Current Neuropharmacology (v.14, #8)

Meet Our Editorial Board Member by Detlev Boison (781-781).

Optic Nerve and Cerebral Edema in the Course of Diabetic Ketoacidosis by |ukasz Szmygel, Wojciech Kosiak, Katarzyna Zorena, Ma|gorzata My|liwiec (784-791).
In the recent years we have been observing an increased incidence of type 1 diabetes in children and adolescents. This leads to a more frequent acute complication of type 1 diabetes among children with hyperglycemia. The most common of these is diabetic ketoacidosis (DKA), while cerebral edema is the most dangerous. In children with DKA, cerebral edema most often presents with clinical symptoms but may also appear in the so-called “subclinical” form. That is why the search continues for new methods of assessing and monitoring cerebral edema in the course of DKA treatment. Ultrasonographic optic nerve sheath diameter (US ONSD) assessment is performed in various clinical scenarios when cerebral edema is suspected. It is most often performed in adult patients but increasingly often in children. US ONSD assessment is useful in the treatment of DKA in children with type 1 diabetes. This manuscript provides an overview of research results available in PubMed and other available databases on the course of treatment of DKA in children with type 1 diabetes.

Neurodegeneration is an initial process in the development of diabetic retinopathy (DR).
High quantities of glutamate, oxidative stress, induction of the renin-angiotensin system (RAS) and elevated levels of RAGE are crucial elements in the retinal neurodegeneration caused by diabetes mellitus. At least, there is emerging proof to indicate that the equilibrium between the neurotoxic and neuroprotective components will affect the state of the retinal neurons.
Somatostatin (SST), pigment epithelium-derived factor (PEDF), and erythropoietin (Epo) are endogenous neuroprotective peptides that are decreased in the eye of diabetic persons and play an essential role in retinal homeostasis. On the other hand, insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) are pivotal proteins which participate in the development of new capillaries and finally cause damage to the retinal neurons. During recent years, our knowledge about the function of growth factors in the pathogenesis of retinal neurodegeneration has increased. However, intensive investigations are needed to clarify the basic processes that contribute to retinal neurodegeneration and its association with damage to the capillary blood vessels. The objective of this review article is to show new insights on the role of neurotransmitters and growth factors in the pathogenesis of diabetic retinopathy. The information contained in this manuscript may provide the basis for novel strategies based on the factors of neurodegeneration to diagnose, prevent and treat DR in its earliest phases.

Retinal Neurodegeneration in the Course of Diabetes-Pathogenesis and Clinical Perspective by Aleksandra Araszkiewicz, Dorota Zozulinska-Ziolkiewicz (805-809).
Diabetic retinopathy is generally considered as a microvascular disease which develops as a result of chronic hyperglycaemia. However, the neuronal apoptosis and reactive gliosis are recently postulated as early changes in diabetic retinopathy. This phenomenon is described as a neurodegeneration and suggests that diabetic retinopathy should be recognized as a neurovascular complication. In this review, we discuss the mechanisms leading to the neurodegeneration of the retina in diabetic patients including: low-grade inflammatory process, oxidative stress, activation of polymorphonuclear neutrophils, glutamate excitotoxicity and imbalance in the neuroprotective factors. Secondly, we point out the clinical significance of measuring the retinal neurodegeneration.

Autophagy in Diabetic Retinopathy by Michelino Di Rosa, Gisella Distefano, Caterina Gagliano, Dario Rusciano, Lucia Malaguarnera (810-825).
Autophagy is an important homeostatic cellular process encompassing a number of consecutive steps indispensable for degrading and recycling cytoplasmic materials. Basically autophagy is an adaptive response that under stressful conditions guarantees the physiological turnover of senescent and impaired organelles and, thus, controls cell fate by various cross-talk signals. Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and accounts for 5% of all blindness. Although, various metabolic disorders have been linked with the onset of DR, due to the complex character of this multi-factorial disease, a connection between any particular defect and DR becomes speculative. Diabetes increases inflammation, advanced glycation end products (AGEs) and oxidative stress in the retina and its capillary cells. Particularly, a great number of evidences suggest a mutual connection between oxidative stress and other major metabolic abnormalities implicated in the development of DR. In addition, the intricate networks between autophagy and apoptosis establish the degree of cellular apoptosis and the progression of DR. Growing data underline the crucial role of reactive oxygen species (ROS) in the activation of autophagy. Depending on their delicate balance both redox signaling and autophagy, being detrimental or beneficial, retain opposing effects. The molecular mechanisms of autophagy are very complex and involve many signaling pathways cooperating at various steps. This review summarizes recent advances of the possible molecular mechanisms in autophagic process that are involved in pathophysiology of DR. In-depth analysis on the molecular mechanisms leading to autophagy in the retinal pigment epithelial (RPE) will be helpful to plan new therapies aimed at preventing or improving the progression of DR.

Neuroretinal Apoptosis as a Vascular Dysfunction in Diabetic Patients by Ma|gorzata Mrugacz, Anna Bryl, Artur Bossowski (826-830).
Background: Diabetic retinopathy (DR) is an important complication of diabetes and is considered one of the main causes of blindness in moderate-income and highly-developed countries. As it is a major socioeconomic problem, defining all mechanisms that may lead to DR development is of great importance. In the 21st century diabetic lesions occurring in the retina are well known. However what kind of retinal neuronal damage occurs in the course of diabetes remains unclear.
Results: In this manuscript we present the most recent knowledge about suggested mechanisms of diabetic retinopathy, including neuroretinal apoptosis. Getting a deep insight into the role of apoptosis and degeneration of retinal neurons leading to DR will have vital consequences.
Conclusion: The findings of this review confirm that it is very likely that in the nearest future diabetic retinopathy treatment will be based on administration of neuroprotective agents. The implementation of neuroprotective drugs may slow down retinopathy progression, making it possible to avoid the currently used therapeutic procedures, such as laser photocoagulation, intravitreous injections or posterior vitrectomy, which are not only risky for the healthy part of the retina but also relatively expensive.

Neurodegeneration and Neuroinflammation in Diabetic Retinopathy: Potential Approaches to Delay Neuronal Loss by Joanna Kad|ubowska, Lucia Malaguarnera, Piotr W||, Katarzyna Zorena (831-839).
In spite of the extensive research the complex pathogenesis of diabetic retinopathy (DR) has not been fully elucidated. For many years it has been thought that diabetic retinopathy manifests only with microangiopathic lesions, which are totally responsible for the loss of vision in diabetic patients. In view of the current knowledge on the microangiopathic changes in the fundus of the eye, diabetic retinopathy is perceived as a neurodegenerative disease. Several clinical tools are available to detect neuronal dysfunction at early stages of diabetes. Many functional changes in the retina can be identified before vascular pathology develops, suggesting that they result from a direct effect of diabetes on the neural retina. In the course of diabetes there is a chronic loss of retinal neurons due to increased frequency of apoptosis. The neuronal apoptosis begins very early in the course of diabetes. This observation has led to suggestions that precautions against DR should be implemented immediately after diabetes is diagnosed. Neurodegeneration cannot be reversed; therefore treatments preventing neuronal cell loss in the retina need to be developed to protect diabetic patients. This review is an attempt to summarize what is currently known about the mechanisms of neuronal apoptosis in the context of diabetic retinopathy and vascular degeneration as well as about potential treatments of DR.

Background: Although the precise pathophysiology of irritable bowel syndrome (IBS) remains unknown, it is generally considered to be a disorder of the brain-gut axis, representing the disruption of communication between the brain and the digestive system. The present review describes advances in understanding the pathophysiology and experimental approaches in studying IBS, as well as providing an update of the therapies targeting brain-gut axis in the treatment of the disease.
Methods: Causal factors of IBS are reviewed. Following this, the preclinical experimental models of IBS will be introduced. Besides, both current and future therapeutic approaches of IBS will be discussed.
Results: When signal of the brain-gut axis becomes misinterpreted, it may lead to dysregulation of both central and enteric nervous systems, altered intestinal motility, increased visceral sensitivity and consequently contributing to the development of IBS. Interference of the brain-gut axis can be modulated by various psychological and environmental factors. Although there is no existing animal experiment that can represent this complex multifactorial disease, these in vivo models are clinically relevant readouts of gastrointestinal functions being essential to the identification of effective treatments of IBS symptoms as well as their molecular targets. Understanding the brain-gut axis is essential in developing the effective therapy for IBS. Therapies include improvement of GI motor functions, relief of visceral hypersensitivity and pain, attenuation of autonomic dysfunctions and suppression of mucosal immune activation.
Conclusion: Target-oriented therapies that provide symptomatic, psychological and physiological benefits could surely help to improve the quality of life of IBS patients.

Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications by Predrag Sikiric, Sven Seiwerth, Rudolf Rucman, Danijela Kolenc, Lovorka Batelja Vuletic, Domagoj Drmic, Tihomir Grgic, Sanja Strbe, Goran Zukanovic, Dalibor Crvenkovic, Goran Madzarac, Iva Rukavina, Mario Sucic, Marko Baric, Neven Starcevic, Zoran Krstonijevic, Martina Lovric Bencic, Igor Filipcic, Dinko Stancic Rokotov, Josipa Vlainic (857-865).
Background: Brain-gut interaction involves, among others, peptidergic growth factors which are native in GI tract and have strong antiulcer potency and thus could from periphery beneficially affect CNS-disorders. We focused on the stable gastric pentadecapeptide BPC 157, an antiulcer peptidergic agent, safe in inflammatory bowel disease trials and now in multiple sclerosis trial, native and stable in human gastric juice.
Methods: Review of our research on BPC 157 in terms of brain-gut axis.
Results: BPC 157 may serve as a novel mediator of Robert's cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds. Stimulated Egr-1 gene, NAB2, FAK-paxillin and JAK-2 pathways are hitherto implicated. Initially corresponding beneficial central influence was seen when BPC 157 was given peripherally and a serotonin release in particular brain areas, mostly nigrostriatal, was changed. BPC 157 modulates serotonergic and dopaminergic systems, beneficially affects various behavioral disturbances that otherwise appeared due to specifically (over)stimulated/damaged neurotransmitters systems. Besides, BPC 157 has neuroprotective effects: protects somatosensory neurons; peripheral nerve regeneration appearent after transection; after traumatic brain injury counteracts the otherwise progressing course, in rat spinal cord compression with tail paralysis, axonal and neuronal necrosis, demyelination, cyst formation and rescues tail function in both short-terms and long-terms; after NSAIDs or insulin overdose or cuprizone encephalopathies were attenuated along with GI, liver and vascular injuries.
Conclusion: BPC 157, a gastric peptide, may serve as remedy in various CNS-disorders.

We examined the influence of adrenalectomy on NSAID-induced small intestinal damage in rats and investigated the possible involvement of adrenal glucocorticoids in the protective effects of urocortin I, a corticotropin-releasing factor (CRF) agonist. Male SD rats without fasting were administered indomethacin s.c. and killed 24 h later in order to examine the hemorrhagic lesions that developed in the small intestine. Urocortin I (20 ?g/kg) was given i.v. 10 min before the administration of indomethacin. Bilateral adrenalectomy was performed a week before the experiment. Indomethacin (10 mg/kg) caused multiple hemorrhagic lesions in the small intestine, which were accompanied by a decrease in mucus secretion and increases in intestinal motility, enterobacterial invasion, and iNOS expression. Adrenalectomy markedly increased the ulcerogenic and motility responses caused by indomethacin, with further enhancements in bacterial invasion and iNOS expression; severe lesions occurred at 3 mg/kg, a dose that did not induce any damage in sham-operated rats. This worsening effect was also observed by the pretreatment with mifepristone (a glucocorticoid receptor antagonist). Urocortin I prevented indomethacin-induced enteropathy, and this effect was completely abrogated by the pretreatment with astressin 2B, a CRF2 receptor antagonist, but was not significantly affected by either adrenalectomy or the mifepristone pretreatment. These results suggested that adrenalectomy aggravated the intestinal ulcerogenic response to indomethacin, the intestinal hypermotility response may be a key element in the mechanism for this aggravation, and endogenous glucocorticoids played a role in intestinal mucosal defense against indomethacin-induced enteropathy, but did not account for the protective effects of urocortin I, which were mediated by the activation of peripheral CRF2 receptors.

Background: The brain and the gut interact bi-directionally through the brain-gut axis. The interaction is mediated by the autonomic nervous system and the hypothalamic-pituitary-adrenocortical (HPA) system. The first brilliant demonstration of the brain-gut interactions was the cephalic phase of gastric and pancreatic secretion discovered by Ivan Pavlov, the first physiologist who was awarded the Nobel Prize for Physiology or Medicine in 1904. This review aims to identify the HPA system as a key hormonal branch of the brain-gut axis in stress.
Methods: We first outlined main components of the brain-gut axis and then focused on the HPA system as a key hormonal branch of the brain-gut axis in stress. We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question.
Results: Seventy-one articles were included in the review, the eleventh of them were articles of Filaretova L. and co-authors. We will discuss in our articles how an endocrinological approach to gastroenterological field can advance our understanding of the HPA axis role in regulation of gastric mucosal integrity and uncover new findings. According to these findings activation of the HPA system is gastroprotective component of the brain-gut axis in stress but not ulcerogenic one as it was generally accepted. Corticotropin-releasing factor (CRF) and glucocorticoids are important natural players provided gastroprotection. The results suggest that an initial action of endogenous glucocorticoids, including stress- and CRF-produced ones, as well as exogenous glucocorticoids, even used at pharmacological doses, is physiological gastroprotective. Prolongation of the hormonal action may lead to the transformation of gastroprotective hormonal effect to proulcerogenic one.
Conclusion: The findings of this review demonstrate that corticotropin-releasing factor and glucocorticoids contribute to the realization of the brain-gut interactions and that activation of the HPA system is gastroprotective component of this interaction in stress.

Background: Nucleobindin2 (NUCB2)/nesfatin-1 plays a well-established role in homeostatic functions associated with food intake and stress integration.
Aim: This review focusses on NUCB2/nesfatin-1's central effects on gastrointestinal functions and will summarize the effects on food intake, motility and secretion with focus on the upper gastrointestinal tract.
Results: We will highlight the stressors that influence brain NUCB2/nesfatin-1 expression and discuss functional implications. In addition to traditional acute psychological and physical stressors such as restraint stress and abdominal surgery we will look at immunological, visceral and metabolic stressors as well as a chronic combination stress model that have been shown to affect NUCB2/nesfatin-1 signaling and describe associated functional consequences.

Mechanisms by which Stress Affects the Experimental and Clinical Inflammatory Bowel Disease (IBD): Role of Brain-Gut Axis by Bartosz Brzozowski, Agnieszka Mazur-Bialy, Robert Pajdo, Slawomir Kwiecien, Jan Bilski, Malgorzata Zwolinska-Wcislo, Tomasz Mach, Tomasz Brzozowski (892-900).
Background: Stress of different origin is known to alter so called “braingut axis” and contributes to a broad array of gastrointestinal disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal diseases. The stressful situations and various stressors including psychosocial events, heat, hypo- and hyperthermia may worsen the course of IBD via unknown mechanism. The aims of this paper were to provide an overview of experimental and clinical evidences that stress activates the brain-gut axis which results in a mucosal mast cells activation and an increase in the production of proinflammatory cytokines and other endocrine and humoral mediators.
Methods: Research and online content related to effects of stress on lower bowel disorders are reviewed and most important mechanisms are delineated.
Results: Brain conveys the neural, endocrine and circulatory messages to the gut via brain-gut axis reflecting changes in corticotrophin releasing hormone, mast cells activity, neurotransmission at the autonomic nerves system and intestinal barrier function all affecting the pathogenesis of animal colitis and human IBD. Stress triggers the hypothalamus-pituitary axis and the activation of the autonomic nervous system, an increase in cortisol levels and proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-8, interleukin-1beta and interleukin-6.
Conclusion: The acute or chronic stress enhances the intestinal permeability weakening of the tight junctions and increasing bacterial translocation into the intestinal wall. An increased microbial load in the colonic tissue, excessive cytokine release and a partially blunted immune reactivity in response to stress result in its negative impact on IBD.

Background: The authors, as internists, registered significant difference in the long lasting actions of surgical and chemical (atropine treatment) vagotomy in patients with peptic ulcer during second half of the last century (efficency, gastric acid secretion, gastrointestinal side effects, briefly benefical and harmful actions were examined).
Aims: 1. Since the authors participated in the establishing of human clinical pharmacology in this field, they wanted to know more and more facts of the acute and chronic effects of surgical and chemical (atropine treatment) on the gastrointestinal mucosal biochemisms and their actions altered by bioactive compounds and scavengers regarding the development of gastric mucosal damage and protection.
Methods. The observations were carried out in animals under various experimental conditions (in intact, pylorus-ligated rats, in different experimental ulcer models, together with application of various mucosal protecting compounds) without and with surgical vagotomy and chemical vagotomy produced by atropine treatment.
Results: 1. No changes were obtained in the cellular energy systems (ATP, ADP, AMP, cAMP, “adenylate pool”, “energy charge“ [(ATP+0.5 ADP)/ (ATP+ADP+AMP)] of stomach (glandular part, forestomach) in pylorus ligated rats after surgical vagotomy in contrast to those produced by only chemical vagotomy; 2. The effects of the gastric mucosal protective compounds [atropine, cimetidine, prostaglandins, scavengers (like vitamin A, ?-carotene), capsaicin] disappeared after surgical vagotomy; 3. The extents of different chemical agents induced mucosal damaging effects were enhanced by surgical vagotomy and was not altered by chemical vagotomy; 4. The existence of feedback mechanisms of pharmacological (cellular and intracellular) regulatory mechanisms between the membrane-bound ATPdependent energy systems exists in the gastric mucosa of intact animals, and after chemical vagotomy, but not after surgical vagotomy.
Conclusions: 1. Increased vagal nerve activity takes place in the gastric mucosal damage; 2 both surgical and chemical vagotomy result mucosal protective affect on the gastric mucosal in different damaging experimental models; 3. The capsaicin-induced gastric mucosal damage depends on the applied doses, presence of anatomically intact vagal nerve (but independent from the chemical vagotomy), 4. The central and pheripheral neural regulations differ during gastric mucosal damage and protection induced by drugs, bioactive compounds, scavengers.

Mesenchymal Stem Cells of Dental Origin-Their Potential for Antiinflammatory and Regenerative Actions in Brain and Gut Damage by Anna Földes, Kristóf Kádár, Beáta Kerémi, Ákos Zsembery, Klára Gyires, Zoltán S. Zádori, Gábor Varga Varga (914-934).
Alzheimer's disease, Parkinson's disease, traumatic brain and spinal cord injury and neuroinflammatory multiple sclerosis are diverse disorders of the central nervous system. However, they are all characterized by various levels of inappropriate inflammatory/immune response along with tissue destruction. In the gastrointestinal system, inflammatory bowel disease (IBD) is also a consequence of tissue destruction resulting from an uncontrolled inflammation. Interestingly, there are many similarities in the immunopathomechanisms of these CNS disorders and the various forms of IBD. Since it is very hard or impossible to cure them by conventional manner, novel therapeutic approaches such as the use of mesenchymal stem cells, are needed. Mesenchymal stem cells have already been isolated from various tissues including the dental pulp and periodontal ligament. Such cells possess transdifferentiating capabilities for different tissue specific cells to serve as new building blocks for regeneration. But more importantly, they are also potent immunomodulators inhibiting proinflammatory processes and stimulating anti-inflammatory mechanisms.
The present review was prepared to compare the immunopathomechanisms of the above mentioned neurodegenerative, neurotraumatic and neuroinflammatory diseases with IBD. Additionally, we considered the potential use of mesenchymal stem cells, especially those from dental origin to treat such disorders. We conceive that such efforts will yield considerable advance in treatment options for central and peripheral disorders related to inflammatory degeneration.

Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation by Klára Gyires, Zoltán S. Zádori (935-951).
Modulating the activity of the endocannabinoid system influences various gastrointestinal physiological and pathophysiological processes, and cannabinoid receptors as well as regulatory enzymes responsible for the synthesis or degradation of endocannabinoids representing potential targets to reduce the development of gastrointestinal mucosal lesions, hemorrhage and inflammation. Direct activation of CB1 receptors by plant-derived, endogenous or synthetic cannabinoids effectively reduces both gastric acid secretion and gastric motor activity, and decreases the formation of gastric mucosal lesions induced by stress, pylorus ligation, nonsteroidal anti-inflammatory drugs (NSAIDs) or alcohol, partly by peripheral, partly by central mechanisms. Similarly, indirect activation of cannabinoid receptors through elevation of endocannabinoid levels by globally acting or peripherally restricted inhibitors of their metabolizing enzymes (FAAH, MAGL) or by inhibitors of their cellular uptake reduces the gastric mucosal lesions induced by NSAIDs in a CB1 receptor-dependent fashion. Dual inhibition of FAAH and cyclooxygenase enzymes induces protection against both NSAID-induced gastrointestinal damage and intestinal inflammation. Moreover, in intestinal inflammation direct or indirect activation of CB1 and CB2 receptors exerts also multiple beneficial effects. Namely, activation of both CB receptors was shown to ameliorate intestinal inflammation in various murine colitis models, to decrease visceral hypersensitivity and abdominal pain, as well as to reduce colitis-associated hypermotility and diarrhea. In addition, CB1 receptors suppress secretory processes and also modulate intestinal epithelial barrier functions. Thus, experimental data suggest that the endocannabinoid system represents a promising target in the treatment of inflammatory bowel diseases, and this assumption is also confirmed by preliminary clinical studies.

Probiotics as an Adjuvant Therapy in Major Depressive Disorder by Josipa Vlaini| Vlaini|, Jelena (952-958).
Background: Major depressive disorder is a common, debilitating psychiatric disorder, which originates from the interaction of susceptibility genes and noxious environmental events, in particular stressful events. It has been shown that dysregulation of hypothalamus-pituitary-adrenal (HPA) axis, imbalance between anti- and pro-inflammatory cytokines, depletion of neurotransmitters (serotonin, norepinephrine and/or dopamine) in the central nervous system, altered glutamatergic and GABAergic transmission have an important role in the pathogenesis of depression. Due to numerous diverse biological events included in the pathophysiology of depression a large number of antidepressant drugs exerting distinct pharmacological effects have been developed. Nevertheless, clinical needs are still not solved.
Results: Relatively new research strategies advanced the understanding of psychiatric illness and their connections with disturbances in gastrointestinal tract. The existence of bidirectional communication between the brain and the gut has been proven, and an increasing body of evidence supports the hypothesis that cognitive and emotional processes are influenced through the brain-gut axis. On the other hand, microbiome may influence brain function and even behavior giving to the specific microorganisms a psychobiotic potential.
Conclusions: In this review we discuss the possibilities of classical antidepressant drug treatment being supported with the psychobiotics/probiotic bacteria in patients suffering from major depressive disorder.

Gut-Brain Axis in Gastric Mucosal Damage and Protection by Dolores Sgambato, Annalisa Capuano, Maria Giuseppa Sullo, Agnese Miranda, Alessandro Federico, Marco Romano (959-966).
Background: The gut-brain axis plays a potential role in numerous physiological and pathological conditions. Several substances link stomach with central nervous system. In particular, hypothalamo-pituitary-adrenocortical axis, thyrotropinreleasing factor-containing nerve fibers and capsaicin-sensitive nerves are principal mediators of the harmful and protective central nervous system-mediated effects on gastric mucosa. Also, existing evidence indicates that nitric oxide, prostaglandins and calcitonin gene-related peptide play a role as final effectors of gastric protection.
Methods: We undertook a structured search of bibliographic databases for peerreviewed research literature with the aim of focusing on the role of gut-brain axis in gastric damage and protection. In particular, we examined manuscripts dealing with the role of steroids, thyrotropin-releasing hormone, prostaglandins, melatonin, hydrogen sulfide and peptides influencing food intake (i.e. leptin, cholecystokinin, peptide YY, central glucagon-like peptide-1, and ghrelin). Also, the role of GABAergic and glutamatergic pathways in gastric mucosal protection have been examined.
Results: We found and reviewed 61 peer-reviewed papers dealing with the major aspects related to the role of gut brain axis in gastric mucosal damage and protection.
Conclusions: A dense neuronal network links stomach with central nervous system and a number of neurotransmitters and peptides functionally and anatomically related to central nervous system play a major role in contributing to gastric mucosal integrity.
Exploiting the mechanisms underlying the connection between brain and gut may lead to a better understanding of the pathophysiology of gastric mucosal injury and to an improvement in the prevention and, eventually, management of gastric damage.

Vagotomy and Gastric Tumorigenesis by Hanne-Line Rabben, Chun-Mei Zhao, Yoku Hayakawa, Timothy C. Wang, Duan Chen (967-972).
Vagotomy reduces gastric acid secretion and was therefore introduced as a surgical treatment for peptic ulcers in the 1970s. Later, it was replaced by acid reducing medication, such as histamine type 2 (H2) receptor antagonists and proton pump inhibitors (PPIs). A large body of evidence has indicated that drug-induced hypochlorhydria per se does not increase the risk of gastric cancer. Early studies on the effects of vagotomy in chemically-induced rodent models of gastric cancer reported an increased risk of developing gastric cancer. This was most likely due to a delayed gastric emptying, which later has been accounted for by including an additional drainage procedure, e.g. pyloroplasty. In a recent study using three different mouse models of gastric cancer (including genetically engineered, chemically-induced and Helicobacter pylori-infected mice), either unilateral vagotomy or bilateral truncal vagotomy with pyloroplasty was found to significantly attenuate tumorigenesis in the denervated side of the stomach at early preneoplastic stages as well as at later stages of tumorigenesis. Consistently, pharmacological denervation using botulinum toxin A or muscarinic acetylcholine receptor 3 (M3R) blockade inhibited tumorigenesis. Moreover, it was found that recurrence of gastric cancer was reduced in patients following vagotomy. Thus, these new findings suggest the potential treatment strategies to target the nerve, neurotransmitters, corresponding receptors and their downstream signaling pathways for the malignancy.