title: Anti-inflammatory effects of the selective phosphodiesterase 3 inhibitor, cilostazol, and antioxidants, enzymatically-modified isoquercitrin and α-lipoic acid, reduce dextran sulphate sodium-induced colorectal mucosal injury in mice.
abstract: Developing effective treatments and preventing inflammatory bowel disease (IBD) are urgent challenges in improving patients' health. It has been suggested that platelet activation and reactive oxidative species generation are involved in the pathogenesis of IBD. We examined the inhibitory effects of a selective phosphodiesterase-3 inhibitor, cilostazol (CZ), and two antioxidants, enzymatically modified isoquercitrin (EMIQ) and α-lipoic acid (ALA), against dextran sulphate sodium (DSS)-induced colitis. BALB/c mice were treated with 0.3% CZ, 1.5% EMIQ, and 0.2% ALA in their feed. Colitis was induced by administering 5% DSS in drinking water for 8days. The inhibitory effects of these substances were evaluated by measuring relevant clinical symptoms (faecal blood, diarrhoea, and body weight loss), colon length, plasma cytokine and chemokine levels, whole genome gene expression, and histopathology. Diarrhoea was suppressed by each treatment, while CZ prevented shortening of the colon length. All treatment groups exhibited decreased plasma levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-α compared with the DSS group. Microarray analysis showed that cell adhesion, cytoskeleton regulation, cell proliferation, and apoptosis, which might be related to inflammatory cell infiltration and mucosal healing, were affected in all the groups. DSS-induced mucosal injuries such as mucosal loss, submucosal oedema, and inflammatory cell infiltration in the distal colon were prevented by CZ or antioxidant treatment. These results suggest that anti-inflammatory effects of these agents reduced DSS-induced mucosal injuries in mice and, therefore, may provide therapeutic benefits in IBD.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical Co. Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kangawa
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. Electronic address: yoshida7@cc.tuat.ac.jp.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Abe
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical Co. Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Seto
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical Co. Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Miyashita
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical Co. Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Michi
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Pharmacokinetics and Safety Department, Drug Research Center, Kaken Pharmaceutical Co. Ltd., 301 Gensuke, Fujieda, Shizuoka 426-8646, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kihara
authors.affiliation: Global Scientific and Regulatory Affairs, San-Ei Gen F. F. I., Inc., 1-1-11 Sanwa-cho, Toyonaka, Osaka 561-8588, Japan.
authors.forename: Shim-Mo
authors.initials: SM
authors.lastname: Hayashi
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D000077407:Cilostazol; D003092:Colitis / Q000473:pathology*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; C016527:isoquercitrin; D008063:Thioctic Acid; D016264:Dextran Sulfate; D011794:Quercetin; D000077407:Cilostazol
keywords: Cilostazol; Colitis; Enzymatically modified isoquercitrin; Interleukin -6; Tumour necrosis factor -α; α-lipoic acid