Department of Surgery, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
Langenbecks Arch Surg. 2012 Oct;397(7):1139-47. doi: 10.1007/s00423-012-0989-6. Epub 2012 Aug 19.
Postoperative ileus (POI) is an iatrogenic complication of abdominal surgery, mediated by a severe inflammation of the muscularis externa (ME). Previously, we demonstrated that intravenous application of the tetravalent guanylhydrazone semapimod (CNI-1493) prevents POI, but the underlying mode of action could not definitively be confirmed. Herein, we investigated the effect of a novel orally active salt of semapimod (CPSI-2364) on POI in rodents and distinguished between its inhibitory peripheral and stimulatory central nervous effects on anti-inflammatory vagus nerve signaling.
Distribution of radiolabeled orally administered CPSI-2364 was analyzed by whole body autoradiography and liquid scintillation counting. POI was induced by intestinal manipulation with or without preoperative vagotomy. CPSI-2364 was administered preoperatively via gavage in a dose- and time-dependent manner. ME specimens were assessed for p38-MAP kinase activity by immunoblotting, neutrophil extravasation, and nitric oxide production. Furthermore, in vivo gastrointestinal (GIT) and colonic transit were measured.
Autoradiography demonstrated a near-exclusive detection of CPSI-2364 within the gastrointestinal wall and contents. Preoperative CPSI-2364 application significantly reduced postoperative neutrophil counts, nitric oxide release, GIT deceleration, and delay of colonic transit time, while intraoperatively administered CPSI-2364 failed to improve POI. CPSI-2364 also prevents postoperative neutrophil increase and GIT deceleration in vagotomized mice.
Orally administered CPSI-2364 shows a near-exclusive dispersal in the gastrointestinal tract and effectively reduces POI independently of central vagus nerve stimulation. Its efficacy after single oral dosage affirms CPSI-2364 treatment as a promising strategy for prophylaxis of POI.
术后肠梗阻（POI）是腹部手术的一种医源性并发症，由外肌严重炎症介导。此前，我们证明静脉应用四价鸟苷酰肼司莫莫德（CNI-1493）可预防 POI，但无法明确其作用机制。在此，我们研究了新型口服司莫莫德盐（CPSI-2364）对啮齿动物 POI 的影响，并区分了其对抗炎迷走神经信号的外周抑制和中枢刺激作用。
通过全身放射自显影和液体闪烁计数分析放射性标记的口服 CPSI-2364 的分布。通过肠道操作诱导 POI，同时或不进行术前迷走神经切断术。CPSI-2364 通过灌胃以剂量和时间依赖性方式术前给药。通过免疫印迹、中性粒细胞渗出和一氧化氮产生评估 ME 标本中 p38-MAP 激酶活性。此外，还测量了体内胃肠道（GIT）和结肠转运。
放射自显影显示 CPSI-2364 几乎完全检测到胃肠道壁和内容物中。术前 CPSI-2364 给药可显著减少术后中性粒细胞计数、一氧化氮释放、GIT 减速和结肠转运时间延迟，而术中给予 CPSI-2364 则不能改善 POI。CPSI-2364 还可预防迷走神经切断术后小鼠的术后中性粒细胞增加和 GIT 减速。
口服 CPSI-2364 在胃肠道中几乎完全分散，并可有效降低 POI，与中枢迷走神经刺激无关。单次口服剂量的疗效证实了 CPSI-2364 治疗作为预防 POI 的有前途策略。
