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Cytoprotective effect of SU-88, an anti-ulcer agent, in the rat.

The gastric cytoprotective action of SU-88, an anti-ulcer agent, was studied in rats. SU-88 dose-dependently prevented the formation of gastric lesions induced by absolute ethanol as observed by PGE2. The efficacy of SU-88 when given i.p. was more potent than the p.o. administration. Indomethacin (5mg/kg, p.o.) given 30 min prior to SU-88 dosing blocked this protective effect, whereas it was not affected when indomethacin was given 30 min after the SU-88 dosing. Cimetidine, on the other hand, failed to exert a protective effect against the ethanol-induced lesions and caused a significant increase in the lesions induced by 0.6N HCI. Pretreatment with SU-88 prior to cimetidine resulted in a marked reduction in the lesions. SU-88 was found to increase the synthesis of gastric glycoproteins and to prevent the reduction of glycoprotein synthesis caused by the administration of absolute ethanol. However, no increase in the synthesis was observed 5 min after the SU-88 dosing, although the lesion was significantly suppressed at that time. These findings indicate that SU-88 possesses a cytoprotective effect and that this effect seems to be mediated by the increase in endogenous PG.

Abstract-The gastric cytoprotective action of SU-88, an anti-ulcer agent, was studied in rats. SU-88 dose-dependently prevented the formation of gastric lesions induced by absolute ethanol as observed by PGE2. The efficacy of SU-88 when given i.p. was more potent than the p.o. administration. Indomethacin (5 mg/kg, p.o.) given 30 min prior to SU-88 dosing blocked this protective effect, whereas it was not affected when indomethacin was given 30 min after the SU-88 dosing. Cimetidine, on the other hand, failed to exert a protective effect against the ethanol induced lesions and caused a significant increase in the lesions induced by 0.6N HCI. Pretreatment with SU-88 prior to cimetidine resulted in a marked reduction in the lesions.
SU-88 was found to increase the synthesis of gastric glycoproteins and to prevent the reduction of glycoprotein synthesis caused by the administration of absolute ethanol.
However, no increase in the synthesis was observed 5 min after the SU-88 dosing, although the lesion was significantly suppressed at that time. These findings indicate that SU-88 possesses a cytoprotective effect and that this effect seems to be mediated by the increase in endogenous PG.
2'-Carboxymethoxy-4,4'-bis(3-methyl-2 butenyloxy)chalcone (SU-88) is a synthetic derivative of sophoradin (1), isolated from the root of a Chinese medical plant, Sophora subprostrata CHUN et T. CHEN. SU-88 was shown to prevent the formation of acute gastric ulcers and accelerate the healing of a chronic ulcer produced by acetic acid (2), although it showed only a slight inhibitory effect regarding gastric secretion and acid output in rats. It has recently been reported that the mechanism for the anti-ulcer effect of SU-88 might be due to a strengthened gastric mucosal barrier through an increase in the mucosal blood flow (3)(4)(5) and the stimulation of biosynthesis of sulfated mucosubstances (6).
Recently, prostaglandins (PG) and PG derivatives have been shown to prevent the formation of an ulcer by a mechanism independent of their anti-secretory properties (7)(8)(9) and to protect the gastric mucosa against lesions induced by various necro tizing agents (10). The exact mechanism for this property of PG called "cytoprotection" is unknown. In addition, mild irritants such as 20% ethanol also exhibit cytoprotective effects against damaging agents (adaptive cyto protection) which is considered to result from the endogenous formation of PG (11-13), suggesting that endogenous PG may play an important role in maintaining the cellular integrity of the gastric mucosa.
These findings prompted us to investigate whether SU-88 also displays some cyto protective effects. In the present study, we examined the effects of SU-88 on acute gastric lesions induced by necrotizing agents. In addition, we also examined the effects of this drug regarding the synthesis of gastric mucus which was postulated as one of the possible mechanisms for cytoprotection.

Induction
of gastric lesions: Gastric lesions were produced according to the method of Robert et al. (10). Male Wistar rats weighing approx. 180 g were fasted for 24 hr and deprived of water for 19 hr prior to the experiments. All rats were housed in wire mesh bottom cages throughout the study to prevent coprophagy. One milliliter of absolute ethanol or 0.6N HCI, employed as necrotizing agents, were administered orally, and 1 hr later, the animals were sacrificed by decapi tation. The stomachs were removed, opened along the greater curvature and washed gently with ice-cold saline. The gastric lesions that occured in the glandular portion were determined. In this study, the length of lesions was measured in millimeters, and lesion severity was expressed as the total length of lesions per stomach.
Drug administration: The drugs tested in this study were freshly prepared just before the experiment as follows: SU-88 and indomethacin was suspended in 0.4% carboxymethyl cellulose (CMC); PG E2 (Sigma) was dissolved in a small volume of ethanol and diluted with water; cimetidine (SK & Fujisawa) was diluted with water. The control rats were given 0.4% CIVIC. Each drug was given 30 or 60 min before the oral administration of the necrotizing agents. Determination of rate of mucus synthesis: The method employed to determine the rate of mucus synthesis in the stomach was similar to that described by Dekanski et al. (14). After determination of gastric lesions, each stomach was separated into the corpus and antrum. Portions of the corpus were punched out in circles, 14 mm diam., to make similar tissue sizes. Each tissue was pre incubated at 37°C for 10 min in 2 ml of Krebs-Medium I, pH 7.4, (15) before the addition of 1 ,eCi of N-acetyl-D-(1 -3H) glucosamine (The Radiochemical Centre, Amersham); and incubation was carried out for 2.5 hr, gassing with 95% 02 and 5% CO2 every 20 min. The incubation was stopped by cooling with ice, draining the medium and washing the tissue twice with 5 ml of ice cold saline. The tissue was then homogenized in 20 (Fig. 1). The damage was, in the most part, limited only to the luminal epithelium cells and not extended into the gland. The effect of SU-88 when given i.p. was more potent than the p.o. administration. On the other hand, cimetidine given 50 mg/ kg i.p. failed to display the preventive effects. SU-88 also significantly prevented the for mation of gastric lesions induced by a subsequent administration of 0.6N HCI. The lesion length was significantly increased by cimetidine (100 mg/kg, i.p.), and the lesion was reduced markedly when SU-88 (100 mg/kg, i.p.) was administered prior to cimetidine, as observed in rats receiving SU 88 only ( Table 2).
Effect of indomethacin before and after the administration of SU-88 on ethanol induced gastric lesions: As shown in Table 3,   Fig. 2, a significant reduction in the lesion was caused when SU-88 was administered from 5 to 180 min at 50 mg/kg and from 5 to 240 min at 100 mg/kg prior to ethanol. Effect of SU-88 on synthesis of gastric glycoproteins: As shown in Table 4, the synthetic activity of glycoproteins in the antrum was about twice as potent as that in the corpus, as determined in terms of the N acetyl-D-(1-3H) glucosamine incorporated. Pretreatment of rats with SU-88 (100 mg/kg, i.p.) 30 min before ethanol caused a sig nificant increase in the glycoprotein synthetic activity, approximately twice in the corpus and four times in the antrum, compared with the value in the controls.
However, no significant change was observed 5 min after the SU-88 dosing (data not shown). In the gastric tissue, which developed apparent lesions by ethanol, a striking decrease in the synthetic activity was noted both in the corpus and antrum. Pretreatment with SU-88 (100 mg/kg, i.p.) prior to ethanol showed a complete halting of the decrease.

Discussion
We demonstrate in the present experiments that SU-88, an anti-ulcer agent, showed cytoprotective action as observed by PG E2 in rats. It has been reported that various types of PG given exogenously can prevent the formation of gastric lesions induced by necrotizing agents such as absolute ethanol (10). On the other hand, the endogenous production of PG caused by mild irritants such as 20% ethanol also can prevent gastric necrosis (11-13).
Recently, Robert (16) reported that sodium salicylate completely prevented the formation of gastric lesions produced by either absolute ethanol or 0.6N HCI. This protective effect was completely inhibited by indomethacin, the PG synthesis inhibitor, and considered to be due to the stimulation of formation of PG by its action as a mild irritant (17).
The protective action of SU-88 with parenteral administration was more potent than that with oral dosing, suggesting that this drug exerts mainly a systemic action rather than a local effect on the gastric mucosa. In order to examine the possible involvement of endogenous PG in the protective action of SU-88, the rats were treated with indomethacin before and after the administration of SU-88. The results indicate that indomethacin blocked the pro tective action by SU-88 when given 30 min prior to SU-88 dosing, but did not have this effect when given 30 min after the SU-88 dosing. These findings were supported by the observation that SU-88 inhibited the activity of the PG inactivating enzyme, 15 hydroxy-PG-dehydrogenase, in the gastric mucosa of hogs, but did not affect the cyclooxygenase activity in vitro (18). Therefore, it may be concluded that the mechanism of the protective action by SU-88 seems to be due to the increase in the endogenous PG content through its in hibitory effects on the PG inactivating enzyme. Table 4. Effect of SU-88 on the incorporation of N-acetyl-D-(1 -3H)glucosamine into rat gastric glycoproteins in ethanol-induced gastric lesions pretreatment with SU-88. However, it is less likely that the increase in the mucus synthesis is the major factor for cytoprotective action because no increase in the rate of mucus synthesis was observed 5 min after the SU-88 dosing, but the lesion was significantly suppressed at that time.
On the other hand, cimetidine, the H2 receptor antagonist, failed to provide any protective effect on ethanol-induced lesions; moreover, lesion severity was significantly increased as a result of 0.6N HCI. Arakawa et al. (28) reported that the increased lesion caused by cimetidine resulted from the deficiency of mucosal PG and the withdrawal of the defensive force against the mucosal damage by the necrotizing agents. Pretreat ment with SU-88 prior to cimetidine was capable of preventing the development of 0.6N HCI-induced lesions as observed when SU-88 was given alone, suggesting that a combined treatment of SU-88 with cimetidine can be useful for therapeutic applications in ulcers.