A new zinc chelator, IPZ-010 ameliorates postoperative ileus.

Abstract

Zinc was discovered to be a novel second messenger in immunoreactive cells. We synthesized a novel free zinc chelator, IPZ-010. Here, we investigated the effects of IPZ-010 in a mouse postoperative ileus model and determined the effects of zinc signal inhibition as a new therapeutic strategy against postoperative ileus. Zinc waves were measured in bone marrow-derived mast cells (BMMCs) loaded with a zinc indicator, Newport green. Degranulation and cytokine expression were measured in BMMCs and bone marrow-derived macrophages (BMDMs). Postoperative ileus model mice were established with intestinal manipulation. Mice were treated with IPZ-010 (30 mg/kg, s.c. or p.o.) 1 h before and 2 h and 4 h after intestinal manipulation. Gastrointestinal transit, inflammatory cell infiltration, and expression of inflammatory mediators were measured. Free zinc waves occurred following antigen stimulation in BMMCs and were blocked by IPZ-010. IPZ-010 inhibited interleukin-6 secretion and degranulation in BMMCs. IPZ-010 inhibited tumor necrosis factor-α mRNA expression in BMMCs stimulated with lipopolysaccharide or adenosine triphosphate, whereas IPZ-010 had no effects on tumor necrosis factor-α mRNA expression in BMDMs stimulated with lipopolysaccharide or adenosine triphosphate. In postoperative ileus model mice, IPZ-010 inhibited leukocyte infiltration and cytokine expression, which ameliorated gastrointestinal transit. Furthermore, ketotifen (1 mg/kg) induced similar effects as IPZ-010. These effects were not amplified by co-administration of IPZ-010 and ketotifen. IPZ-010 inhibited zinc waves, resulting in inhibition of inflammatory responses in activated BMMCs in vitro. Targeting zinc waves in inflammatory cells may be a novel therapeutic strategy for treating postoperative ileus.

• Authors: Hitomi Kimura, Yutaka Yoneya, Shoma Mikawa, Noriyuki Kaji, Hiroki Ito, Yasuaki Tsuchida, Hirotsugu Komatsu, Takahisa Murata, Hiroshi Ozaki, Ryota Uchida, Keigo Nishida, Masatoshi Hori
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 123 Pg. 109773 (Mar 2020) ISSN: 1950-6007 [Electronic] France
• PMID: 31862476 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier Masson SAS.

Chemical References

• Anti-Inflammatory Agents
• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• CD68 antigen, human
• Chelating Agents
• Ethylenediamines
• Inflammation Mediators
• Lipopolysaccharides
• RNA, Messenger
• Adenosine Triphosphate
• Zinc
• N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
• Ketotifen

Topics

• Adenosine Triphosphate (pharmacology)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Antigens, CD (metabolism)
• Antigens, Differentiation, Myelomonocytic (metabolism)
• Chelating Agents (chemistry, pharmacology, therapeutic use)
• Disease Models, Animal
• Ethylenediamines (pharmacology, therapeutic use)
• Gastrointestinal Transit (drug effects)
• Ileus (drug therapy, pathology, physiopathology)
• Inflammation Mediators (metabolism)
• Ketotifen (pharmacology)
• Lipopolysaccharides (pharmacology)
• Macrophages (metabolism)
• Mast Cells (drug effects, metabolism)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neutrophils (metabolism)
• Postoperative Complications (drug therapy, pathology, physiopathology)
• RNA, Messenger (genetics, metabolism)
• Zinc (metabolism)