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Neuropeptide Y Receptor Y1 (NPY Y1) Inhibition Attenuates Intestinal Inflammation in Murine Colitis and Human IBD Biopsy Cultures
Author(s) -
Chandrasekharan Bindu,
Saeedi Bejan,
Dhere Tanvi,
Neish Andrew S
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.859.4
Subject(s) - neuropeptide y receptor , colitis , inflammatory bowel disease , medicine , ulcerative colitis , inflammation , tumor necrosis factor alpha , gastroenterology , ex vivo , in vivo , diarrhea , colonoscopy , pharmacology , endocrinology , immunology , receptor , neuropeptide , biology , disease , colorectal cancer , microbiology and biotechnology , cancer
Rationale Inflammatory bowel disease, characterized by intestinal inflammation, is commonly treated with drugs targeted against the pro‐inflammatory cytokine tumor necrosis factor (TNF). However anti‐TNF drugs are expensive, and some patients stop responding to anti‐TNF's over time. Aim Based on our published findings that neuropeptide Y (NPY) can regulate TNF levels in the gut, we investigated the efficacy of neuropeptide Y (NPY) inhibition in attenuating intestinal inflammation by selectively blocking NPY receptor Y1 (NPY Y1) in mouse model of dextran sodium sulfate(DSS)‐induced colitis, and in colonic biopsies from patients with inflammatory bowel disease (IBD) ex vivo . Methods Colitis was induced in mice (129S strain) by administration of 3% DSS in drinking water for 7 days. NPY Y1 inhibition was achieved via intra rectal administration of NPYY1 antagonist BIBP‐3222 (@ 10 mg/kg of mouse body weight) on alternate days during the DSS treatment. Mice were monitored for weight loss, fecal blood and diarrhea (clinical score), colon length, histological score, TNF expression (by real time PCR and enzyme linked immunosorbent assay/ELISA) and on day 7 subjected to endoscopy. Colonic biopsies were obtained from healthy volunteers (n = 10) and IBD patients (n = 8), and biopsies were cultured ex vivo in presence or absence of BIBP‐3222 (0.1mM) for 24 h (at 37°C, 5% CO 2 ). Results In mouse models of (DSS)‐induced colitis, NPY Y1 inhibition resulted in significant protective effects as determined from the clinical score and histological scores, colon length and endoscopic colitis score (p < 0.05). TNF mRNA was also significantly downregulated in the colon of DSS + BIBP‐treated mice as compared to DSS ‐ treated mice (p < 0.05). Colonic biopsies from IBD patient's ex vivo depicted significant increase in TNF levels as compared to biopsies from healthy subjects (p < 0.05). Incubation of IBD patient biopsies with BIBP‐3222 was effective in significantly inhibiting TNF release by at least 50 % as determined by ELISA (p < 0.05). Conclusions Taken together, our data suggests that NPYY1 inhibition is effective in attenuating intestinal inflammation in murine colitis and human IBD biopsies ex vivo . Support or Funding Information We acknowledge the support from Litwin‐IBD Pioneers Initiative grant from Crohn's & Colitis Foundation (B.C) and the U.S. National Institutes of Health grants AI64462 & DK089763 (A.S.N.) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .