Intestinal dysmotility and enteric neurochemical changes in a Parkinson's disease rat model.

Gastrointestinal disorders, constipation in particular, are the most common non-motor dysfunctions affecting Parkinson's disease (PD) patients. We have previously reported that rats bearing unilateral nigrostriatal lesion caused by 6-hydroxydopamine (6-OHDA) stereotaxic injection develop severe constipation together with a region-specific decrease of neuronal nitric oxide synthase (nNOS) in enteric neurons of the lower intestinal tract. Here, we extend these observations on other enteric neuronal subpopulations, investigating also the propulsive activity of isolated colonic specimens.

Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome.

Objectives: Serotonin (5-hydroxytryptamine, 5-HT) metabolism may be altered in gut disorders, including in the irritable bowel syndrome (IBS). We assessed in patients with IBS vs. healthy controls (HCs) the number of colonic 5-HT-positive cells; the amount of mucosal 5-HT release; their correlation with mast cell counts and mediator release, as well as IBS symptoms; and the effects of mucosal 5-HT on electrophysiological responses in vitro.

The proton pump inhibitor test for gastroesophageal reflux disease: optimal cut-off value and duration.

Background: There is no accepted gold standard for the diagnosis of gastroesophageal reflux disease (GERD).

Aim: To assess the optimal cut-off value and duration of the proton pump inhibitor (PPI) test in GERD patients with and without oesophagitis.

Methods: Prospective study of 544 patients undergoing upper GI endoscopy and treated for 2 weeks with PPIs at double dose, and for 3 additional months at standard dose.

Herpes simplex virus type 1 infection of the rat enteric nervous system evokes small-bowel neuromuscular abnormalities.

Background & Aims: Infectious agents, such as neurotropic viruses, are proposed to disrupt the enteric neuromuscular system, leading to dysmotility, although the mechanisms are unknown. Our purpose was to assess whether herpes simplex virus type-1 (HSV-1) establishes an enteric-neuronal infection and induces gut dysmotility.

Methods: Rats were inoculated with HSV-1 intranasally and after 4 weeks intragastrically.

The genetics of the serotonin transporter and irritable bowel syndrome.

Serotonin transporter (SERT) mediates the intracellular reuptake of released serotonin, thus regulating its biological functions. Abnormalities in serotonin reuptake can alter enteric serotonergic signalling, leading to sensory, motor and secretory gut dysfunctions, which contribute to the pathophysiology of irritable bowel syndrome (IBS). This relationship has fostered the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of IBS.

Novel therapeutic targets for enteric nervous system disorders.

There is a large unmet need for effective drugs for the treatment of gastrointestinal disorders, notably irritable bowel syndrome, functional dyspepsia and gastroesophageal reflux disease. The market value for an effective irritable bowel syndrome therapeutic agent is estimated at over US10 billion dollars per annum. Each of these disorders seems to have a neural component, involving the intrinsic innervation of the gastrointestinal system, its extrinsic innervation or both.

Sera of patients with celiac disease and neurologic disorders evoke a mitochondrial-dependent apoptosis in vitro.

Background & Aims: The mechanisms underlying neurologic impairment in celiac disease remain unknown. We tested whether antineuronal antibody-positive sera of patients with celiac disease evoke neurodegeneration via apoptosis in vitro.

Methods: SH-Sy5Y cells were exposed to crude sera, isolated immunoglobulin (Ig) G and IgG-depleted sera of patients with and without celiac disease with and without neurologic disorders, and antineuronal antibodies.

[Recent insights into the pathogenesis of abdominal symptoms in functional bowel disorders].

In the gut, 5-HT acts as a paracrine signalling molecule released by enterochromaffin cells and as a transmitter released by some descending serotonergic interneurons. It has a prominent role in the regulation of motility, vascular tone, secretion and perception both in normal and under certain pathophysiological conditions, such as the carcinoid syndrome and the irritable bowel syndrome (IBS). Serotonin is known to markedly influence bowel function by activating at least five receptor types (5-HT(1,2,3,4,7)).

Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome.

Background & Aims: Intestinal mast cell infiltration may participate to abdominal pain in irritable bowel syndrome (IBS) patients. However, the underlying mechanisms remain unknown. We assessed the effect of mast cell mediators released from the colonic mucosa of IBS patients on the activation of rat sensory neurons in vitro.

Drugs acting on serotonin receptors for the treatment of functional GI disorders.

In the gut, serotonin (5-hydroxytryptamine: 5-HT) exerts a variety of effects on intrinsic enteric neurons, extrinsic afferents, enterocytes and smooth muscle cells, which are related to the expression of multiple 5-HT receptor types and subtypes regulating motility, vascular tone, secretion and perception. Agonists and antagonists at 5-HT receptors have gained access to the market for the two major variants of the irritable bowel syndrome (IBS), a functional disorder characterized by abdominal pain associated with diarrhea and/or constipation in the absence of any organic abnormality. Indeed, the 5-HT3 receptor antagonist alosetron is available in the US market for the treatment of women with severe, diarrhea-predominant IBS (D-IBS) refractory to conventional therapy, whereas tegaserod, a partial 5-HT4 receptor agonist, has been approved by the FDA and other regulatory agencies for the treatment of women with constipation-predominant IBS (C-IBS) or functional constipation.

Enteric neuroplasticity evoked by inflammation.

Neuroplastic changes in the enteric nervous system (ENS) may be observed in physiological states, such as development and aging, or occur as a consequence of different pathological conditions, ranging from enteric neuropathies (e.g., Hirschsprung's disease) to intestinal (e.

5-HT7 receptors modulate peristalsis and accommodation in the guinea pig ileum.

Background & Aims: The 5-hydroxytryptamine 7 (5-HT7) receptors mediate intestinal smooth muscle relaxation. In this study, we evaluated the expression of 5-HT7 receptors in the guinea pig ileum and their role in peristalsis and accommodation of the circular muscle.

Methods: We used immunohistochemistry and confocal microscopy with whole tissue and cultured myenteric neurons.

Characterization of prejunctional serotonin receptors modulating [3H]acetylcholine release in the human detrusor.

Bladder overactivity (OAB) is a chronic and debilitating lower urinary tract (LUT) disorder that affects millions of individuals worldwide. LUT symptoms associated with OAB, such as urgency and urinary incontinence, cause a hygienic and social concern to patients, but their current pharmacological treatment is largely inadequate due to the lack of uroselectivity. Although OAB etiology remains multifactorial and poorly understood, increasing evidence indicates that serotonin [5-hydroxytryptamine (5-HT)] is an endogenous substance involved in the control of micturition at central and peripheral sites.

Galanin receptors in the rat gastrointestinal tract.

Galanin functions are mediated by three distinct G-protein-coupled receptors, galanin receptor 1 (GalR1), GalR2 and GalR3, which activate different intracellular signaling pathways. Here, we quantified mRNA levels of GalR1, GalR2 and GalR3 in the gastrointestinal tract using real time RT-PCR. GalR1 and GalR2 mRNAs were detected in all segments with the highest levels in the large intestine and stomach, respectively.

N-methyl-D-aspartate receptors mediate endogenous opioid release in enteric neurons after abdominal surgery.

Background & Aims: We tested the hypothesis that N-methyl-D-aspartate (NMDA) receptors mediate surgery-induced opioid release in enteric neurons.

Methods: We used mu opioid receptor (muOR) internalization as a measure of opioid release with immunohistochemistry and confocal microscopy. MuOR internalization was quantified in enteric neurons from nondenervated and denervated ileal segments of guinea pig after abdominal laparotomy with and without pretreatment with NMDA-receptor antagonists acting at different recognition sites (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,b] cyclohepten-5,10-imine (MK-801) or (D) 2-amino-5-phosphopenoic acid (AP-5) at .

Expression of galanin receptor messenger RNAs in different regions of the rat gastrointestinal tract.

Galanin effects are mediated by three G-protein-coupled receptors: galanin receptor 1 (GalR1), GalR2 and GalR3. We quantified mRNA levels of GalR1, GalR2 and GalR3 in the rat stomach, small and large intestine using real-time RT-PCR. All three GalR mRNAs were detected throughout the gut at different levels.

Alterations in colonic motility and relationship to pain in colonic diverticulosis.

Background And Aims: Although the pathophysiologic basis of colonic diverticular disease is understood incompletely, there is agreement that abnormal colon motility probably plays a major role. However, several different abnormalities have been reported in such patients. The purpose of this study was to assess whether patients with diverticulosis display an abnormal duration of regular colonic contractile patterns, which has been observed in other conditions characterized by spasticity of the viscus, such as the irritable bowel syndrome.

Prokinetics in the treatment of acute intestinal pseudo-obstruction.

Acute colonic pseudo-obstruction (Ogilvie's syndrome) is characterized by an acute obstruction of the large bowel that is unrelated to mechanical causes. The evidence that cholinesterase inhibitors are effective in relieving acute colonic pseudo-obstruction raised interest in the pharmacological management of this condition. This review analyzes the pharmacological treatment of patients with Ogilvie's syndrome.

Progress with novel pharmacological strategies for gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease (GORD) is a chronic disorder characterised by an increased exposure of the oesophagus to intragastric contents. Currently, GORD symptoms are maintained under control with antisecretory agents, mainly gastric proton pump inhibitors (PPIs). Although impaired oesophageal motility may partly underlie the pathophysiology of GORD, the use of prokinetic agents has been found to be unsatisfactory.

Anti-HuD-induced neuronal apoptosis underlying paraneoplastic gut dysmotility.

Background & Aims: The role of autoimmunity underlying paraneoplastic gut dysmotility remains unsettled. Because anti-Hu antibodies may impair enteric neuronal function, we tested whether anti-HuD-positive sera from patients with paraneoplastic gut dysmotility or commercial anti-HuD antibodies activated the apoptotic cascade in a neuroblastoma cell line and cultured myenteric neurons.

Methods: Anti-HuD antibodies from patients with severe paraneoplastic gut dysmotility were characterized by immunofluorescence and immunoblot.

Peristalsis regulation by tachykinin NK1 receptors in the rabbit isolated distal colon.

In the gastrointestinal tract, tachykinin NK1 receptors are widely distributed in a number of neuronal and nonneuronal cells involved in the control of gut motor activity. In particular, in the rabbit isolated distal colon, which is a suitable model system to investigate the contribution of tachykinins as noncholinergic excitatory transmitters, the influence of NK1 receptors in the regulation of peristalsis is not known. The selective NK1-receptor antagonists SR-140333 (0.

Neurochemically distinct classes of myenteric neurons express the mu-opioid receptor in the guinea pig ileum.

The mu-opioid receptor (muOR), which mediates many of the opioid effects in the nervous system, is expressed by enteric neurons. The aims of this study were to determine whether 1) different classes of myenteric neurons in the guinea pig ileum contain muOR immunoreactivity by using double- and triple-labeling immunofluorescence and confocal microscopy, 2) muOR immunoreactivity is localized to enteric neurons immunoreactive for the endogenous opioid enkephalin, and 3) muOR immunoreactivity is localized to interstitial cells of Cajal visualized by c-kit. In the myenteric plexus, 50% of muOR-immunoreactive neurons contained choline acetyltransferase (ChAT) immunoreactivity, whereas about 43% of ChAT-immunoreactive neurons were muOR immunoreactive.

Clinical and morphofunctional features of idiopathic myenteric ganglionitis underlying severe intestinal motor dysfunction: a study of three cases.

Ganglionitis, i.e., the inflammatory neuropathy characterized by a marked lymphoplasmacellular infiltrate in the myenteric plexus, may underlie a variety of paraneoplastic, infectious, or neurological disorders, although occasional cases are idiopathic in origin.

Facilitation of acetylcholine signaling by the dithiocarbamate fungicide propineb.

Dithiocarbamates (DTCs) are used mainly in agriculture as pesticides and as alcohol deterrent drugs. Neurological complications as well as movement disorders characterized by plastic rigidity, muscle twitch and paralysis are the prevailing symptoms in chronically exposed animals and humans. We investigated whether propineb interfered with peripheral cholinergic transmission in various isolated model systems.