Understanding the potential causes of gastrointestinal dysfunctions in multiple system atrophy.

Multiple system atrophy (MSA) is a rare, progressive neurodegenerative disorder characterised by autonomic, pyramidal, parkinsonian and/or cerebellar dysfunction. Autonomic symptoms of MSA include deficits associated with the gastrointestinal (GI) system, such as difficulty swallowing, abdominal pain and bloating, nausea, delayed gastric emptying, and constipation. To date, studies assessing GI dysfunctions in MSA have primarily focused on alterations of the gut microbiome, however growing evidence indicates other structural components of the GI tract, such as the enteric nervous system, the intestinal barrier, GI hormones, and the GI-driven immune response may contribute to MSA-related GI symptoms. Here, we provide an in-depth exploration of the physiological, structural, and immunological changes theorised to underpin GI dysfunction in MSA patients and highlight areas for future research in order to identify more suitable pharmaceutical treatments for GI symptoms in patients with MSA.

Gastrointestinal consequences of lipopolysaccharide-induced lung inflammation.

BACKGROUND: Respiratory inflammation is the body's response to lung infection, trauma or hypersensitivity and is often accompanied by comorbidities, including gastrointestinal (GI) symptoms. Why respiratory inflammation is accompanied by GI dysfunction remains unclear. Here, we investigate the effect of lipopolysaccharide (LPS)-induced lung inflammation on intestinal barrier integrity, tight-junctions, enteric neurons and inflammatory marker expression. METHODS: Female C57bl/6 mice (6-8 weeks) were intratracheally administered LPS (5 µg) or sterile saline, and assessed after either 24 or 72 h. Total and differential cell counts in bronchoalveolar lavage fluid (BALF) were used to evaluate lung inflammation. Intestinal barrier integrity was assessed via cross sectional immunohistochemistry of tight junction markers claudin-1, claudin-4 and EpCAM. Changes in the enteric nervous system (ENS) and inflammation in the intestine were quantified immunohistochemically using neuronal markers Hu + and nNOS, glial markers GFAP and S100ß and pan leukocyte marker CD45. RESULTS: Intratracheal LPS significantly increased the number of neutrophils in BALF at 24 and 72 h. These changes were associated with an increase in CD45 + cells in the ileal mucosa at 24 and 72 h, increased goblet cell expression at 24 h, and increased expression of EpCAM at 72 h. LPS had no effect on the expression of GFAP, S100ß, nor the number of Hu + neurons or proportion of nNOS neurons in the myenteric plexus. CONCLUSIONS: Intratracheal LPS administration induces inflammation in the ileum that is associated with enhanced expression of EpCAM, decreased claudin-4 expression and increased goblet cell density, these changes may contribute to systemic inflammation that is known to accompany many inflammatory diseases of the lung.

Anti-Inflammatory Influences of Cystic Fibrosis Transmembrane Conductance Regulator Drugs on Lung Inflammation in Cystic Fibrosis.

Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) which instigates a myriad of respiratory complications including increased vulnerability to lung infections and lung inflammation. The extensive influx of pro-inflammatory cells and production of mediators into the CF lung leading to lung tissue damage and increased susceptibility to microbial infections, creates a highly inflammatory environment. The CF inflammation is particularly driven by neutrophil infiltration, through the IL-23/17 pathway, and function, through NE, NETosis, and NLRP3-inflammasome formation. Better understanding of these pathways may uncover untapped therapeutic targets, potentially reducing disease burden experienced by CF patients. This review outlines the dysregulated lung inflammatory response in CF, explores the current understanding of CFTR modulators on lung inflammation, and provides context for their potential use as therapeutics for CF. Finally, we discuss the determinants that need to be taken into consideration to understand the exaggerated inflammatory response in the CF lung.

Quantitation and chemical coding of enteroendocrine cell populations in the human jejunum.

Recent studies reveal substantial species and regional differences in enteroendocrine cell (EEC) populations, including differences in patterns of hormone coexpression, which limit extrapolation between animal models and human. In this study, jejunal samples, with no histologically identifiable pathology, from patients undergoing Whipple's procedure were investigated for the presence of gastrointestinal hormones using double- and triple-labelling immunohistochemistry and high-resolution confocal microscopy. Ten hormones (5-HT, CCK, secretin, proglucagon-derived peptides, PYY, GIP, somatostatin, neurotensin, ghrelin and motilin) were localised in EEC of the human jejunum. If only single staining is considered, the most numerous EEC were those containing 5-HT, CCK, ghrelin, GIP, motilin, secretin and proglucagon-derived peptides. All hormones had some degree of colocalisation with other hormones. This included a population of EEC in which GIP, CCK and proglucagon-derived peptides are costored, and four 5-HT cell populations, 5-HT/GIP, 5-HT/ghrelin, 5-HT/PYY, and 5-HT/secretin cell groups, and a high degree of overlap between motilin and ghrelin. The presence of 5-HT in many secretin cells is consistent across species, whereas lack of 5-HT and CCK colocalisation distinguishes human from mouse. It seems likely that the different subclasses of 5-HT cells subserve different roles. At a subcellular level, we examined the vesicular localisation of secretin and 5-HT, and found these to be separately stored. We conclude that hormone-containing cells in the human jejunum do not comply with a one-cell, one-hormone classification and that colocalisations of hormones are likely to define subtypes of EEC that have different roles.

The effect of high-fat diet-induced metabolic disturbance on corneal neuroimmune features.

PURPOSE: The highly innervated cornea is susceptible to nerve loss secondary to systemic diseases such as diabetes and metabolic disturbances caused by high-fat diet. In this study, we characterize the effect of high-fat diet on the mouse corneal neuroimmune phenotype, including changes to corneal nerve density and resident immune cells, alongside the clinical assessment of corneal thickness and endothelial cell density. METHODS: Male C57Bl6/J mice, aged 10 weeks, were fed a high-fat diet (60 kcal% fat, 5.2 kcal/g) or control diet (10 kcal%, 3.8 kcal/g) for 16 weeks. At the study endpoint, metabolic parameters (HbA1c, weight, fasting glucose, body fat) were measured to confirm metabolic disturbance. Clinical imaging of the anterior segment was performed using optical coherence tomography to measure the corneal epithelial and stromal thickness. Corneal sensory nerves were visualized using flatmount immunostaining and confocal microscopy. The topographical distribution and density of sensory nerves (BIII-tubulin+), intraepithelial CD45+ and MHC- II+ cells, stromal macrophages (IBA1+CD206+) and endothelial cells (ZO-1+) were analysed using FIJI. RESULTS: High-fat diet mice had significantly higher blood HbA1c, higher body weight, a higher percentage of body fat and elevated fasting glucose compared to the control diet mice. Corneal epithelial and stromal thickness was similar in both groups. The sum length of the basal nerve plexus was lower in the central and peripheral cornea of mice fed a high-fat diet. In contrast, the sum length of superficial nerve terminals was similar between groups. Epithelial immune cell density was two-fold higher in the central corneas of high-fat diet mice compared to control diet mice. IBA1+CD206+ macrophage density was similar in the anterior stroma of both groups but was significantly higher in the posterior stroma of the peripheral cornea in the high-fat diet mice compared to controls. The percentage of nerve-associated MHC-II+ cells in the epithelium and stroma was higher in HFD mice compared to controls. Endothelial cell density was similar in the corneas of high-fat diet mice compared to controls. CONCLUSION: Together with corneal neuropathy, corneal immune cells in mice fed a high-fat diet were differentially affected depending on their topographical distribution and location within cornea, and appeared in closer proximity to epithelial and stromal nerves, suggesting a local neuroimmune disruption induced by systemic metabolic disturbance.

Agonist-dependent development of delta opioid receptor tolerance in the colon.

The use of opioid analgesics is severely limited due to the development of intractable constipation, mediated through activation of mu opioid receptors (MOR) expressed by enteric neurons. The related delta opioid receptor (DOR) is an emerging therapeutic target for chronic pain, depression and anxiety. Whether DOR agonists also promote sustained inhibition of colonic transit is unknown. This study examined acute and chronic tolerance to SNC80 and ARM390, which were full and partial DOR agonists in neural pathways controlling colonic motility, respectively. Excitatory pathways developed acute and chronic tolerance to SNC80, whereas only chronic tolerance developed in inhibitory pathways. Both pathways remained functional after acute or chronic ARM390 exposure. Propagating colonic motor patterns were significantly reduced after acute or chronic SNC80 treatment, but not by ARM390 pre-treatment. These findings demonstrate that SNC80 has a prolonged inhibitory effect on propagating colonic motility. ARM390 had no effect on motor patterns and thus may have fewer gastrointestinal side-effects.

Distributions and relationships of chemically defined enteroendocrine cells in the rat gastric mucosa.

This paper provides quantitative data on the distributions of enteroendocrine cells (EEC), defined by the hormones they contain, patterns of colocalisation between hormones and EEC relations to nerve fibres in the rat gastric mucosa. The rat stomach has three mucosal types: non-glandular stratified squamous epithelium of the fundus and esophageal groove, a region of oxyntic glands in the corpus, and pyloric glands of the antrum and pylorus. Ghrelin and histamine were both contained in closed cells, not contacting the lumen, and were most numerous in the corpus. Gastrin cells were confined to the antrum, and 5-hydroxytryptamine (5-HT) and somatostatin cells were more frequent in the antrum than the corpus. Most somatostatin cells had basal processes that in the antrum commonly contacted gastrin cells. Peptide YY (PYY) cells were rare and mainly in the antrum. The only numerous colocalisations were 5-HT and histamine, PYY and gastrin and gastrin and histamine in the antrum, but each of these populations was small. Peptide-containing nerve fibres were found in the mucosa. One of the most common types was vasoactive intestinal peptide (VIP) fibres. High-resolution analysis showed that ghrelin cells were closely and selectively approached by VIP fibres. In contrast, gastrin cells were not selectively innervated by VIP or CGRP fibres. The study indicates that there are distinct populations of gastric EEC and selective innervation of ghrelin cells. It also shows that, in contrast to EEC of the small intestine, the majority of EEC within the stomach contained only a single hormone.

Relationships of endocrine cells to each other and to other cell types in the human gastric fundus and corpus.

Gastric endocrine cell hormones contribute to the control of the stomach and to signalling to the brain. In other gut regions, enteroendocrine cells (EECs) exhibit extensive patterns of colocalisation of hormones. In the current study, we characterise EECs in the human gastric fundus and corpus. We utilise immunohistochemistry to investigate EECs with antibodies to ghrelin, serotonin (5-HT), somatostatin, peptide YY (PYY), glucagon-like peptide 1, calbindin, gastrin and pancreastatin, the latter as a marker of enterochromaffin-like (ECL) cells. EECs were mainly located in regions of the gastric glands populated by parietal cells. Gastrin cells were absent and PYY cells were very rare. Except for about 25% of 5-HT cells being a subpopulation of ECL cells marked by pancreastatin, colocalisation of hormones in gastric EECs was infrequent. Ghrelin cells were distributed throughout the fundus and corpus; most were basally located in the glands, often very close to parietal cells and were closed cells i.e., not in contact with the lumen. A small proportion had long processes located close to the base of the mucosal epithelium. The 5-HT cells were of at least three types: small, round, closed cells; cells with multiple, often very long, processes; and a subgroup of ECL cells. Processes were in contact with their surrounding cells, including parietal cells. Mast cells had very weak or no 5-HT immunoreactivity. Somatostatin cells were a closed type with long processes. In conclusion, four major chemically defined EEC types occurred in the human oxyntic mucosa. Within each group were cells with distinct morphologies and relationships to other mucosal cells.

Inflammation-associated changes in DOR expression and function in the mouse colon.

Endogenous opioids activate opioid receptors (ORs) in the enteric nervous system to control intestinal motility and secretion. The µ-OR mediates the deleterious side effects of opioid analgesics, including constipation, respiratory depression, and addiction. Although the δ-OR (DOR) is a promising target for analgesia, the function and regulation of DOR in the colon are poorly understood. This study provides evidence that endogenous opioids activate DOR in myenteric neurons that may regulate colonic motility. The DOR agonists DADLE, deltorphin II, and SNC80 inhibited electrically evoked contractions and induced neurogenic contractions in the mouse colon. Electrical, chemical, and mechanical stimulation of the colon evoked the release of endogenous opioids, which stimulated endocytosis of DOR in the soma and proximal neurites of myenteric neurons of transgenic mice expressing DOR fused to enhanced green fluorescent protein. In contrast, DOR was not internalized in nerve fibers within the circular muscle. Administration of dextran sulfate sodium induced acute colitis, which was accompanied by DOR endocytosis and an increased density of DOR-positive nerve fibers within the circular muscle. The potency with which SNC80 inhibited neurogenic contractions was significantly enhanced in the inflamed colon. This study demonstrates that DOR-expressing neurons in the mouse colon can be activated by exogenous and endogenous opioids. Activated DOR traffics to endosomes and inhibits neurogenic motility of the colon. DOR signaling is enhanced during intestinal inflammation. This study demonstrates functional expression of DOR by myenteric neurons and supports the therapeutic targeting of DOR in the enteric nervous system. NEW & NOTEWORTHY DOR is activated during physiologically relevant reflex stimulation. Agonist-evoked DOR endocytosis is spatially and temporally regulated. A significant proportion of DOR is internalized in myenteric neurons during inflammation. The relative proportion of all myenteric neurons that expressed DOR and the overlap with the nNOS-positive population are increased in inflammation. DOR-specific innervation of the circular muscle is increased in inflammation, and this is consistent with enhanced responsiveness to the DOR agonist SNC80.

PARP inhibition in platinum-based chemotherapy: Chemopotentiation and neuroprotection.

Cisplatin, carboplatin and oxaliplatin represent the backbone of platinum therapy for several malignancies including head and neck, lung, colorectal, ovarian, breast, and genitourinary cancer. However, the efficacy of platinum-based drugs is often compromised by a plethora of severe toxicities including sensory and enteric neuropathy. Acute and chronic neurotoxicity following platinum chemotherapy is a major constraint, contributing to dose-reductions, treatment delays, and cessation of treatment. Identifying drugs that effectively prevent these toxic complications is imperative to improve the efficacy of anti-cancer treatment and patient quality of life. Oxidative stress and mitochondrial dysfunction have been highlighted as key players in the pathophysiology of platinum chemotherapy-induced neuropathy. Inhibition of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated upon DNA damage, has demonstrated substantial sensory and enteric neuroprotective capacity when administered in combination with platinum chemotherapeutics. Furthermore, administration of PARP inhibitors alongside platinum chemotherapy has been found to significantly improve progression-free survival in patients with breast and ovarian cancer when compared to those receiving chemotherapy alone. This review summarises the current knowledge surrounding mitochondrial damage and oxidative stress in platinum chemotherapy-induced neuropathy and highlights a potential role for PARP in chemopotentiation and neuroprotection.

The role of the gastrointestinal barrier in obesity-associated systemic inflammation.

Systemic inflammation is a key contributor to the onset and progression of several obesity-associated diseases and is thought to predominantly arise from the hyperplasia and hypertrophy of white adipose tissue. However, a growing body of works suggests that early changes in the gastrointestinal (GI) barrier may contribute to both local, within the GI lining, and systemic inflammation in obesity. Intestinal barrier dysfunction is well-characterized in inflammatory GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and is known to contribute to systemic inflammation. Thus, drawing parallels between GI disorders, where intestinal permeability and systemic inflammation are prominent features, and obesity-induced GI manifestations may provide insights into the potential role of the intestinal barrier in systemic inflammation in obesity. This review summarizes the current literature surrounding intestinal barrier dysfunction in obesity and explores the potential role of intestinal hyperpermeability and intestinal barrier dysfunction in the development of systemic inflammation and GI dysfunction in obesity.

Do Bacterial Outer Membrane Vesicles Contribute to Chronic Inflammation in Parkinson's Disease?

Parkinson's disease (PD) is an increasingly common neurodegenerative disease. It has been suggested that the etiology of idiopathic PD is complex and multifactorial involving environmental contributions, such as viral or bacterial infections and microbial dysbiosis, in genetically predisposed individuals. With advances in our understanding of the gut-brain axis, there is increasing evidence that the intestinal microbiota and the mammalian immune system functionally interact. Recent findings suggest that a shift in the gut microbiome to a pro-inflammatory phenotype may play a role in PD onset and progression. While there are links between gut bacteria, inflammation, and PD, the bacterial products involved and how they traverse the gut lumen and distribute systemically to trigger inflammation are ill-defined. Mechanisms emerging in other research fields point to a role for small, inherently stable vesicles released by Gram-negative bacteria, called outer membrane vesicles in disease pathogenesis. These vesicles facilitate communication between bacteria and the host and can shuttle bacterial toxins and virulence factors around the body to elicit an immune response in local and distant organs. In this perspective article, we hypothesize a role for bacterial outer membrane vesicles in PD pathogenesis. We present evidence suggesting that these outer membrane vesicles specifically from Gram-negative bacteria could potentially contribute to PD by traversing the gut lumen to trigger local, systemic, and neuroinflammation. This perspective aims to facilitate a discussion on outer membrane vesicles in PD and encourage research in the area, with the goal of developing strategies for the prevention and treatment of the disease.

Gastrointestinal Dysfunction in Parkinson's Disease: Current and Potential Therapeutics.

Abnormalities in the gastrointestinal (GI) tract of Parkinson's disease (PD) sufferers were first reported over 200 years ago; however, the extent and role of GI dysfunction in PD disease progression is still unknown. GI dysfunctions, including dysphagia, gastroparesis, and constipation, are amongst the most prevalent non-motor symptoms in PD. These symptoms not only impact patient quality of life, but also complicate disease management. Conventional treatment pathways for GI dysfunctions (i.e., constipation), such as increasing fibre and fluid intake, and the use of over-the-counter laxatives, are generally ineffective in PD patients, and approved compounds such as guanylate cyclase C agonists and selective 5-hyroxytryptamine 4 receptor agonists have demonstrated limited efficacy. Thus, identification of potential targets for novel therapies to alleviate PD-induced GI dysfunctions are essential to improve clinical outcomes and quality of life in people with PD. Unlike the central nervous system (CNS), where PD pathology and the mechanisms involved in CNS damage are relatively well characterised, the effect of PD at the cellular and tissue level in the enteric nervous system (ENS) remains unclear, making it difficult to alleviate or reverse GI symptoms. However, the resurgence of interest in understanding how the GI tract is involved in various disease states, such as PD, has resulted in the identification of novel therapeutic avenues. This review focuses on common PD-related GI symptoms, and summarizes the current treatments available and their limitations. We propose that by targeting the intestinal barrier, ENS, and/or the gut microbiome, may prove successful in alleviating PD-related GI symptoms, and discuss emerging therapies and potential drugs that could be repurposed to target these areas.

Ivacaftor Alters Macrophage and Lymphocyte Infiltration in the Lungs Following Lipopolysaccharide Exposure.

Background and purpose: Cystic fibrosis (CF) is associated with a myriad of respiratory complications including increased susceptibility to lung infections and inflammation. Progressive inflammatory insults lead to airway damage and remodeling, resulting in compromised lung function. Treatment with ivacaftor significantly improves respiratory function and reduces the incidence of pulmonary exacerbations; however, its effect on lung inflammation is yet to be fully elucidated. Experimental approach: This study investigates the effects of ivacaftor on lung inflammation in a lipopolysaccharide (LPS) exposure mouse model (C57BL/6). All groups received intratracheal (IT) administration of LPS (10 µg). Prophylactic treatment involved intraperitoneal injections of ivacaftor (40 mg/kg) once a day beginning 4 days prior to LPS challenge. The therapeutic group received a single intraperitoneal ivacaftor injection (40 mg/kg) directly after LPS. Mice were culled either 24 or 72 h after LPS challenge, and serum, bronchoalveolar lavage fluid (BALF), and lung tissue samples were collected. The degree of inflammation was assessed through cell infiltration, cytokine expression, and histological analysis. Key results: Ivacaftor did not decrease the total number of immune cells within the BALF; however, prophylactic treatment did significantly reduce macrophage and lymphocyte infiltration. Prophylactic treatment exhibited a significant negative correlation between the immune cell number and ivacaftor concentrations in BALF; however, no significant changes in the cytokine expression or histological parameters were determined. Conclusions and implications: Ivacaftor possesses some inherent immunomodulatory effects within the lungs following LPS inoculation; however, further analysis of larger sample sizes is required to confirm the results.

The association of enteric neuropathy with gut phenotypes in acute and progressive models of Parkinson's disease.

Parkinson's disease (PD) is associated with neuronal damage in the brain and gut. This work compares changes in the enteric nervous system (ENS) of commonly used mouse models of PD that exhibit central neuropathy and a gut phenotype. Enteric neuropathy was assessed in five mouse models: peripheral injection of MPTP; intracerebral injection of 6-OHDA; oral rotenone; and mice transgenic for A53T variant human α-synuclein with and without rotenone. Changes in the ENS of the colon were quantified using pan-neuronal marker, Hu, and neuronal nitric oxide synthase (nNOS) and were correlated with GI function. MPTP had no effect on the number of Hu+ neurons but was associated with an increase in Hu+ nuclear translocation (P < 0.04). 6-OHDA lesioned mice had significantly fewer Hu+ neurons/ganglion (P < 0.02) and a reduced proportion of nNOS+ neurons in colon (P < 0.001). A53T mice had significantly fewer Hu+ neurons/area (P < 0.001) and exhibited larger soma size (P < 0.03). Treatment with rotenone reduced the number of Hu+ cells/mm2 in WT mice (P < 0.006) and increased the proportion of Hu+ translocated cells in both WT (P < 0.02) and A53T mice (P < 0.04). All PD models exhibited a degree of enteric neuropathy, the extent and type of damage to the ENS, however, was dependent on the model.

ATH434 Reverses Colorectal Dysfunction in the A53T Mouse Model of Parkinson's Disease.

BACKGROUND: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson's disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. OBJECTIVE: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic mice. METHODS: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion ("treatment group"), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion ("prevention group"). RESULTS: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. CONCLUSION: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD.

Impact of chemotherapy-induced enteric nervous system toxicity on gastrointestinal mucositis.

PURPOSE OF REVIEW: Chemotherapy is a first-line treatment for many cancers; however, its use is hampered by a long list of side-effects. Gastrointestinal mucositis is a common and debilitating side-effect of anticancer therapy contributing to dose reductions, delays and cessation of treatment, greatly impacting clinical outcomes. The underlying pathophysiology of gastrointestinal mucositis is complex and likely involves several overlapping inflammatory, secretory and neural mechanisms, yet research investigating the role of innervation in gastrointestinal mucositis is scarce. This review provides an overview of the current literature surrounding chemotherapy-induced enteric neurotoxicity and discusses its implications on gastrointestinal mucositis. RECENT FINDINGS: Damage to the intrinsic nervous system of the gastrointestinal tract, the enteric nervous system (ENS), occurs following chemotherapeutic administration, leading to altered gastrointestinal functions. Chemotherapeutic drugs have various mechanisms of actions on the ENS. Oxidative stress, direct toxicity and inflammation have been identified as mechanisms involved in chemotherapy-induced ENS damage. Enteric neuroprotection has proven to be beneficial to reduce gastrointestinal dysfunction in animal models of oxaliplatin-induced enteric neuropathy. SUMMARY: Understanding of the ENS role in chemotherapy-induced mucositis requires further investigation and might lead to the development of more effective therapeutic interventions for prevention and treatment of chemotherapy-induced gastrointestinal side-effects.

Investigation of nerve pathways mediating colorectal dysfunction in Parkinson's disease model produced by lesion of nigrostriatal dopaminergic neurons.

BACKGROUND: Gastrointestinal (GI) dysfunction, including constipation, is a common non-motor symptom of Parkinson's disease (PD). The toxin 6-hydroxydopamine (6OHDA) produces the symptoms of PD, surprisingly including constipation, after it is injected into the medial forebrain bundle (MFB). However, the mechanisms involved in PD-associated constipation caused by central application of 6OHDA remain unknown. We investigated effects of 6OHDA lesioning of the MFB on motor performance and GI function. METHODS: Male Sprague Dawley rats were unilaterally injected with 6OHDA in the MFB. Colorectal propulsion was assessed by bead expulsion after 4 weeks and by recording colorectal contractions and propulsion after 5 weeks. Enteric nervous system (ENS) neuropathy was examined by immunohistochemistry. KEY RESULTS: When compared to shams, 6OHDA-lesioned rats had significantly increased times of bead expulsion from the colorectum, indicative of colon dysmotility. Administration of the colokinetic, capromorelin, that stimulates defecation centers in the spinal cord, increased the number of contractions and colorectal propulsion in both groups compared to baseline; however, the effectiveness of capromorelin in 6OHDA-lesioned rats was significantly reduced in comparison with shams, indicating that 6OHDA animals have reduced responsiveness of the spinal defecation centers. Enteric neuropathy was observed in the distal colon, revealing that lesion of the MFB has downstream effects at the cellular level, remote from the site of 6OHDA administration. CONCLUSIONS & INFERENCES: We conclude that there are trans-synaptic effects of the proximal, forebrain, lesion of pathways from the brain that send signals down the spinal cord, at the levels of the defecation centers and the ENS.

Squalamine Restores the Function of the Enteric Nervous System in Mouse Models of Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α-synuclein (α-syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo, have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α-syn. OBJECTIVE: Here we explore the electrophysiological effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α-syn mutant. METHODS: GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. RESULTS: Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. CONCLUSION: These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD.

Chronic isolation stress is associated with increased colonic and motor symptoms in the A53T mouse model of Parkinson's disease.

BACKGROUND: Chronic stress exacerbates motor deficits and increases dopaminergic cell loss in several rodent models of Parkinson's disease (PD). However, little is known about effects of stress on gastrointestinal (GI) dysfunction, a common non-motor symptom of PD. We aimed to determine whether chronic stress exacerbates GI dysfunction in the A53T mouse model of PD and whether this relates to changes in α-synuclein distribution. METHODS: Chronic isolation stress was induced by single-housing WT and homozygote A53T mice between 5 and 15 months of age. GI and motor function were compared with mice that had been group-housed. KEY RESULTS: Chronic isolation stress increased plasma corticosterone and exacerbated deficits in colonic propulsion and whole-gut transit in A53T mice and also increased motor deficits. However, our results indicated that the novel environment-induced defecation response, a common method used to evaluate colorectal function, was not a useful test to measure exacerbation of GI dysfunction, most likely because of the reported reduced level of anxiety in A53T mice. A53T mice had lower corticosterone levels than WT mice under both housing conditions, but single-housing increased levels for both genotypes. Enteric neuropathy was observed in aging A53T mice and A53T mice had a greater accumulation of alpha-synuclein (αsyn) in myenteric ganglia under both housing conditions. CONCLUSIONS & INFERENCES: Chronic isolation stress exacerbates PD-associated GI dysfunction, in addition to increasing motor deficits. However, these changes in GI symptoms are not directly related to corticosterone levels, worsened enteric neuropathy, or enteric αsyn accumulation.