Corticotrophin-releasing factor-mediated effects of DA-9701 in Postoperative Ileus Guinea Pig Model

Background: Postoperative ileus (POI) is abdominal surgery-induced impaired gastrointestinal (GI) motility. We aimed to investigate the effects of DA-9701, a prokinetic agent formulated from Pharbitis Semen and Corydalis tuber, likely mediated via corticotrophin-releasing factor (CRF) pathways, in a POI model. Methods: A laparotomy with cecal manipulation was performed to induce POI in guinea pigs. GI transit was measured based on charcoal migration after intragastric administration of DA-9701 1, 3, and 10 mg kg⁻¹. CRF1 receptor antagonist, CP-154 526 (subcutaneous) or agonist, human/rat (h/r) CRF (intraperitoneal) was injected. Then, plasma adrenocorticotropic hormone (ACTH) levels were measured, and the average intensity of the CRF expression was analyzed in the proximal colon and hypothalamus, and c-Fos in the hypothalamus. Key Results: DA-9701 significantly increased delayed GI transit in POI in a dose-dependent manner and decreased plasma ACTH levels at 10 mg kg⁻¹. CP-154 526 significantly decreased plasma ACTH levels but was not as effective on GI transit as DA-9701 was. h/r CRF did not significantly affect GI transit and plasma ACTH levels. No significant difference was observed in GI transit and plasma ACTH levels in both groups administered DA-9701 with h/r CRF and h/r CRF alone. CRF expression in the proximal colon decreased after DA-9701 administration, but not significantly, compared with levels in POI alone. However, CRF expression in the hypothalamus was significantly lower in the DA-9701-pretreated POI than in the untreated POI. Conclusions and Inferences: The DA-9701-induced improvement in GI transit and inhibition of plasma ACTH levels was mediated by the central CRF pathway.