Dehydroepiandrosterone sulfate improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome

Abstract

Stress-induced altered visceral sensation and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). These responses were demonstrated to be peripheral corticotropin-releasing factor (CRF) dependent and also mediated via proinflammatory cytokine in animal IBS model. Dehydroepiandrosterone sulfate (DHEA-S) is known to have anti-inflammatory properties by suppressing proinflammatory cytokine release. We hypothesized that DHEA-S improves stress-induced visceral changes and is beneficial for IBS treatment. We explored the effects of DHEA-S on lipopolysaccharide (LPS)-or repeated water avoidance stress (WAS)-induced visceral allodynia and increased colonic permeability (rat IBS models). The threshold of visceromotor response, i.e. abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue. DHEA-S abolished visceral allodynia and colonic hyperpermeability induced by LPS in a dosedependent manner. It also blocked repeated WAS-or peripheral injection of CRF-induced visceral changes. These effects by DHEA-S in LPS model were reversed by bicuculline, a γaminobutyric acid (GABA)A receptor antagonist, N G-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, naloxone, an opioid receptor antagonist, or sulpiride, a dopamine D2 receptor antagonist. However, domperidone, a peripheral dopamine D2 receptor antagonist did not modify the effects. Peripheral injection of astressin2-B, a selective CRF receptor subtype 2 (CRF2) antagonist also reversed these effects. In conclusion, DHEA-S blocked stress-induced visceral changes via GABAA, NO, opioid, central dopamine D2 and peripheral CRF2 signaling. DHEA-S may be useful for IBS treating.

Losartan improves visceral sensation and gut barrier in a rat model of irritable bowel syndrome

“…Sulpiride, a dopamine D 2 receptor antagonist (Wako Pure Chemical Industries), was dissolved in dimethyl sulfoxide. The doses of the chemicals were determined according to the previous reports . The volume of injection was 0.2 mL.…”

“…The electrode leads were connected to an EMG amplifier, and EMG signals were amplified, filtered (3000 Hz), digitized by a PowerLab system (AD Instruments) and recorded using computer software (LabChart 7, AD Instruments). Colonic distention was performed according to a previous publication . That is to say, ascending method of limits phasic distention was implemented by inflating the balloon by water using a syringe manually with the distention increased progressively in 0.1 mL increments every 5 seconds until significant abdominal muscle contractions, that is, VMR, were visible (Figure A).…”

“…Colonic permeability was assessed as previously described . The rats anesthetized by intraperitoneal administration of the mixture of medetomidine hydrochloride (Orion Pharma Ltd., Dhaka, Bangladesh, 0.15 mg kg −1 ), midazolam (Sandoz, Tokyo, Japan, 2 mg kg −1 ) and butorphanol tartrate (Meiji Seika Pharma, Tokyo, Japan, 2.5 mg kg −1 ) were placed in a supine position on a heating pad (37ºC), and laparotomy was performed.…”

“…The rats were returned to their home cages, and after 2.5 hours, they underwent surgery for electrode implantation and balloon placement again. The second measurement of threshold was performed 3 hours after the injection followed by the measurement of colonic permeability …”

“…The injection and the stress session were implicated for 3 days. The threshold was again measured at 24 hours after undergoing the last stress session followed by the measurement of colonic permeability …”