Gastroduodenal ulcers in rats induced by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP): requirement for gastric acid secretion and the role of prostaglandins.
To better study the neuropathophysiology of duodenal and gastric ulcers (DU & GU) an appropriate animal model is needed. One such model was recently provided by 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), a neurotoxin, which reliably induces DU and GU in rats that are macroscopically similar to human ulcers. However, the underlying ulcerogenic mechanism is not known. Accordingly, we investigated the roles of prostaglandins (PG) (cytoprotective factors) and omeprazole and atropine (inhibitors of gastric acid secretion) in DU, with GU as the secondary outcome measure. Compounds known to effectively inhibit gastric acid secretion in rats, omeprazole or atropine, totally prevented DU and GU. Doses of misoprostol, a PGE1 analog, that are known to be cytoprotective but not anti-secretory in rats decreased the frequency of DU but not GU. Meclofenamate or BW755c, compounds known to inhibit both cyclo-oxygenase and lipo-oxygenase and thus eicosanoid formation, worsened DU & GU. In order to further evaluate the role of PGs, levels of PGE2-alpha in gastric and duodenal mucosa were measured using an RIA assay. Following 4 days of MPTP injections, PGE2-alpha levels were significantly lowered in duodenal but not gastric mucosa. Thus, as in human ulcer disease, 1) MPTP-induced ulcers in rats also appears to require at least some gastric acid; 2) prostaglandins have an anti-ulcer effect against MPTP-induced DU but not GU. In addition, the mechanisms of DU and GU appear to be different even though there is a single etiology namely, MPTP.
Keshavarzian
A
A
Department of Medicine, Loyola University Medical School, Maywood, IL.
Haydek
J M
JM
Zepeda
D O
DO
Stinneford
J G
JG
Fields
J Z
JZ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D004381:Duodenal Ulcer / Q000139:chemically induced*; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D007279:Injections, Subcutaneous; D016595:Misoprostol; D009853:Omeprazole / Q000494:pharmacology; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013276:Stomach Ulcer / Q000139:chemically induced*; D013997:Time Factors
D011453:Prostaglandins; D016595:Misoprostol; D001285:Atropine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000527:Alprostadil; D009853:Omeprazole