Decreased tyrosine kinase C expression may reflect developmental abnormalities in Hirschsprung's disease and idiopathic slow-transit constipation

Facer, P.; Knowles, C H; Thomas, Paul; Tam, Paul Kwong Hang; Williams, Norman S.

doi:10.1046/j.1365-2168.2001.01731.x

Cited by 18 publications

(8 citation statements)

References 32 publications

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“…109,110 Investigators have also evaluated other potential mechanisms, including proto-oncogenes, tyrosine kinase C, autonomic neuropathy, overexpression of progesterone receptors, infectious agents, autoimmunity, medications, as well as gut hormones. [111][112][113][114][115][116][117][118][119][120] A number of studies suggest that alterations in 5-HT signaling may contribute to the symptoms of chronic constipation, but again, inconsistencies exist among these investigations (Table 2). 84,91,92,121 Overall, there appears to be a link between serotonin and chronic constipation, but it is not yet clear whether there is decreased serotonin availability at the receptors or a decrease in receptor density and function.…”

Section: Chronic Constipationmentioning

confidence: 99%

Serotonin and Its Role in Colonic Function and in Gastrointestinal Disorders

Costedio¹,

Hyman²,

Mawe³

2007

Diseases of the Colon &Amp; Rectum

155

131

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Serotonin (5-HT) is most commonly thought of as a neurotransmitter in the central nervous system. However, the predominant site of serotonin synthesis, storage, and release is the enterochromaffin cells of the intestinal mucosa. Within the intestinal mucosa, serotonin released from EC cells activates neural reflexes associated with intestinal secretion, motility, and sensation. Two important receptors for serotonin that are located in the neural circuitry of the intestines are the 5-HT(3) and 5-HT(4) receptors; these are the targets of drugs designed to treat gastrointestinal disorders. 5-HT(3) receptor antagonists are used to treat nausea and emesis associated with chemotherapy and for functional disorders associated with diarrhea. 5-HT(4) receptor agonists are used as promotility agents to promote gastric emptying and to alleviate constipation. Because of the importance of serotonin in normal gut function and sensation, a number of studies have investigated potential changes in mucosal serotonin signaling in pathologic conditions. Despite the inconsistencies in the current literature, changes in serotonin signaling have now been demonstrated in inflammatory bowel disease, irritable bowel syndrome, postinfectious irritable bowel syndrome, and idiopathic constipation. Emerging evidence has led to many contradictory theories regarding serotonin signaling and its roles in the pathology of gut disorders. This review summarizes the current medications affecting serotonin signaling and provides an overview of our current knowledge of the changes in serotonin that occur in pathologic conditions.

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Section: Chronic Constipationmentioning

confidence: 99%

Serotonin and Its Role in Colonic Function and in Gastrointestinal Disorders

Costedio¹,

Hyman²,

Mawe³

2007

Diseases of the Colon &Amp; Rectum

155

131

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“…In addition, abnormalities in the expression of various other signalling molecules, such as the cell adhesion molecules NCAM [50] and L1 [37,77], tyrosine kinase C [25], and components of the extracellular matrix, such as laminin, collagen IV, and nidogen [80,81,83] are seen. There is convincing evidence that AChE, in its so-called nonclassical aspect, functions as a signalling molecule (see below), placing it firmly in the context of the network of abnormalities that characterize HSCR.…”

Section: Acetylcholinesterase In Hscrmentioning

confidence: 99%

Acetylcholinesterase in Hirschsprung?s disease

Moore

Johnson

2005

Ped Surgery Int

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The association between the congenital absence of colonic ganglion cells and an increased acetylcholinesterase (AChE) expression in the affected tissue is of diagnostic importance in Hirschsprung's disease (HSCR). Investigation of AChE's function in development may also help unravel some of the complex pathophysiology in HSCR. Normal nerves do not stain for AChE, but increased AChE expression is associated with the hypertrophied extrinsic nerve fibres of the aganglionic segment in HSCR. Although a high degree of histochemical diagnostic accuracy exists, results are not always uniform, and false positives and false negatives are reported. False negative results are primarily related to age, and an absence of AChE reaction does not exclude HSCR in neonates within the first 3 weeks after birth. AChE staining results may lack uniformity, resulting in a number of technical modifications that have been made to improve standardization of AChE staining. At least two distinct histological patterns are described, types A and B. The interpretation of increased AChE staining patterns in ganglionated bowel at the time of surgical pull-through remains a problem in patients with HSCR. The development of rapid staining techniques has helped to identify normal ganglionated bowel with greater certainty. The presence of fine AChE neurofibrils in the ganglionated segment has contributed to the debate surrounding intestinal neuronal dysplasia. Quantitative assay of cholinesterase activity confirms the pattern of histochemical staining. AChE is particularly increased in relation to butrylcholinesterase, with one molecular form, the G4 tetrameric form, predominating. It is likely that the raised levels of AChE in aganglionic tissue are the transcriptional consequence of the abnormalities in signalling molecules that characterize HSCR. Evidence suggests that this AChE is functioning in a nonenzymatic capacity to promote cell adhesion and differentiation and that the hypertrophied nerves and neurofibrils may be the result of this increased AChE expression.

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“…There are several ideas regarding the role of NT‐3 in enteric structures. Abnormal expression of the high‐affinity NT‐3 receptor trkC during development was postulated to play a role in the pathogenesis of Hirschsprung's disease (Facer et al, 2001). In adults, subcutaneously administered NT‐3 was shown to accelerate colonic transit, to increase stool frequency and to reduce constipation (Coulie et al, 2000; Parkman et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Neurotrophins in murine viscera: a dynamic pattern from birth to adulthood

Lommatzsch

Quarcoo²,

Schulte‐Herbrüggen³

et al. 2005

Intl J of Devlp Neuroscience

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There is growing evidence that target-derived neurotrophins regulate the function of visceral neurons after birth. However, the postnatal profile of neurotrophin supply from internal organs is poorly described. In this study, we compared neurotrophin concentrations in lysates of murine peripheral target tissues (lung, heart, liver, colon, spleen, thymus, kidney and urinary bladder) at different time points after birth. In most organs, there was a decrease of neurotrophin concentrations in the first weeks after birth. In contrast, there were characteristic increases of specific neurotrophins during adolescence or adulthood. These increases were found for nerve growth factor (NGF) in the heart, thymus, kidney and liver, for brain-derived neurotrophic factor (BDNF) in the lung, and for neurotrophin-3 (NT-3) in the colon. In conclusion, we show that neurotrophins display a very differential and dynamic profile in internal organs after birth.

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Decreased tyrosine kinase C expression may reflect developmental abnormalities in Hirschsprung's disease and idiopathic slow-transit constipation

Abstract: Decreased trk C expression may reflect developmental abnormalities in Hirschsprung's disease and idiopathic STC. Trk C activation by NT-3 or drugs may provide novel treatments. Presented in abstract form to the Pacific Association of Pediatric Surgeons, Las Vegas, Nevada, USA, May 2000

Cited by 18 publications

References 32 publications

Serotonin and Its Role in Colonic Function and in Gastrointestinal Disorders

Serotonin and Its Role in Colonic Function and in Gastrointestinal Disorders

Acetylcholinesterase in Hirschsprung?s disease

Neurotrophins in murine viscera: a dynamic pattern from birth to adulthood

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