Glial-derived neurotrophic factor reduces inflammation and improves delayed colonic transit in rat models of dextran sulfate sodium-induced colitis.
BACKGROUND
Intestinal inflammation is well known to cause gut dysmotility through the effects on the enteric nervous system. Glial-derived neurotrophic factor (GDNF) has been demonstrated to have anti-inflammatory effects and neuronal protective actions. The aim of this study was to investigate whether the GDNF could improve inflammation-induced gut dysmotility.


METHODS
Recombinant adenoviral vectors encoding GDNF (Ad-GDNF) were administered intracolonically in experimental colitis induced by dextran sulfate sodium (DSS). The disease activity index (DAI) and histological score were measured. Colonic transit was measured by using phenol red and assessed with the geometric center. PGP 9.5 immunostaining was used to examine the number and distribution of enteric neurons. The expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and myeloperoxidase (MPO) activity were measured by ELISA assay. The expression of Akt, caspase-3, bcl-2 and PGP 9.5 was analyzed by western blot assay.


RESULTS
A significant neuronal cell loss and a significant delay in colonic transit accompanied with the neuronal loss following inflammation were observed. GDNF prevented partially the loss of enteric neurons and ameliorated significantly experimental colitis and delayed colonic transit by, at least in part, down-regulation of TNF-α and IL-1β expression, decrease of infiltration of leukocytes, and inhibition of neuronal cell apoptosis.


CONCLUSIONS
GDNF reduces inflammation and improves delayed colonic transit in DSS-induced colitis. GDNF may be a useful therapeutic agent for the treatment of gut dysmotility in patients with UC.
Department of Geriatrics Medicine and Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Gong Xiang
GX
Liu
Department of Geriatrics Medicine and Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Ying Xue
YX
Yang
Department of Geriatrics Medicine and Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Jing
J
Yan
Department of Geriatrics Medicine and Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Tao
T
Zhang
Department of Geriatrics Medicine and Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Yu Pei
YP
Zou
Department of Geriatrics Medicine and Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: huangxiaoli@hotmail.com.
Xiao Li
XL
Huang
Department of Geriatrics Medicine and Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: ganhuatian@hotmail.com.
Hua Tian
HT
Gan
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D016264:Dextran Sulfate; D005772:Gastrointestinal Transit / Q000187:drug effects*; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000235:genetics; D053583:Interleukin-1beta / Q000276:immunology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000893:Anti-Inflammatory Agents; D051100:Glial Cell Line-Derived Neurotrophic Factor; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D051057:Proto-Oncogene Proteins c-akt
Dysmotility; Enteric neurons; Glial-derived neurotrophic factor (GDNF); Inflammation; Ulcerative colitis