Role of brain-gut axis in healing of gastric ulcers.
The previous studies demonstrated the pivotal role of capsaicin-sensitive peptidergic sensory neurons and vagal nerves in the maintenance of gastric mucosal integrity. The aim of the present study was: 1). to examine the effect of the functional ablation of sensory neurons with neurotoxic dose of capsaicin and surgical vagotomy on the course of healing of gastric ulcer in rat, and 2). to compare the ulcer healing action of leptin in rats with or without capsaicin-induced inactivation of sensory neurons. Three series of experiments (A, B and C) were performed in Wistar rats with gastric ulcers induced by acetic acid method. In series A, the course of ulcer healing was compared in rats with intact and capsaicin-inactivated sensory neurons. In the series B, the effect of vagotomy on the ulcer healing and accompanying changes in GBF were determined at day 8 and 16 after ulcer induction. The rats of series C, consisting of animals with intact nerves or those with capsaicin-denervation, received the 7-day treatment with exogenous leptin (10 microg/kg i.p. twice daily) to check whether blockade of sensory nerves could influence the acceleration of ulcer healing by this peptide. Capsaicin-induced ablation of sensory neurons significantly delayed ulcer healing and this was accompanied by the significant fall in the GBF and the significant rise in the gastric mucosal gene expression of IL-1beta and TNF-alpha. Vagotomy significantly delayed ulcer healing and led to decrease in GBF at ulcer margin. Treatment with exogenous leptin significantly accelerated ulcer healing, increased the GBF at ulcer margin and upregulated mRNA for iNOS and these effects were attenuated in rats with capsaicin-deactivation of sensory neurons. We conclude that: 1). vagal and sensory neurons contribute to the gastric ulcer healing process possibly due to the increase of GBF, the limitation of inflammatory response, and overexpression of TGFalpha and iNOS resulting in NO release, and 2). the acceleration of ulcer healing by leptin was attenuated in animals with capsaicin-denervation suggesting an involvement of neuropeptides released from sensory afferent nerves in the ulcer healing effect of this hormone.
Konturek
P C
PC
Department of Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany.
Brzozowski
T
T
Burnat
G
G
Kwiecien
S
S
Pawlik
T
T
Hahn
E G
EG
Konturek
S J
SJ
D019342:Acetic Acid / Q000009:adverse effects; D000818:Animals; D001921:Brain / Q000502:physiology*; D002211:Capsaicin / Q000008:administration & dosage / Q000009:adverse effects; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005753:Gastric Mucosa / Q000098:blood supply / Q000473:pathology / Q000502:physiology; D041981:Gastrointestinal Tract / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D020738:Leptin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008565:Membrane Proteins; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000737:chemistry; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014628:Vagotomy / Q000009:adverse effects / Q000379:methods; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D007375:Interleukin-1; D007527:Isoenzymes; D020738:Leptin; D008565:Membrane Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D019342:Acetic Acid; D002211:Capsaicin