BRAIN RESEARCH ELSEVIER Brain Research 673 (1995) 153-156 Short communication Apolipoprotein A-IV acts centrally in the brain to reduce the severity of gastric ulceration in the rat Toshikatsu Okumura a, Ian L. Taylor b, Koji Fukagawa c, Patrick Tso c, Theodore N. Pappas a,. a Department of Surgery, Duke University Medical Center and Veterans Administration Medical Center, Durham, NC 27710, USA b Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA c Department of Physiology, Louisiana State University Medical Center, Shreveport, LA 71130, USA Accepted 6 December 1994 Abstract We have recently reported that apolipoprotein A-IV (apo A-IV), a protein associated with lipoproteins, acts in the brain to inhibit gastric acid secretion. In the present study, we determined whether or not apo A-IV has an anti-ulcer action via the central nervous system using Sprague-Dawley rats. Intracisternal injection of apo A-IV dose-dependently (2.0-4.0 /~g/rat) reduced the severity of gastric mucosal lesions induced by intravenous injection of 2-deoxy-D-glucose or subcutaneous administration of indomethacine. A higher dose (15/xg) of apo A-IV injected intraperitoneally failed to inhibit the development of gastric mucosal damage evoked by these ulcerogenic agents. These results suggest for the first time that apo A-IV has an anti-ulcer action through a central mechanism. Keywords: Apolipoprotein A-IV; Gastric ulceration; Central nervous system; 2-Deoxy-D-glucose; Indomethacin Apolipoprotein A-IV (apo A-IV) is a protein syn- thesized predominantly in the small intestine [2,18]. Absorption of dietary fat markedly stimulates the syn- thesis and secretion of apo A-IV [1,7,10]. Intraduode- nal infusion of fat significantly increases not only serum but cerebrospinal fluid apo A-IV [3,4]. Although accu- mulating evidence demonstrated that the metabolism and synthesis of apo A-IV are closely associated with lipid ingestion [1,6,7,8,10,12,16], its physiological func- tion was unclear. We recently made a novel observa- tion that intracisternal injection of apo A-IV inhibits gastric acid secretion in a dose-dependent manner in pylorus-ligated conscious rats [14]. To our knowledge, this was the very first report that demonstrated that an apolipoprotein such as apo A-IV can affect gut func- tions centrally. Gastric acid secretion is closely associ- ated with the development of gastric ulceration. The evidence that apo A-IV has a gastric antisecretory action led us to speculate that centrally administered * Corresponding author. Department of Surgery, PO Box 3479, Duke University Medical Center, Durham, NC 27710, USA. Fax: (1) (919) 681-7934. 0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0006-8993(94)01432-9 apo A-IV might have a protective effect on the gastric mucosa against ulcerogenic stimuli. In the present study, we have examined the effect of intracisternal injection of apo A-IV on two models of experimental ulceration in the rat. Acute gastric mucosal lesions were induced by intravenous bolus injection of 2-de- oXy-D-glucose (2-DG) or subcutaneous administration of indomethacin. Apo A-IV was purified by preparative polyacr- lamide gel electrophoresis and the purity of the apo A-IV was verified by analytical polyacrylamide gel elec- trophoresis as described previously [8]. Apo A-IV was dissolved in normal saline just before experiments. Indomethacin and 2-deoxy-D-glucose were obtained from Sigma Chemicals (St. Louis, MO) and dissolved in 7.5% sodium bicarbonate or saline, respectively, imme- diately before each experiment. Male Sprague-Dawley rats, weighing 250-300 g, were housed under controlled light/dark conditions (lights on: 07.00-19.00 h) with room temperature regu- lated to 23-25°C. Rats were allowed free access to food (Solid Rat Chow, Purina, Richmond, IN) and tap water. All the experiments were performed in con- scious animals deprived of food for 24 h but with free access to water up to the initiation of the experiments.