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Quebrachitol-induced gastroprotection against acute gastric lesions: Role of prostaglandins, nitric oxide and [K.sub.ATP.K.+] channels.

Abstract

The effect of Quebrachitol (2-0-methyl-L-inositol), a bioactive component from Magonia glabrata fruit extract was investigated against gastric damage induced by absolute ethanol (96%, 0.2 ml/animal) and indomethacin (30mg/kg, p.o.), in mice. Quebrachitol at oral doses of 12.5, 25, and 50mg/kg markedly attenuated the gastric lesions induced by ethanol to the extent of 69%, 64%, and 53% and against indomethacin by 55%, 59%, and 26%, respectively. While pretreatment with TRPV1 antagonist capsazepine (5 mg/kg, i.p.) failed to block effectively the gastroprotective effect of quebrachitol (25 mg/kg) against ethanol damage, the non-selective cyclooxygenase inhibitor indomethacin (10mg/kg, p.o.), almost abolished it. Furthermore, quebrachitol effect was significantly reduced in mice pretreated with L-NAME, or glibenclamide, the respective inhibitors of nitric oxide synthase and [K.sup.ATP.sub.ATP.K.sup.+] channel activation. Thus we provide the first evidence that quebrachitol reduces the gastric damage induced by ethanol and indomethacin, at least in part, by mechanisms that involve endogenous prostaglandins, nitric oxide release, and or the activation of [K.sub.ATP.K.sup.+] channels.

[C] 2007 Elsevier GmbH. All rights reserved.

Keywords: Quebrachitol; Gastroprotection; Ethanol; Prostaglandins; Nitric oxide; Potassium channels

Introduction

Both experimental and clinical evidence suggests that oxidative stress is involved in many gastrointestinal pathologies including gastric ulcer. Fruits and vegetables contain bioactive chemical constituents, which are capable to scavenge free radicals, reduce oxidative stress and offer gastroprotection (Ligumsky et al., 1995; Thompson et al., 2006). Quebrachitol (2-0-methyl-L-inositol, m.w. 194.2) (Fig. 1) is a plant derived cyclitol (Clark, 1936; Lemos et al., 2006) and has similar physiological effects as inositol. Inositol is required for the proper formulation of cell membranes and in mammals, it exists in phosphoinositides and in free form and participates in transmembrane signaling mechanism (Almeida et al., 2003). It has a membrane stabilization property and acts as a cryoprotectant (Orthen and Popp, 2000; Hincha and Hagemann, 2004). Although quebrachitol (QCT) closely resembles glucose in structure and has a sweetening taste, when taken orally it does not relieve hypoglycemia, raise the blood sugar or lead to the deposition of glycogen in the liver (McCance and Lawrence, 1933). Peroxynitrite (ONOO) scavenging and laxative effects of QCT have been described in literature (Aurousseau et al., 1964; Kim et al., 2004). QCT also showed free radical scavenging ability in DPPH (1,1-diphenyl-2-picrylhy-drazyl) assay (Lemos et al., 2006) and cytoprotection against cell death induced by 6-OHDA in rat mesencephalic cell cultures in vitro (Nobre Junior et al., 2006).

Human gastric mucosal cells express the mitochondrial and cytosolic isoforms of creatinine kinase and adenylate kinase that participate in intracellular energy transfer systems, and an altered functioning of these systems and oxidative phosphorylation may account for mucosal ulceration (Gruno et al., 2006). Since QCT manifests membrane stabilization, free radical scavenging and cytoprotective properties, the present study was aimed to examine whether quebrachitol affords gastroprotection against gastric damage induced by ethanol and indomethacin in mice, and further to assess the possible mechanism.

Materials and methods

Plant material and isolation of QCT (2-0-methyl-L-inositol)

Magonia glabrata St. Hill (Sapindaceae) fruits were collected in Iraucuba, Ceara, Brazil, in January 2003, and identified by Dr. Afranio G. Fernandes, botanist of the Federal University of Ceara. A voucher specimen (#15198) has been deposited at Herbarium Prisco Bezerra. QCT (Fig. 1) was extracted and isolated from the pericarp of M. glabrata dried fruits as per procedures described earlier (Lemos et al., 2006), and on dry weight basis, its yield was 7.2%. The chemical identification was done based on spectral analysis, determination of physical properties and by comparison with literature data.

Drugs

Capsaicin, indomethacin, glibenclamide, diazoxide, L-arginine, [N.sup.w]-nitro-L-arginine methyl ester (L-NAME) were purchased from Sigma-Aldrich (St. Louis, MO). Absolute ethanol was obtained from Synth (Brazil) and prostaglandin analog (misoprostol) from Continental Pharma (Cytotec[R], Italy). All solvents used were of analytical grade.

Animals

Male Swiss mice (20-25 g) obtained from the Central Animal House of this University were used. Experimental groups consisted of 08 animals per group. They were housed at 24 [+ or -] 2[degrees]C under a 12-h light/12-h dark cycle and had free access to standard pellet diet (Purina chow) and tap water. The animals were deprived of food for 15 h before experimentation, but had free access to drinking water. The Institutional Ethics Committee on the Care and Use of Animals for experimentation approved the experimental protocols, and all experiments were performed in accordance with the guidelines of National Institute of Health, Bethseda, USA.

Gastric damage induced by ethanol

Groups of mice (n=8) were treated with QCT (12.5, 25 and 50 mg/kg, p.o.), misoprostol (50 ug/kg, p.o.), or vehicle (0.9% saline in a volume of 10m1/kg). One hour after treatment, each animal was given orally 0.2ml of ethanol (96%) and they were sacrificed 30 min later (Robert, 1979). The stomachs were excised, opened along the greater curvature, rinsed with saline (0.9%) and the mucosal lesion area ([mm.sup.2]) was measured by planimetry using a transparent grid (area: 1 [mm.sup.2]) placed on the glandular mucosal surface and was expressed in percentage (%) in relation to total area of corpus.

Gastric damage induced by indomethacin

Mice in groups (n=8) were treated with QCT (12.5,25 and 50mg/kg, p.o.), misoprostol (50 [micro]g/kg, p.o.) or vehicle (0.9% saline in a volume of 10ml/kg). One hour after treatment, each animal received an oral dose of 30 mg/kg indomethacin and they were sacrificed 6h later (Rainsford, 1982). The stomachs were removed, immersed in 5% formalin for 30min, and then opened along the greater curvature to register the incidence and extent of ulceration according to the following scale: 0=no petichal haemorrhages or erosions; 1=upto 5 petechial; 2=upto 5 petechial with erosions of depth 1 mm; 3 = upto 10 petichal; 4 = upto 10 petechial with erosions of depth above 1 mm. The mean ulcer score for each animal was calculated and compared between groups.

Effects of capsazepine and indomethacin pretreatments on quebrachitol (QCT) gastroprotection

Groups of mice (n = 8) were pretreated with vehicle (0.9% saline, 10 ml/kg), QCT (25 mg/kg, p.o.), capsaicin (0.3 mg/kg, p.o.), and misoprostol (50 [micro]g/kg, p.o.), alone, or in their combinations with capsazepene (5 mg/kg, i.p.), indomethacin (10 mg/kg, p.o.) prior to the oral administration of 0.2 ml of ethanol (96%). When given alone, QCT, capsaicin, and misoprostol were administered 1 h before ethanol. Indomethacin and capsazepene were administered 2 h and 30 min, respectively, prior to ethanol.

Role of nitric oxide on the gastroprotective effect of quebrachitol (QCT)

Mice (n = 8/per group) were pretreated with vehicle (0.9% saline, 10 ml/kg), QCT (25 mg/kg, p.o.), L-arginine (600 mg/kg, i.p.) alone, or in their combinations with L-NAME (20 mg/kg, i.p.) prior to induction of gastric damage with ethanol (0.2 ml of ethanol, 96%). While QCT was administered 1h before, L-NAME and L-arginine were given 30 min prior to ethanol.

Role of [K.sub.ATP]-channels on the gastroprotective effect of quebrachitol (QCT)

Groups of mice (n = 8) were pretreated with vehicle (0.9% saline, 10ml/kg), QCT (25 mg/kg, p.o.), diazoxide (3 mg/kg, i.p.) alone, or in their combinations with glibenclamide (5 mg/kg, i.p.) prior to the oral administration of 0.2 ml of ethanol (96%). QCT was given 1h before, whereas diazoxide was administered 30 min prior to ethanol or glibenclamide. Glibenclamide was administered 30 min before QCT.

Statistical analysis

The results are presented as the mean [+ or -] S.E.M. of 8 animals per group. Statistical analysis was carried out using one way analysis of variance (ANOVA) followed by Tukey or Kruskall-Wallis post hoc test for multiple comparisons. P-values less than 0.05 (p < 0.05) were considered as indicative of statistical significance.

Results

Effect of quebrachitol (QCT) on gastric damage induced by ethanol and indometacin

The effects of orally administered QCT on gastric damage induced by absolute ethanol and indomethacin are shown in Table 1. Orally administered absolute ethanol (0.2 ml/animal) and indomethacin (30 mg/kg) induced severe gastric mucosal damage. QCT at the tested doses of 12.5, 25 and 50 mg/kg exhibited a dose unrelated protective effect against ethanol-induced gastric lesions and compared to vehicle group, the extent of inhibitions for the respective doses employed were 69%, 64% and 53%. Against indomethacin ulceration, the protection was significant only at lower doses (12.5 and 25 mg/kg) of QCT, with 55% and 59% decrease of gastric lesion scores, respectively. Misoprostol, the positive control included for the study also offered significant protection.
Table 1. Effect of quebrachitol on gastric damage induced by absolute
ethanol and indomethacin in mice

Treatment Dose (p.o.) Ethanol lesion area Indomethacin
 (m[m.sup.2]) lesion score

Control - 22.30 [+ or -] 2.77 24.43
(vehicle) [[+ or -]1.81

Quebrachitol 12.5mg/kg 6.98[+ or -]2.72 (a) 11.00 [+ or -]
 3.65 (a)

 25 mg/kg 8.03[+ or -] 2.51 (a) 9.87 [+ or -]
 2.39 (a)

 50mg/kg 10.53[+ or -]2.63 (a) 18.13 [+ or -]
 4.15

Misoprostol 50[micro]g/kg 8.86[+ or -]0.53 (a) 9.70 [+ or -]
 0.85 (a)

Data are presented as mean [+ or -] S.E.M. of 8 animals in each
group. Gastric damage was induced by oral administration of either
absolute ethanol (96%, 0.2 ml/animal) or indomethacin (30 mg/kg), 1 h
after completion of pretreatment with vehicle or quebrachitol.
(a/* < 05 vs. control (ANOVA followed by Tukey or Kruskall-Wallis
test).


Effects of capsazepine and indomethacin pretreatments on quebrachitol (QCT) gastroprotection

In mice pretreated with vanilloid antagonist capsazepine, the gastroprotective effect of QCT (25 mg/kg) on ethanol induced injury persisted unlike that of capsaicin (0.3 mg/kg, p.o.), which was completely prevented (Fig. 2A). On the other hand, indomethacin (10 mg/kg, p.o) pretreatment almost completely abolished the protective effect of QCT as well as that of 100 ug/kg misoprostol (Fig. 2B). These data indicate that the gastroprotective effect of QCT is mediated by endogenous prostaglandins and not through activation of capsaicin-sensitive primary afferents.

[FIGURE 2 OMITTED]

Effects of L-arginine and L-NAME on quebrachitol (QCT) gastroprotection

Fig. 3 represents the results obtained with L-NAME pretreatment on the gastroprotective effect of QCT. L-NAME (20 mg/kg, i.p.) significantly blocked the gastro protection produced by QCT and L-arginine (600 mg/kg, i.p.), suggesting the likely participation of nitric oxide.

[FIGURE 3 OMITTED]

Effects of glibenclamide and diazoxide on quebrachitol (QCT) gastroprotection

Pretreatment with [K. sub.ATP.sup.+] channel blocker, glibenclamide (5 mg/kg, i.p.), also significantly reduced the gastroprotection produced by QCT and diazoxide (3 mg/kg, i.p.) (Fig. 4), indicating a role for [K.sub.ATP.sup.+] channels in gastroprotection.

[FIGURE 4 OMITTED]

Discussion

In the recent past several reports documented the gastroprotective activity of phytochemical constituents that include flavonoids, oleo-resins, terpenes, xanthones, saponins, alkaloids, and tannins (Rao et al., 1997; Paiva et al., 1998; Santos and Rao, 2001; Baggio et al., 2005; Morikawa et al., 2006). This study describes for the first time that QCT, a sugar like molecule has the gastroprotective function. QCT significantly prevented gastric damage induced by both ethanol and indomethacin at smaller doses (12.5 and 25 mg/kg, p.o.). This finding is consistent with the studies of Gharzouli et al. (2001) that report the protective effect of mannitol, glucose-fructose-sucrose-maltose mixture and natural honey against ethanol-induced gastric damage in rats. QCT is non-toxic and acute oral administration to mice up to 5 g/kg did not manifest signs of toxicity or significant changes in body weights of animals, in acute toxicity studies (data not shown). In our previous work, QCT demonstrated an antioxidant activity in DPPH assay and a cytoprotective function in rat fetal mesencephalic cell cultures exposed to a high concentration of neurotoxin, 6-OHDA (Nobre Junior et al., 2006) and in the current study, it offered cytoprotection against gastric mucosal damage induced by ethanol and indomethacin.

Cytoprotection in the stomach, consisting in the mucus secretion, mucous circulation intensification and bicarbonate secretion to the gastric lumen, is highly dependent on the products of arachidonic acid pathway and peroxidative-antioxidative balance. It has been firmly established that oxidative stress and impaired prostaglandin synthesis contribute to gastric mucosal damage in experimental models of gastric lesions induced by both ethanol and indomethacin (Chattopadhyay et al., 2006). Prostaglandins perform a number of important functions in the gastrointestinal tract, particularly with respect to resistance of the mucosa to injury. It has been proposed that after oral administration of nonsteroidal antiinflammatory durgs (NSAIDs), reduced levels of gastric mucosal adenosine triphosphate (ATP) in response to mitochondrial damage constitute the earliest event on topical mucosal erosions. Cells have defective mitochondrial function, which may be due to altered antioxidant defences and possibly altered free radical formation. Besides the scavenging action on free radicals (Lemos et al., 2006), being a sugar derivative, QCT might possibly improve the mitochondrial energy metabolism preventing the decreases in high-energy phosphate stores (ATP) caused by gastrotoxicants, ethanol and indo- methacin. In this context previous works have shown that acute treatment with ethanol or indomethacin can cause vascular ischemic injury and further a cellular energy deficit in gastric mucosa (Martin et al., 1982).

Nitric oxide (NO) also appears to be a key mediator of gastrointestinal mucosal defence. NO, produced via activity of NO-synthase (NOS), appears to be one of the major factors, involved in the regulation of the gastric blood flow (GBF) and gastric microcirculation (Wallace, 2006). NO releasing drugs protect against ethanol-induced gastric lesions, and conversely, inhibition of NO synthesis increases the susceptibility of the stomach to ethanol injury (Kawano and Tsuji, 2000). Some plant-derived substances have been shown to attenuate ethanol- and stress-induced gastric lesions via activation of prostaglandin, nitric oxide and sensory nerve pathways and improve microcirculation (Zayachkivska et al., 2004; Brzozowski et al., 2005). In the present study, L-arginine (600mg/kg)-and QCT (25 mg/kg)-induced gastroprotection was reversed by L-NAME, a non-selective NOS inhibitor, suggesting that the gastroprotective effect of QCT is mediated, in part, by NO. It has been suggested that capsaicin-sensitive afferent neurons play a role in gastroprotection via with or without interaction with TRPV1 (transient receptor potential vanillod-1) involving endogenous prostaglandins (Takeuchi et al., 2003; Fukushima, et al., 2006). In order to verify the role of prostaglandins and TRPV1 in the gastroprotection afforded by QCT, mice were pretreated with indomethacin, a non-selective cyclooxygenase inhibitor and capsazepene an antagonist of TRPV1. The results reveal that the gastroprotection by QCT against ethanol-induced mucosal injury is resistant to capsazepene but is vulnerable to indomethacin, suggesting a role for endogenous prostaglandins and not the capsaicin-sensitive afferent neuron in gastroprotection. More recent studies point out a role for endogenous glucocorticoid hormones (released as a consequence of stress reaction) in gastroprotection. This hormonally mediated gastroprotection appears to persist even after chemical ablation of primary afferent neurons by a neurotoxic dose of capsaicin (Filaretova,2006). Nevertheless, our experimental results strongly indicate the role of endogenous prostaglandins in QCT promoted gastroprotection. It has been shown that prostaglandins mediated gastroprotection involve, at least in part, by opening [K.sub.ATP.sup.+] channels (Peskar et al., 2002). In the present study, glibenclamide, a blocker of [K.sub.ATP.sup.+] channels significantly antagonized the protective effect of QCT and diazoxide. Since the protection afforded by QCT is additionally indomethacin-sensitive, we may consider that endogenous prostaglandins act as activators of [K.sub.ATP.sup.+] channels.

In conclusion, the results of this study indicate a cytoprotective role of quebrachitol affording gastroprotection against gastric damage induced by ethanol and indomethacin, which is possibly mediated, in part, by endogenous prostaglandins, nitric oxide release and [K.sub.ATP.sup.+] channel opening and suggest that it might serve as a lead compound for future development of novel therapies that combat NSAIDs-associated gastropathy.

Acknowledgements

The study was supported by grants from CNPq and CAPES. The technical assistance of Antonia Dannyella Marques Ferreira is gratefully acknowledged.

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* Corresponding author. Tel: + 558533668341;

fax: +5585 33668333.

E-mail address: flavia@ufc.br (F.A. Santos).

0944-7113/$-see front matter [C] 2007 Elsevier GmbH. All rights reserved.

doi:10.1016/j.phymed.2007.09.002

T.M. de Olida (a), T.L.G. Lemos (b),L.L. Machado (b), V.S. Rao (a), F.A. Santos (a)*

(a) Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, P.O. Box 3157, 60430-270 Fortaleza, CE, Brazil

(b)Department of Organic and Inorganic Chemistry, Federal University of Ceara, P.O. Box 12200, 60451-970 Fortaleza, CE, Brazil
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Author:de Olida, T.M.; Lemos, T.L.G.; Machado, L.L.; Rao, V.S.; Santos, F.A.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:3BRAZ
Date:May 1, 2008
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