Calcineurin inhibition by polaprezinc in rats with experimentally-induced colitis

• Published in: Life sciences (1973) 2011-02, Vol.88 (9), p.432-439
• Main Authors: Zhang, Yajing, Okamura, Shinichi, Kudo, Tomohiro, Masuo, Takashige, Mori, Masatomo
• Format: Article
• Language: English
• Subjects: Administration, Rectal; Animals; Anti-Ulcer Agents - pharmacology; Calcineurin; Calcineurin - metabolism; Calcineurin Inhibitors; Carnosine - analogs & derivatives; Carnosine - pharmacology; Cell Survival - drug effects; cell viability; Colitis; Colitis - chemically induced; Colitis - drug therapy; colon; cyclosporine; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; gene expression; Gene Expression - drug effects; Humans; Immunosuppressive agents; in vitro studies; inflammation; interleukin-2; Interleukin-2 - genetics; Interleukin-2 - metabolism; intestinal mucosa; Intestinal Mucosa - drug effects; Intestinal Mucosa - enzymology; Jurkat Cells; Male; NFATC transcription factors; NFATC Transcription Factors - metabolism; Organometallic Compounds - pharmacology; Polaprezinc; protein synthesis; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; T-lymphocytes; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; therapeutics; transcription factors; Trinitrobenzenesulfonic Acid - toxicity; Zinc; Zinc Compounds - pharmacology
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2010.12.018

We investigated the therapeutic effect of polaprezinc (PZ), N-(3-aminopropionyl)- l-histidinato zinc, in rats with experimentally-induced colitis by focusing on calcineurin (CN) inhibition. CN plays a crucial role in T-cell activation and cytokine gene expression and is targeted by immunosuppressants such as cyclosporine and FK506. Colitis was induced into male Wistar rats by trinitrobenzene sulfonic acid and was treated with intrarectally administered PZ. The inflammation was assessed by the macroscopic damage score, colon wet weight, and proinflammatory mediator expression by RT-PCR analysis. Protein expression of calcineurin and the activation of its substrate, the nuclear factor of activated T cells (NFAT) transcription factor, were also studied. Calcineurin inhibition by PZ was investigated in in vitro experiments using colonic mucosa, purified calcineurin enzyme, and Jurkat T cells. CN was activated in the colitic mucosa; PZ treatment inhibited CN activation, the expression of proinflammatory cytokines in the mucosa, and thereby ameliorated the experimental colitis in rats. In in vitro experiments, PZ inhibited CN activity, NFAT activation, interleukin-2 expression, and the growth of Jurkat T cells. In the effective concentrations, PZ did not affect cell viability. Our results suggest that PZ can be used as an immunosuppressive agent for the treatment of colitis through its inhibitory effect on CN activity.