Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with irritable bowel syndrome

Department of Psychosomatic Medicine, Tohoku University School of Medicine, Sendai, Japan.
Gut (Impact Factor: 14.66). 08/2004; 53(7):958-64. DOI: 10.1016/S0016-5085(03)82897-4
Source: PubMed


Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. We hypothesised that peripheral administration of alpha-helical CRH (alphahCRH), a non-selective CRH receptor antagonist, would improve gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation in IBS patients.
Ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, were studied. The tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline. Visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale. The same measurements were repeated after administration of alphahCRH (10 micro g/kg).
ES induced significantly higher motility indices of the colon in IBS patients compared with controls. This response was significantly suppressed in IBS patients but not in controls after administration of alphahCRH. Administration of alphahCRH induced a significant increase in the barostat bag volume of controls but not in that of IBS patients. alphahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by ES in IBS patients. Plasma adrenocorticotropic hormone and serum cortisol levels were generally not suppressed by alphahCRH.
Peripheral administration of alphahCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients.

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Available from: Jun Tayama, Oct 04, 2015
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    • "CRH expression and biological function are mediated by its membrane receptors, CRH-R1 and CRH-R2 (Grammatopoulos, 2012). CRH is involved in the pathogenesis of a number of inflammatory disorders, such as allergic diseases (Vasiadi et al., 2012), irritable bowel syndrome (Sagami et al., 2004) and some pain syndromes (La et al., 2008). CRH can also activate microglia in the process of neuropathology (Wang et al., 2007), but the underlying mechanism is not fully understood. "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) plays a critical role in the pathogenesis of neuropathic pain, but its regulation of BDNF release is not fully understood. To further understand the regulation of BDNF release, the microglial cell line, C8-D1A (microglia, in short), were cultured as a model. The levels of BDNF were determined by enzyme-linked immunoassay. Apoptotic microglia were assessed by flow cytometry. The protease-activated receptor 2 (PAR2) was activated by tryptase. Exposure to corticotripin releasing hormone (CRH) induced BDNF release from microglia. Apoptosis was evident in microglia after activation by CRH. Tryptase-induced PAR2 activation reduced the frequency of apoptosis of microglia, but enhanced the BDNF levels in the culture medium, which was partially blocked by PAR2 antagonists. We conclude that PAR2 agonists can promote the BDNF release from microglia; the PAR2 antagonists may be a potential therapeutic target to attenuate the BDNF-related neuropathic pain.
    Cell Biology International 01/2014; 38(1). DOI:10.1002/cbin.10185 · 1.93 Impact Factor
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    • "IBS is perhaps the best example where annual direct and indirect management costs are estimated to be $8 and $25 billion respectively with evidence pointing to its origin in childhood of those with CFAP [1,2,7–11]. As opposed to chronic abdominal pain where there is demonstrable pathology, i.e. celiac disease, inflammatory bowel disease, etc., for which there are established treatment strategies with mostly predictable outcomes, treatment for FGID remains unproven and published results mostly difficult to interpret [12] [13] [14] [15] [16] [17]. Median arcuate ligament syndrome (MALS), also known as celiac artery compression syndrome, was first described by Harjola in 1963 [18]. "
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    ABSTRACT: Median arcuate ligament syndrome (MALS) is a vascular compression syndrome with symptoms that overlap chronic functional abdominal pain (CFAP). We report our experience treating MALS in a pediatric cohort previously diagnosed with CFAP. We prospectively evaluated 46 pediatric (<21years of age) patients diagnosed with MALS at a tertiary care referral center from 2008 to 2012. All patients had previously been diagnosed with CFAP. Patients were evaluated for celiac artery compression by duplex ultrasound and diagnosis was confirmed by computed tomography. Quality of life (QOL) was determined by pre- and postsurgical administration of PedsQL™ questionnaire. The patients underwent laparoscopic release of the median arcuate ligament overlying the celiac artery which included surgical neurolysis. We examined the hemodynamic changes in parameters of the celiac artery and perioperative QOL outcomes to determine correlation. All patients had studies suggestive of MALS on duplex and computed tomography; 91% (n=42) positive for MALS were females. All patients underwent a technically satisfactory laparoscopic surgical release resulting in a significant improvement in blood flow through the celiac artery. There were no deaths and a total of 9 complications, 8 requiring a secondary procedure; 33 patients were administered QOL surveys. 18 patients completed the survey with 15 (83%) patients reporting overall improvement in the QOL. Overall, 31/46 patients (67%) reported improvement of symptoms since the time of surgery. MALS was found to be more common in pediatric females than males. Laparoscopic release of the celiac artery can be performed safely in the pediatric population. Surgical release of the artery and resultant neurolysis resulted in significant improvement in the blood flow, symptoms, and overall QOL in this cohort. The overall improvement in QOL outcome measures after surgery leads us to conclude that MALS might be earlier diagnosed and possibly treated in patients with CFAP. We recommend a multidisciplinary team approach to care for these complex patients.
    Journal of Pediatric Surgery 11/2013; 48(11):2261-70. DOI:10.1016/j.jpedsurg.2013.03.003 · 1.39 Impact Factor
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    • "Preclinical and early clinical studies support the possibilities that pharmacological interventions targeting CRF1 signaling may have potential therapeutic benefits in alleviating stress sensitive disorders [10], [11]. For instance, the peptide CRF receptor antagonist, α–CRF9–41, injected into the circulation alleviates symptoms in a subclass of IBS patients [12]. As peptide compounds are less desirable in drug development, non-peptide small molecule CRF receptor antagonists are being developed to treat anxiety, depression, alcoholism, drug relapse and stress-related gastrointestinal diseases [10], [13]–[15]. "
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    ABSTRACT: Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67-87% and decreased WAS-induced-FPO by 23-53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.
    PLoS ONE 09/2013; 8(9):e73749. DOI:10.1371/journal.pone.0073749 · 3.23 Impact Factor
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