levamisole analogues rather than the envisioned that if, in fact, the protonated state of levamisole was counter ions were responsible for the activities Figure 5E—H, K, L, responsible for its antiangiogenic effect, permanently cationic and Table 1.
N-Methyllevamisole triflate 7a showed an IC50 for analogues obtained through N-alkylation could have potential as tissue non-specific alkaline phosphatase of 0. Since the novel inhibitors Figure 1B. The synthesized analogues were trifluoroacetate 7b showed no inhibition at 2 mM or higher, tested alongside a selection of commercially available compounds however, we speculate that the triflate counter ion may account for Figure 3. The chemistry of levamisole has been investigated to some As mentioned vide supra levamisole is an inhibitor of alkaline extent, e.
Generic structures of compounds studied. A Levamisole and resonance forms of protonated levamisole; B resonance forms of N- substituted analogues of levamisole. Since the inhibitory effects in the angiogenesis inhibitory activity [52]. Figure 6 shows the effect of various has been shown to be a regulator of angiogenesis [54].
Rather curiously, however, elevated methylimidazole, respectively. Thus, to make experiments showed that N-methyllevamisole triflate 7a exerted sure whether or not this was an artifact in the assay, we also tested its cluster-inducing effect already at 30 mM Figure 6F , which is 7a for its ability to activate SIRT1 compared to resveratrol, by closer to a physiologically relevant concentration than the 1 mM following standard protocols given by the supplier.
These concentration used in the initial screen. N-methylimidazole had an experiments ruled out interaction with this regulatory enzyme effect at 10 mM Figure 6O , but no effect at 1 mM Figure 6P. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders.
In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms.
The ENS produces more than 30 neurotransmitters and has more neurons than the spine. Hormones and peptides that the ENS releases into the blood circulation cross the blood—brain barrier e. The brain—gut axis is becoming increasingly important as a therapeutic target for gastrointestinal and psychiatric disorders, such as inflammatory bowel disease IBD 3 , depression 4 , and posttraumatic stress disorder PTSD 5.
The gut is an important control center of the immune system and the vagus nerve has immunomodulatory properties 6. As a result, this nerve plays important roles in the relationship between the gut, the brain, and inflammation. There are new treatment options for modulating the brain—gut axis, for example, vagus nerve stimulation VNS and meditation techniques.
These treatments have been shown to be beneficial in mood and anxiety disorders 7 — 9 , but also in other conditions associated with increased inflammation In particular, gut-directed hypnotherapy was shown to be effective in both, irritable bowel syndrome and IBD 11 , Finally, the vagus nerve also represents an important link between nutrition and psychiatric, neurological and inflammatory diseases. The vagus nerve carries an extensive range of signals from digestive system and organs to the brain and vice versa.
It is the tenth cranial nerve, extending from its origin in the brainstem through the neck and the thorax down to the abdomen. The vagus nerve exits from the medulla oblongata in the groove between the olive and the inferior cerebellar peduncle, leaving the skull through the middle compartment of the jugular foramen.
In the neck, the vagus nerve provides required innervation to most of the muscles of the pharynx and larynx, which are responsible for swallowing and vocalization. In the thorax, it provides the main parasympathetic supply to the heart and stimulates a reduction in the heart rate. In the intestines, the vagus nerve regulates the contraction of smooth muscles and glandular secretion.
Preganglionic neurons of vagal efferent fibers emerge from the dorsal motor nucleus of the vagus nerve located in the medulla, and innervate the muscular and mucosal layers of the gut both in the lamina propria and in the muscularis externa The celiac branch supplies the intestine from proximal duodenum to the distal part of the descending colon 15 , The abdominal vagal afferents, include mucosal mechanoreceptors, chemoreceptors, and tension receptors in the esophagus, stomach, and proximal small intestine, and sensory endings in the liver and pancreas.
The sensory afferent cell bodies are located in nodose ganglia and send information to the nucleus tractus solitarii NTS see Figure 1. The NTS projects, the vagal sensory information to several regions of the CNS, such as the locus coeruleus LC , the rostral ventrolateral medulla, the amygdala, and the thalamus The vagus nerve is responsible for the regulation of internal organ functions, such as digestion, heart rate, and respiratory rate, as well as vasomotor activity, and certain reflex actions, such as coughing, sneezing, swallowing, and vomiting Its activation leads to the release of acetylcholine ACh at the synaptic junction with secreting cells, intrinsic nervous fibers, and smooth muscles ACh binds to nicotinic and muscarinic receptors and stimulates muscle contractions in the parasympathetic nervous system.
Animal studies have demonstrated a remarkable regeneration capacity of the vagus nerve. For example, subdiaphragmatic vagotomy induced transient withdrawal and restoration of central vagal afferents as well as synaptic plasticity in the NTS Further, the regeneration of vagal afferents in rats can be reached 18 weeks after subdiaphragmatic vagotomy 20 , even though the efferent reinnervation of the gastrointestinal tract is not restored even after 45 weeks Alongside the sympathetic nervous system and the enteric nervous system ENS , the parasympathetic nervous system represents one of the three branches of the autonomic nervous system.
The definition of the sympathetic and parasympathetic nervous systems is primarily anatomical. The vagus nerve is the main contributor of the parasympathetic nervous system. Other three parasympathetic cranial nerves are the nervus oculomotorius, the nervus facialis, and the nervus glossopharyngeus. The most important function of the vagus nerve is afferent, bringing information of the inner organs, such as gut, liver, heart, and lungs to the brain.
This suggests that the inner organs are major sources of sensory information to the brain. The gut as the largest surface toward the outer world and might, therefore, be a particularly important sensory organ. Historically, the vagus has been studied as an efferent nerve and as an antagonist of the sympathetic nervous system.
Most organs receive parasympathetic efferents through the vagus nerve and sympathetic efferents through the splanchnic nerves. Together with the sympathetic nervous systems, the parasympathetic nervous system is responsible for the regulation of vegetative functions by acting in opposition to each other The parasympathetic innervation causes a dilatation of blood vessels and bronchioles and a stimulation of salivary glands.
On the contrary, the sympathetic innervation leads to a constriction of blood vessels, a dilatation of bronchioles, an increase in heart rate, and a constriction of intestinal and urinary sphincters.
In the gastrointestinal tract, the activation of the parasympathetic nervous system increases bowel motility and glandular secretion. In contrast to it, the sympathetic activity leads to a reduction of intestinal activity and a reduction of blood flow to the gut, allowing a higher blood flow to the heart and the muscles, when the individual faces existential stress.
The ENS arises from neural crest cells of the primarily vagal origin and consists of a nerve plexus embedded in the intestinal wall, extending across the whole gastrointestinal tract from the esophagus to the anus.
It is estimated that the human ENS contains about — million neurons. This is the largest accumulation of nerve cells in the human body 23 — It consists of two ganglionated plexuses—the submucosal plexus, which regulates gastrointestinal blood flow and controls the epithelial cell functions and secretion and the myenteric plexus, which mainly regulates the relaxation and contraction of the intestinal wall The ENS serves as intestinal barrier and regulates the major enteric processes, such as immune response, detecting nutrients, motility, microvascular circulation, and epithelial secretion of fluids, ions, and bioactive peptides On the other hand, the ENS in the small and large bowel also is able to function quite independent of vagal control as it contains full reflex circuits, including sensory neurons and motor neurons.
They regulate muscle activity and motility, fluid fluxes, mucosal blood flow, and also mucosal barrier function.
ENS neurons are also in close contact to cells of the adaptive and innate immune system and regulate their functions and activities. Aging and cell loss in the ENS are associated with complaints, such as constipation, incontinence, and evacuation disorders. The connection between the CNS and the ENS, also referred to as the brain—gut axis enables the bidirectional connection between the brain and the gastrointestinal tract.
It is responsible for monitoring the physiological homeostasis and connecting the emotional and cognitive areas of the brain with peripheral intestinal functions, such as immune activation, intestinal permeability, enteric reflex, and enteroendocrine signaling 1. This brain—gut axis, includes the brain, the spinal cord, the autonomic nervous system sympathetic, parasympathetic, and ENS , and the hypothalamic—pituitary—adrenal HPA axis 1. Environmental stress, as well as elevated systemic proinflammatory cytokines, activates the HPA axis through secretion of the corticotropin-releasing factor CRF from the hypothalamus This stimulation, in turn, leads to cortisol release from the adrenal glands.
Cortisol is a major stress hormone that affects many human organs, including the brain, bones, muscles, and body fat. Both neural vagus and hormonal HPA axis lines of communication combine to allow brain to influence the activities of intestinal functional effector cells, such as immune cells, epithelial cells, enteric neurons, smooth muscle cells, interstitial cells of Cajal, and enterochromaffin cells These cells, on the other hand, are under the influence of the gut microbiota.
The gut microbiota has an important impact on the brain—gut axis interacting not only locally with intestinal cells and ENS, but also by directly influencing neuroendocrine and metabolic systems Emerging data support the role of microbiota in influencing anxiety and depressive-like behaviors Studies conducted on germ-free animals demonstrated that microbiota influence stress reactivity and anxiety-like behavior and regulate the set point for HPA activity. Thus, these animals generally show a decreased anxiety 35 and an increased stress response with augmented levels of ACTH and cortisol In case of food intake, vagal afferents innervating the gastrointestinal tract provide a rapid and discrete account of digestible food as well as circulating and stored fuels, while vagal efferents together with the hormonal mechanisms codetermine the rate of nutrient absorption, storage, and mobilization Histological and electrophysiological evidence indicates that visceral afferent endings of the vagus nerve in the intestine express a diverse array of chemical and mechanosensitive receptors.
These receptors are targets of gut hormones and regulatory peptides that are released from enteroendocrine cells of the gastrointestinal system in response to nutrients, by distension of the stomach and by neuronal signals They influence the control of food intake and regulation of satiety, gastric emptying and energy balance 39 by transmitting signals arising from the upper gut to the nucleus of the solitary tract in the brain Most of these hormones, such as peptide cholecystokinin CCK , ghrelin, and leptin are sensitive to the nutrient content in the gut and are involved in regulating short-term feelings of hunger and satiety Cholecystokinin regulates gastrointestinal functions, including inhibition of gastric emptying and food intake through activation of CCK-1 receptors on vagal afferent fibers innervating the gut In addition, CCK is important for secretion of pancreatic fluid and producing gastric acid, contracting the gallbladder, decreasing gastric emptying, and facilitating digestion Saturated fat, long-chain fatty acids, amino acids, and small peptides that result from protein digestion stimulate the release of CCK from the small intestine There are various biologically active forms of CCK, classified according to the number of amino acids they contain, i.
In rats, both long- and short-chain fatty acids from food activate jejunal vagal afferent nerve fibers, but do so by distinct mechanisms Short-chain fatty acids, such as butyric acid have a direct effect on vagal afferent terminals while the long-chain fatty acids activate vagal afferents via a CCK-dependent mechanism. CCK is also present in enteric vagal afferent neurons, in cerebral cortex, in the thalamus, hypothalamus, basal ganglia, and dorsal hindbrain, and functions as a neurotransmitter It directly activates vagal afferent terminals in the NTS by increasing calcium release Further, there is evidence that CCK can activate neurons in the hindbrain and intestinal myenteric plexus a plexus which provides motor innervation to both layers of the muscular layer of the gut , in rats and that vagotomy or capsaicin treatment results in an attenuation of CCK-induced Fos expression a type of a proto-oncogene in the brain There is also substantial evidence that elevated levels of CCK induce feelings of anxiety Therefore, CCK is used as a challenge agent to model anxiety disorders in humans and animals Ghrelin is another hormone released into circulation from the stomach and plays a key role in stimulating food intake by inhibiting vagal afferent firing Circulating ghrelin levels are increased by fasting and fall after a meal Central or peripheral administration of acylated ghrelin to rats acutely stimulates food intake and growth hormone release, and chronic administration causes weight gain In humans, intravenous infusion or subcutaneous injection increases both feelings of hunger and food intake, since ghrelin suppresses insulin release Therefore, it is not surprising that secretion is disturbed in obesity and insulin resistance Leptin receptors have also been identified in the vagus nerve.
Studies in rodents clearly indicate that leptin and CCK interact synergistically to induce short-term inhibition of food intake and long-term reduction of body weight The epithelial cells that respond to both ghrelin and leptin are located near the vagal mucosal endings and modulate the activity of vagal afferents, acting in concert to regulate food intake 58 , After fasting and diet-induced obesity in mice, leptin loses its potentiating effect on vagal mucosal afferents The gastrointestinal tract is the key interface between food and the human body and can sense basic tastes in much the same way as the tongue, through the use of similar G-protein-coupled taste receptors Different taste qualities induce the release of different gastric peptides.
Bitter taste receptors can be considered as potential targets to reduce hunger by stimulating the release of CCK Further, activation of bitter taste receptors stimulates ghrelin secretion 62 and, therefore, affects the vagus nerve. The gastrointestinal tract is constantly confronted with food antigens, possible pathogens, and symbiotic intestinal microbiota that present a risk factor for intestinal inflammation It is highly innervated by vagal fibers that connect the CNS with the intestinal immune system, making vagus a major component, the neuroendocrine-immune axis.
This axis is involved in coordinated neural, behavioral, and endocrine responses, important for the first-line defense against inflammation Counter-regulatory mechanisms, such as immunologically competent cells and anti-inflammatory cytokines normally limit the acute inflammatory response and prevent the spread of inflammatory mediators into the bloodstream.
The anti-inflammatory capacities of the vagus nerve are mediated through three different pathways The first pathway is the HPA axis, which has been described above. The second pathway is the splenic sympathetic anti-inflammatory pathway, where the vagus nerve stimulates the splenic sympathetic nerve. The last pathway, called the cholinergic anti-inflammatory pathway CAIP , is mediated through vagal efferent fibers that synapse onto enteric neurons, which in turn release ACh at the synaptic junction with macrophages Compared to the HPA axis, the CAIP has some unique properties, such as a high speed of neural conductance, which enables an immediate modulatory input to the affected region of inflammation Therefore, the CAIP plays a crucial role in the intestinal immune response and homeostasis, and presents a highly interesting target for the development of novel treatments for inflammatory diseases related to the gut immune system 6 , The inflammation-sensing and inflammation-suppressing functions outlined above provide the principal components of the inflammatory reflex The appearance of pathogenic organisms activates innate immune cells that release cytokines.
These in turn activate sensory fibers that ascend in the vagus nerve to synapse in the nucleus tractus solitarius.
Increased efferent signals in the vagus nerve suppress peripheral cytokine release through macrophage nicotinic receptors and the CAIP. Vagus nerve stimulation is a medical treatment that is routinely used in the treatment of epilepsy and other neurological conditions. VNS studies are not just clinically, but also scientifically informative regarding the role of the vagus nerve in health and disease. Vagus nerve stimulation works by applying electrical impulses to the vagus nerve.
The stimulation of the vagus nerve can be performed in two different ways: a direct invasive stimulation, which is currently the most frequent application and an indirect transcutaneous non-invasive stimulation. Invasive VNS iVNS requires the surgical implantation of a small pulse generator subcutaneously in the left thoracic region. Electrodes are attached to the left cervical vagus nerve and are connected to the pulse generator by a lead, which is tunneled under the skin.
The generator delivers intermittent electrical impulses through the vagus nerve to the brain It is postulated that these electrical impulses exert antiepileptic 75 , antidepressive 76 , and anti-inflammatory effects by altering the excitability of nerve cells.
Here, the stimulator is usually attached to the auricular concha via ear clips and delivers electrical impulses at the subcutaneous course of the afferent auricular branch of the vagus nerve Five years later, the stimulation of the vagus nerve for the treatment of refractory depression was approved by the U. Since then, the safety and efficacy of VNS in depression has been demonstrated in numerous observational studies as can be seen below.
In contrast, there is no randomized, placebo-control clinical trial that reliably demonstrates antidepressant effects of VNS. The mechanism by which VNS may benefit patients nonresponsive to conventional antidepressants is unclear, with further research needed to clarify this Functional neuroimaging studies have confirmed that VNS alters the activity of many cortical and subcortical regions Through direct or indirect anatomic connections via the NTS, the vagus nerve has structural connections with several mood regulating limbic and cortical brain areas Thus, in chronic VNS for depression, PET scans showed a decline in resting brain activity in the ventromedial prefrontal cortex vmPFC , which projects to the amygdala and other brain regions modulating emotion VNS results in chemical changes in monoamine metabolism in these regions possibly resulting in antidepressant action 84 , The relationship between monoamine and antidepressant action has been shown by various types of evidence.
All drugs that increase monoamines—serotonin 5-HT , NE, or dopamine DA —in the synaptic cleft have antidepressant properties Accordingly, depletion of monoamines induces depressive symptoms in individuals who have an increased risk of depression In rats, it has been shown that VNS treatments induce large time-dependent increases in basal neuronal firing in the brainstem nuclei for serotonin in the dorsal raphe nucleus Thus, chronic VNS was associated with increased extracellular levels of serotonin in the dorsal raphe Several lines of evidence suggest that NE is a neurotransmitter of major importance in the pathophysiology and treatment of depressive disorders Thus, experimental depletion of NE in the brain led to a return of depressive symptoms after successful treatment with NE antidepressant drugs The LC contains the largest population of noradrenergic neurons in the brain and receives projections from NTS, which, in turn, receives afferent input from the vagus nerve Thus, VNS leads to an enhancement of the firing activity of NE neurons 93 , and consequently, an increase in the firing activity of serotonin neurons The pharmacologic destruction of noradrenergic neurons resulted in the loss of antidepressant VNS effects In case of DA, it has been shown that the short-term effects 14 days 94 and the long-term effects 12 months 97 of VNS in treatment of resistant major depression may lead to brainstem dopaminergic activation.
DA is a catecholamine that to a large extent is synthesized in the gut and plays a crucial role in the reward system in the brain Further, beneficial effects of VNS might be exerted through a monoamine-independent way. Thus, VNS treatments might result in dynamic changes of monoamine metabolites in the hippocampus 93 and several studies reported the influence of VNS on hippocampal neurogenesis 99 , This process has been regarded as a key biological process indispensable for maintaining the normal mood Serotonin is also an important neurotransmitter in the gut that can stimulate peristalsis and induce nausea and vomiting by activating the vagus nerve.
In addition, it is essential for the regulation of vital functions, such as appetite and sleep, and contributes to feelings of well-being. Serotonin is released from enterochromaffin cells in response to mechanical or chemical stimulation of the gastrointestinal tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem.
As a result, interactions between the vagus nerve and serotonin systems in the gut and in the brain appear to play an important role in the treatment of psychiatric conditions. Major depressive disorder ranks among the leading mental health causes of the global burden of disease With a lifetime prevalence of 1. The pathophysiology of depression is complex and includes social environmental stress factors; genetic and biological processes, such as the overdrive of the HPA axis, inflammation 31 , and disturbances in monamine neurotransmission as described above For example, a lack of the amino acid tryptophan, which is a precursor to serotonin, can induce depressive symptoms, such as depressed mood, sadness, and hopelessness The overdrive of the HPA axis is most consistently seen in subjects with more severe i.
It has been shown that chronic exposure to elevated inflammatory cytokines can lead to depression This might be explained by the fact that cytokine overexpression leads to a reduction of serotonin levels In line with that, treatment with anti-inflammatory agents has the potential to reduce depressive symptoms In line, IBD are important risk factor for mood and anxiety disorders , and these psychiatric conditions increase the risk of exacerbation of IBD A European multicenter study demonstrated a positive effect of VNS on depressive symptoms, in patients with treatment-resistant depression Several other studies also demonstrated an increasing long-term benefit of VNS in recurrent treatment-resistant depression 84 , 85 , Further, a 5-year prospective observational study which compared the effects of treatment as usual and VNS as adjunctive treatment with treatment as usual only in treatment-resistant depression, showed a better clinical outcome and a higher remission rate in the VNS group This was even the case in patients with comorbid depression and anxiety who are frequent non-responders in trials on antidepressant drugs.
It is important to note that all these studies were open-label and did not use a randomized, placebo-controlled study design. Patients with depression have elevated plasma and cerebrospinal fluid concentrations of proinflammatory cytokines.
The benefit of VNS in depression might be due to the inhibitory action on the production of proinflammatory cytokines and marked peripheral increases in anti-inflammatory circulating cytokines Altered CRH production and secretion might result from a direct stimulatory effect, transmitted from the vagus nerve through the NTS to the paraventricular nucleus of the hypothalamus.
The gut microbiota is the potential key modulator of the immune and the nervous systems Targeting it could lead to a greater improvement in the emotional symptoms of patients suffering from depression or anxiety.
There is growing evidence that nutritional components, such as probiotics , , gluten , as well as drugs, such as anti-oxidative agents and antibiotics , have a high impact on vagus nerve activity through the interaction with the gut microbiota and that this effect varies greatly between individuals.
Indeed, animal studies have provided evidence that microbiota communication with the brain involves the vagus nerve and this interaction can lead to mediating effects on the brain and subsequently, behavior For example, Lactobacillus -species have received tremendous attention due to their use as probiotics and their health-promoting properties Bravo et al.
It has been shown that chronic treatment with L. In addition, L. Importantly, L. This is not surprising, since alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression , The antidepressive and anxiolytic effects of L. In line with that, in a model of chronic colitis associated to anxiety-like behavior, the anxiolytic effect obtained with a treatment with Bifidobacterium longum , was absent in mice that were vagotomized before the induction of colitis In humans, psychobiotics, a class of probiotics with anti-inflammatory effects might be useful to treat patients with psychiatric disorders due to their antidepressive and anxiolytic effects Differences in the composition of the gut microbiota in patients with depression compared with healthy individuals have been demonstrated Importantly, the fecal samples pooled from five patients with depression transferred into germ-free mice, resulted in depressive-like behavior.
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