Corticotropin-releasing Factor Signaling Pathways Research Articles

Nesfatin-1 influences the excitability of gastric distension-responsive neurons in the ventromedial hypothalamic nucleus of rats.

The present study investigated the effects of nesfatin-1 on gastric distension (GD)-responsive neurons via an interaction with corticotropin-releasing factor (CRF) receptor signaling in the ventromedial hypothalamic nucleus (VMH), and the potential regulation of these effects by hippocampal projections to VMH. Extracellular single-unit discharges were recorded in VHM following administration of nesfatin-1. The projection of nerve fibers and expression of nesfatin-1 were assessed by retrograde tracing and fluoro-immunohistochemical staining, respectively. Results showed that there were GD-responsive neurons in VMH; Nesfatin-1 administration and electrical stimulation of hippocampal CA1 sub-region altered the firing rate of these neurons. These changes could be partially blocked by pretreatment with the non-selective CRF antagonist astressin-B or an antibody to NUCB2/nesfatin-1. Electrolytic lesion of CA1 hippocampus reduced the effects of nesfatin-1 on VMH GD-responsive neuronal activity. These studies suggest that nesfatin-1 plays an important role in GD-responsive neuronal activity through interactions with CRF signaling pathways in VMH. The hippocampus may participate in the modulation of nesfatin-1-mediated effects in VMH.

Expression of corticotropin-releasing factor and urocortins in the normal and Schistosoma mansoni-infected mouse ileum.

Corticotropin-releasing factor (CRF) and urocortins (UCNs) are important ligands in the CRF signaling pathways, which are most known for their role in the hypothalamic-pituitary-adrenal stress axis. However, peripheral CRF signaling also has profound effects on gastrointestinal functions. Although the murine animal model is highly relevant for the exploration of this complexly balanced pathway via genetic manipulation, little is known about the expression of CRF and UCNs in the mouse intestine. This study aims to investigate the cellular localization of CRF and UCNs in the ileum and to explore whether and how this cellular expression is altered in conditions of intestinal Schistosoma mansoni-induced inflammation. The results show a distinct expression pattern for the different CRF receptor ligands in the ileum. CRF was located in nerve fibers and stromal cells. All UCNs were expressed in polymorphonuclear leukocytes. Furthermore, UCN2 and UCN3 were found in the musculature. During acute schistosomiasis, UCN1 showed an increased immunoreactivity in blood vessels and UCN3 was de novo expressed mainly in submucous neurons. Typical features of S. mansoni-inflamed ileum, such as nerve fiber sprouting, muscle layer thickening and granuloma formation thus all have an impact on the CRF signaling pathways. In conclusion, we outline for the first time the expression of CRF signaling ligands in the mouse ileum; our results point to important changes of this signaling system in S. mansoni-induced intestinal inflammation, which warrants further functional investigation with specific focus on CRF2, given the exclusive binding of UCN2 and UCN3 to this receptor.

Differential expression of corticotropin releasing factor and urocortins in the Schistosoma mansoni‐infected mouse ileum (214.2)

Corticotropin releasing factor (CRF) and urocortins (UCNs) are important ligands in the CRF signaling pathways, most well‐known from the hypothalamic‐pituitary‐adrenal stress axis. However, peripheral CRF signaling has profound effects on gastrointestinal functions. Despite the potential of the murine animal model in elucidating this complexly balanced pathway through genetic manipulation, little is known regarding the expression of CRF and UCNs in the intestinal wall of the mouse. This study therefore investigates the cellular localization of CRF and UCNs in the ileum and examines how this cellular expression is altered in intestinal schistosomiasis. The results show a diverse expression of CRF and UCNs in the enteric nervous system, granulocytes and the ileal musculature. Of special interest was the de novo expression of UCN3 in a majority of submucous vasodilator/secretomotor neurons, possibly strengthening CRF2‐mediated effects during inflammation. In conclusion, we outline for the first time the ileal expression of CRF signaling ligands in the mouse, and point to important changes of this signaling system in intestinal inflammation.Grant Funding Source: Supported by a grant of the Flemish Organization for Scientific Research (FWO G.0179.08)

Multi-center randomized controlled trial of cognitive treatment, placebo, oxybutynin, bladder training, and pelvic floor training in children with functional urinary incontinence

Functional urinary incontinence causes considerable morbidity in 8.4% of school-age children, mainly girls. To compare oxybutynin, placebo, and bladder training in overactive bladder (OAB), and cognitive treatment and pelvic floor training in dysfunctional voiding (DV), a multi-center controlled trial was designed, the European Bladder Dysfunction Study. Seventy girls and 27 boys with clinically diagnosed OAB and urge incontinence were randomly allocated to placebo, oxybutynin, or bladder training (branch I), and 89 girls and 16 boys with clinically diagnosed DV to either cognitive treatment or pelvic floor training (branch II). All children received standardized cognitive treatment, to which these interventions were added. The main outcome variable was daytime incontinence with/without urinary tract infections. Urodynamic studies were performed before and after treatment. In branch I, the 15% full response evolved to cure rates of 39% for placebo, 43% for oxybutynin, and 44% for bladder training. In branch II, the 25% full response evolved to cure rates of 52% for controls and 49% for pelvic floor training. Before treatment, detrusor overactivity (OAB) or pelvic floor overactivity (DV) did not correlate with the clinical diagnosis. After treatment these urodynamic patterns occurred de novo in at least 20%. The mismatch between urodynamic patterns and clinical symptoms explains why cognitive treatment was the key to success, not the added interventions. Unpredictable changes in urodynamic patterns over time, the response to cognitive treatment, and the gender-specific prevalence suggest social stress might be a cause for the symptoms, mediated by corticotropin-releasing factor signaling pathways.

Corticotropin releasing factor—Distribution in rat intestine and role in neuroprotection

Aims of the present study were to describe the distribution of corticotropin releasing factor (CRF) immunoreactivity in rat small and large intestines, to quantify the percentage of CRF-immunoreactive (CRF-IR) enteric neurons, to reveal possible CRF immunoreactivity in cultured myenteric neurons from rat ileum and to examine if additions of CRF, urocortin 1 (Ucn1), CRF antagonist or vasoactive intestinal peptide (VIP) affect neuronal survival in vitro. Co-localization of CRF- and VIP-immunoreactivity was examined, as well as a possible interplay between CRF and VIP in neuroprotection. Further we wanted to elucidate if mast cells affect neuronal survival via CRF signaling. Networks of CRF-containing nerve cell bodies and fibers were detected in rat intestine. CRF-IR neurons contained to a high degree also VIP. A low number of cultured myenteric neurons was CRF-IR. CRF, Ucn1 or CRF-antagonist did not promote neuronal survival of cultured myenteric neurons, while VIP significantly enhanced neuronal survival. Simultaneous presence of CRF attenuated the VIP mediated increase in neuronal survival. Co-culturing neurons and mast cells resulted in a marked reduction in neuronal survival, not executed via CRF signaling pathways. Conclusion: CRF is present in enteric neurons and counteracts the neuroprotective effect of VIP in vitro.

Neuroendocrine Control of the Gut During Stress: Corticotropin-Releasing Factor Signaling Pathways in the Spotlight

Stress affects the gastrointestinal tract as part of the visceral response. Various stressors induce similar profiles of gut motor function alterations, including inhibition of gastric emptying, stimulation of colonic propulsive motility, and hypersensitivity to colorectal distension. In recent years, substantial progress has been made in our understanding of the underlying mechanisms of stress's impact on gut function. Activation of corticotropin-releasing factor (CRF) signaling pathways mediates both the inhibition of upper gastrointestinal (GI) and the stimulation of lower GI motor function through interaction with different CRF receptor subtypes. Here, we review how various stressors affect the gut, with special emphasis on the central and peripheral CRF signaling systems.

Role of corticotropin-releasing factor pathways in stress-related alterations of colonic motor function and viscerosensibility in female rodents

Clinical reports have shown that irritable bowel syndrome (IBS) is comorbid with anxiety/depression and stress-related events, and that the disorder is more prevalent among women than among men. In rodents, colorectal distention (CRD) induces abdominal contractions, and this visceromotor response is used to assess visceral pain. The activation of brain corticotropin-releasing factor (CRF) pathways has a key role in the behavioral and visceral responses to stress. In this review of experimental studies that delineate the underlying mechanisms of the stress response, we focused on CRF signaling pathways and sex hormones in modulating visceral hypersensitivity induced by CRD in rodents. The findings of our recent research on the development of an experimental model of visceral pain in female rats and the modulation of the hyperalgesic response to CRD by CRF antagonists were integrated with those of the published literature. A MEDLINE search of the years 1981 to 2005 was conducted using the key words stress, CRF, CRH, CRF1 receptor, IBS, CRD, female rat, visceral pain, estrogen, and anxiety. CRF and other related mammalian peptides (urocortins) interact with the distinct CRF subtype 1 and 2 receptors. Well-documented preclinical studies have established the role of brain CRF1 receptors in mediating stress-related anxiogenic and visceral (stimulation of colonic motor function and sensitization to repeated CRD) responses in male rodents, whereas more limited studies have been performed in female rats. Our recent study indicated that the CRF1 antagonist antalarmin prevents visceral hypersensitivity induced by 2 sets of CRD in female rats. In several models of visceral pain induced by CRD, sex differences and a sensitization action of estrogen were reported. Our preliminary evidence indicated a potentiating interaction between CRF-CRF1 pathways and estrogen in the stimulation of colonic motor responses that may take place within the enteric neurons of the colon, where both CRF1 and estrogen receptors are present. The results of this review suggest that overactivity of CRF1 signaling in the brain and the gut may have relevance in understanding the comorbidity of anxiety/depression and IBS in diarrhea-predominant female patients. Targeting these mechanisms with CRF1 antagonists may provide a novel therapeutic strategy.

Interaction of neuropeptide Y and corticotropin-releasing factor signaling pathways in AR-5 amygdalar cells

Corticotropin-releasing factor (CRF) is a 41 amino acid neuropeptide which is involved in the stress response. CRF and neuropeptide Y (NPY) produce reciprocal effects on anxiety in the central nucleus of the amygdala. The molecular mechanisms of possible CRF-NPY interactions in regulating anxiety behavior is not known. In the central nervous system, the action of NPY leads to inhibition of cAMP production while CRF is known to stimulate levels of cAMP in the brain. Consequently, we hypothesized that NPY may antagonize anxiety-like behavior by counter-regulating CRF-stimulated cAMP accumulation and activation of the protein kinase A pathway. We have engineered an immortalized amygdalar cell line (AR-5 cells) which express via RT-PCR, the CRF 2α, Y 1 and Y 5 NPY receptor. In addition, in these cells CRF treatment results in significant concentration-dependent increases in cAMP production. Furthermore, incubation of 3 μM CRF with increasing concentrations of NPY was able to significantly inhibit the increases in cAMP compared to that observed with 3 μM CRF treatment alone. These findings suggest that CRF and NPY may counter-regulate each other in amygdalar neurons via reciprocal effects on the protein kinase A pathway.

A syndrome produced by diverse nocuous agents. 1936.

A syndrome produced by diverse nocuous agents. 1936.