ÓÄÊ 612.325:615.322]-084

Zayachkivska O. S., Konturek S.J., Drozdowicz D., Brzozowski T., Gzhegotsky M.R. Influence of plant-originated gastroprotective and antiulcer substances on gastric mucosal repair (review of literature and own data)

 îãëÿä³ ë³òåðàòóðè ïðåäñòàâëåíî ñó÷àñíèé ïîãëÿä íà ôóíêö³îíàëüí³ ìîæëèâîñò³ ãàñòðîïðîòåêòîðíèõ ³ ïðîòèâèðàçêîâèõ ðå÷îâèí ðîñëèííîãî ïîõîäæåííÿ.  îñíîâ³ ³íòåðåñó äî ö³º¿ ãðóïè ðå÷îâèí ðîñëèííîãî ïîõîäæåííÿ ëåæàòü äàí³ ïðî ¿õíþ âèðàæåíó çàõèñíó ä³þ, ùî ðåàë³çóºòüñÿ ó â³äíîâëåíí³ ñëèçîâî¿ îáîëîíêè øëóíêà ÷åðåç åêñïðåñ³þ ð³çíîìàí³òíèõ ôàêòîð³â ðîñòó, ñóïðåñ³¿ íåéòðîô³ë/öèòîê³í³íîâîãî êàñêàäó ó òðàâí³é ñèñòåì³, âïëèâ³ íà ñêåâ³íäæ ðåàêö³¿, ïðîÿâëÿþ÷è àíòèîêñèäàíòíó, àíòèíóêëåîë³òè÷íó òà àíòèêàíöåðîãåííó 䳿, ãàëüìóþ÷è àêòèâí³ñòü öèòîõðîìó Ð-450. Äîñë³äæåíî öèòîïðîòåêòîðí³ âëàñòèâîñò³ åêñòðàêò³â ñîôàðàäèíó (ñîëîí), íàñ³ííÿ àìàðàíòó òà ãðåéïôðóòîâèõ çåðíÿòîê çà óìîâ åêñïåðèìåíòàëüíîãî óðàæåííÿ ñëèçîâî¿ øëóíêà 100%-ì åòàíîëîì. Îòðèìàí³ ðåçóëüòàòè ñâ³ä÷àòü ïðî âèðàæåí³ ãàñòðîïðîòåêòîðí³ âëàñòèâîñò³ äîñë³äæóâàíèõ ðå÷îâèí ³ äîö³ëüí³ñòü ¿õíüîãî çàñòîñóâàííÿ ó ïðîô³ëàêòèö³ òà òåðàﳿ ãàñòðîåíòåðîëîã³÷íèõ õâîðîá.

INTRODUCTION and known to account for gastroprotection by various irritants and ulcerogens [2, 15, 16, 38]. All mucosal layers play a role as a barrier that This article overviews the potential role limits exposure of the gastric mucosal cells to and also some basic mechanisms of plant- numerous injurious luminal agents. Mucosal originated gastroprotective substances applied surface epithelium is a subject of attack by intragastrically (ig). Recent studies found that physical, chemical or microbiological agents different substances from plant sources, not from the gastric lumen, which are involved in only afford gastroprotection, but also facili- multiple pathologies, such as gastritis, peptic tate ulcer healing. They may also possess an ulcer or gastric cancer. Over the last decade, anti-inflammatory action by suppressing the considerable progress has been made in un- neutrophil/cytokine cascade in GIT [1, 46], derstanding the cellular and molecular mecha- promote tissue repair through expression of nisms involved in mucosal injury and repair in various growth factors [22], exhibit antioxi- gastrointestinal tract (GIT). These significant dant action [22, 29], scavenging reactive oxy- findings provide a fundamental basis to iden- gen species (ROS) [28, 34], show anti- tify the etiology and pathogenesis of various nucleolytic, cytochome P450 2F1 inhibitory gut mucosal injury-related diseases and to acitivity, anti-necrotic and anti-carcinogenic develop new therapeutic approaches. Pre- activities [4, 44]. treatment with different substances could effectively prevent gastric mucosa from the METHODS development of erosions and ulcerations. This action, called gastro- or cytoprotection is not Wistar male rats weighing 200-220 g were related to the inhibition of gastric acid secretion used in studies with production of acute gast-

© Zayachkivska O. S., Konturek S.J., Drozdowicz D., Brzozowski T., Gzhegotsky M.R.

118 ISSN 0201-8489 Ô³ç³îë. æóðí., 2004, Ò. 50, ¹ 6 Zayachkivska O. S., Konturek S.J., Drozdowicz D., Brzozowski T., Gzhegotsky M.R. ric lesions and measurement of gastric blood have been used in practical and folk medicine flow. All animals were fasted 24 h before the of many countries due to their beneficial ef- study but had free access to water. They were fects on the mucosa of GIT. In China and placed in individual Bollman cages to prevent Japan, polyphenol extracts such as Sopharadin coprophagy. extracts, containing flavonoids and its syn- Acute gastric lesions were induced by thetic flavonoid derivative known as Solon are ig administration of 100% ethanol in a vol- widely employed in peptic ulcer therapy and ume of 1 ml using special oro-gastric metal also as additives and nutritional supplements, tube. One hour after ethanol administration, mainly because of their strong inhibition of the animals were lightly anesthetized with prostaglandin (PG) metabolism and leukotriene ether and after midline incision, the stom- inhibition [26]. According to our experience, ach was approached using electrolytic Solon (Taisho Pharmaceutical Co, Tokyo, Ja- regional H2-gas clearance technique applied pan) given ig results in dose-dependent pro- by employing Electrolytic Blood Flow Meter tection against acute gastric lesions produced (Biomedical Science Co., Tokyo, Japan) with by 100% ethanol, the corrosive substance for single electrode both for the generation of the gastric mucosa (Fig.1). The gastropro- H2 and measurement of its concentration tection by Solon is accompanied by dose-de- as described previously [23] . The tested pendent increase in gastric mucosal blood plant-originated preparations were admin- flow. Both the gastroprotection and gastric istered at various doses 30 min before etha- hyperemia can be attenuated by the pretreat- nol application and in case of L-NNA ad- ment with nonspecific NOS inhibitor such as ministration, this agent was injected intra- L-NNA, indicating that local release of NO, venously (iv) at various doses about 30 min possibly due to increased expression and ac- before application of tested plant gastro- tivity of NOS plays a major role in Solon- protector agent. Then, the animals were induced gastroprotection. Our previous stu- killed by blow to the head and the stomach dies [23,25] with that agent demonstrated was removed, opened alone the greater that it enhances the healing of chronic gas- curvature and the area of gastric lesions tric and duodenal ulcers induced by acetic was measured by planimetry (morphomat, acid and that it acts probably through the in- Carl Zeiss, Berlin, Germany). The area of crease in mucosal PG content probably due lesions in each animal was expressed in to inhibition of 15-OG-PG dehydrogenase, a mm2. Several groups of animals, each PG hydrolyzing enzyme. This agent is of spe- consisting of 6-8 animals were used. cial interest as it is widely used in Japan as Mean values were calculated for the area gastric protective and anti-ulcer agent in of gastric lesions and the gastric blood flow. combination with classic antiulcer drugs such The results were analyzed by Student’s t test, as H2-receptor antagonists or proton pump and P values less than 0.05 were considered inhibitors. The major factor responsible for significant. All results are given as means ± the gastroprotection by Sopharadin deriva- standard error of mean (SEM). tives are probably flavonoids, the biologically active agents with high pharmacological po- Plant-originated gastroprotective substanc- tency [18]. es, results of their protective action on gas- In Ukraine, therapeutic effect of Ama- tric mucosal lesions and gastric blood flow ranth, that was found to be related to scav- and discussion of the results enging of endogenous ROS, was shown to There are various plant-originated “gastro- account for the maintenance of integrity and protectors” with different composition that homeostasis of oral and gastric mucous [20].

ISSN 0201-8489 Ô³ç³îë. æóðí., 2004, Ò. 50, ¹ 6 119 Influence of plant-originated gastroprotective In accordance with our experience, Amaranth patients suffering from gastroenteritis, abdomi- seed extract resulted in gastroprotection nal pain or diarrhea, because the berberine- against 100% ethanol and its favorable effect free fraction of the extract from this plant has could be reversed by the pretreatment with anti-inflammatory activity and additive effect neurotoxic dose of capsaicin that is known to on the cytoprotection and reduction of gastric cause functional ablation of sensory afferent acid secretion [19]. nerves and release gastroprotective sensory Grape seeds (GSP) and skins are good neuropeptides such as calcitonin-gene related sources of phytochemicals such as gallic acid, peptide (CGRP) (Fig.2). Based on the results catechin and epicatechin exert scavenging of we can speculate that Amaranth acts on gas- ROS [20-25]. The data demonstrate that this tric mucosa to stimulate af- ferent nerves and increases gastric microcirculation, but 90 80 further studies are required ) to examine the protection by 2 75 Amaranth in depth. 60 In India, an important 60 gastroprotective effect was shown in studies on several 45 40 experimental ulcer models in rats using aqueous extract 30 GBF (% control) of Neem (Aradirchta in- 20 dica) bark [12], ethanol ex- MEAN LESION AREA (mm 15 tract of Aqeratum cony- 0 0 zoides [43], Bacopa mon- Veh 6,25 12,5 25 50 100 niera and Azadirachla indica Solon (mg/kg i.g.) extract [14]. In Mexico the root bark of Hippocratea 100 60 excelsa, locally known as ) “Cancerina”[15] and Aza- 2 dirachta indica extract [16] 75 45 are used in gastric disorders. In Spain, the flavonoid frac- tion (ethyacetate extract) of 50 30 the plant Erica andevalensis

Cabezudo-Rivera [17] of GBF (% control) 25 15 the plant ternatin, tetra- MEAN LESION AREA (mm methoxyflavone from Eglets viscose are used due to their 0 0 prostaglandins –indepen- VehSolon Veh Solon (50 mg/kg i.g.) (50 mg/kg i.g.) dent mechanism of gastro- + L-NNA (50 mg/kg i.g.) protection [18]. In Chinese medicine Fig. 1. Mean area of 100% ethanol-induced gastric lesions and the gastric blood phellodendri cortex (Phel- flow (expressed as percent of control) in rats without (vehicle only) and with pretreatment with graded doses of Solon. Each column is a mean (± SEM) of lodendron amurense) Rup- 5-8 rats. Asterisk indicates significant (P < 0.05) change as compared to the recht has been used to treat vehicle (control) values.

120 ISSN 0201-8489 Ô³ç³îë. æóðí., 2004, Ò. 50, ¹ 6 Zayachkivska O. S., Konturek S.J., Drozdowicz D., Brzozowski T., Gzhegotsky M.R. extract may serve as a potential therapeutic Gingo biloba extract can improve memory, tool in cardioprotection via a number of novel prevents pancreatitis and enhances gastropro- molecular mechanisms [26, 27]. GSP improve tection against necrotizing agents and acce- insulin sensitivity and/or ameliorate ROS for- lerates healing in rats with duodenal ulcer by mation and reduce the signs/symptoms of cytoprotetive and antioxidant actions [32,33]. chronic age-related disorders including syn- Extract from Petasites hybridus with three drome X [28]. Identification of these compo- main compounds oxopetasan esters, petasin nents has been interpreted on molecular ba- and isopetasin inhibit the biosyntesis of the sis of “French Paradox” in which good red vasoconstrictive peptide leukotrienes, this ef- wine is beneficial for the cardiovascular sys- fect may contribute to gastroprotection and tem [29]. spasmolytic activity [34]. The influence of black currant juice on Grapefruit-seed extract (GSE), containing protein and lipid oxidation lowering effect was flavonoids, has been shown to possess anti- similar in magnitude to the liver protecting bacterial, antiviral and antifungal properties agent kolaviron [30, 31]. The results of inves- [35, 36]. This beneficial action of GSE was tigations of modulatory effects of kolaviron, attributed to the antioxidative activity of cit- a bioflavonoid from Gacinia kola, natural an- rus flavonoids found in grapefruit [37] such tioxidant, on drug-induced kidney toxicity show as naringenin because this major flavonoid an interference in the cellular redox status and found in the grapefruit juice, exhibited the depression of membrane protein activities that potent anti-Helicobacter pylori activity in vitro may be relevant to chemoprevention of oxi- [38] and was also recently implicated in dant-induced genotoxicity and possibly human cytoprotection against injury induced by algal carcinogenesis [30]. toxins in isolated hepatocytes [39]. Moreover, naringenin, the bioactive component of GSE, sho- 25 100 wed anti-cancer activity against human breast can- ) 2 20 80 cers [40]. Therapeutic ef- ficacy of citrus fruits such as red grapes and grape- 15 60 fruits is emphasized by the fact that they contain dif- 10 40 ferent classes of polyphe- GBF (% control) nolic flavonoids, that were

MEAN LESION AREA (mm 5 20 shown to inhibit platelet ag- gregation thus decreasing the risk of coronary throm- 0 0 Veh + Capsaicin bosis and myocardial inf- denervation 0,25 0,50 1,0 1,0 arction [41]. The invol- Amaranth (mL/d) vement of flavonoids in the Fig. 2. Mean area of 100% ethanol-induced gastric lesions and the gastric blood mechanism of gastric mu- flow (expressed as percent of control) in rats without (vehicle only) and with cosal defense has been pretreatment with graded doses of Amaranth (extract of Amaranth seeds) with- little studied. Our recent out or with sensory denervation by neurotoxic dose of capsaicin (125 mg of study with GSE (Citro- capsaicin injected s.c. 2 weeks before experiment). Each column is a mean (± SEM) of 5-8 rats. Asterisk indicates significant (P < 0.05) change as compared to kvapky, HERB-PHARMA, the vehicle (control) values. spol s.r.o., Welke Ludince,

ISSN 0201-8489 Ô³ç³îë. æóðí., 2004, Ò. 50, ¹ 6 121 Influence of plant-originated gastroprotective Slovakia) confirmed that in vitro GSE is a gastroprotective effect of naringenin and ac- highly antibacterial and antifungal agent. Most companying increase in the mucus secretion important, we found that this extract in minute were, in part, attenuated by indomethacin sug- doses causes dose-dependent diminution of gesting the involvement of endogenous pros- acute gastric lesions induced in rats by 100% taglandins (PG) in the mechanism of this fla- ethanol. The mechanism of this protection ap- vonoid-induced gastroprotection [43]. pears to be dependent on the functional ac- Our group demonstrated long time ago that tivity of sensory nerves releasing CGRP because a) 100 100 capsaicin-induced deac-

tivation of these nerves ) 2 markedly reduced protec- 80 80 tion and increased gastric circulation provoked by 60 60 GSE and b) exogenous CGRP, administered in phy- 40 siological dose to replenish 40 GBF (% control) the deficiency of this pep- tide caused by capsaicin, MEAN LESION AREA (mm 20 20 restored the protective ef- ficacy of GSE. No study 0 0 so far has been undertaken Veh 8163264 to examine the gastropro- GSE (mg/kg i.g.) tective or ulcer healing ef- ficacy of GSE but the fact 125 + 90 that it is a potent anti-H. ++ pylori substance and exerts ) profound gastroprotection 2 100 + in laboratory animals sug- + 60 gests that it should be also 75 effective in humans. Citro- + kvapky is available in Po- land and Slovakia without 50 30 GBF (% control) prescription and it does not ++ cause any side effects nor MEAN LESION AREA (mm 25 inhibits gastric acid secre- tion (Fig. 3). 0 0 In another report, narin- VehGSE Veh GSE CGRP (32 mg/kg i.g.) (32 mg/kg i.g.)(10 µg/kg s.c.) genin, a major GSE fla- + CAPSAICIN DENERVATION vonoid, was reported to ex- hibit gastroprotection against Fig. 3. Mean area of 100% ethanol-induced gastric lesions and the gastric blood the gastric injury induced by flow (expressed as percent of control) in rats without (vehicle only) and with absolute ethanol predomi- pretreatment with graded doses of grapefruit seed extract (GSE) (upper panel) nantly due to the increase and effects of capsaicin denervation without or with addition of calcitonin-gene related peptide (CGRP) (lower panel). Each column is a mean (± SEM) of 5-8 in the mucus secretion [43]. rats. Asterisk indicates significant (P < 0.05) change as compared to the vehicle It is of interest that this (control) values.

122 ISSN 0201-8489 Ô³ç³îë. æóðí., 2004, Ò. 50, ¹ 6 Zayachkivska O. S., Konturek S.J., Drozdowicz D., Brzozowski T., Gzhegotsky M.R. meciadanol, a synthetic flavonoid, similar to on sensory neurons to stimulate their memb- catechin flavonoid, that inhibits histidine de- rane receptors and release various kinins such carboxylase and decreases histamine content as CGRP and substance P. When applied in in the stomach, attenuated gastric mucosal large dose, it destroys selectively C-fiber lesions produced by ethanol and aspirin via neurons leading to inactivation of sensory mechanism independent of gastric acid secre- nerves and the loss of all reflexes in which tion and endogenous prostaglandins (PG) [47]. these nerves are involved. In smaller dose, One of the most interesting substances that capsaicin is the potent gastroprotective agent has been obtained from chilly peppers and is and stimulant of gastric microcirculation. present in spicy plants such as ginger or black According to our experience (Fig 4), capsaicin pepper is capsaicin [8]. This substance acts in dose range from 0.1 to o.5 mg/kg given ig 100 50 reduced dose-dependently the ethanol-induced acute gastric

) hemorrhagic lesions and this 2 80 40 is accompanied by the dose- dependent increase in gastric 60 30 microcirculation. These ef- fects can be abolished, also

40 20 dose-dependently, by the pre- treatment with L-NNA that GBF (% control) reverses also the gastric hy- 20 10 MEAN LESION AREA (mm peremic effects of capsaicin. Capsaicin is ineffective in 0 0 rats with inactivated sensory Veh 0,12 0,25 0,5 nerves by large dose of cap- CAPSAICIN (mg/kg i.g.) saicin (125 mg sc two weeks 80 50 before the experiment). Clini- cal usefulness of capsaicin

) has not been so far demon- 2 40 60 strated but it is an excellent tool to study the implication of 30 sensory nerves in the gastro- 40 protection induced by various gastrorpotective agents in- 20 GBF (% control) cluding GSE, amaranth and 20 various gastroprotective drugs 10 MEAN LESION AREA (mm and substances [48-51]. Table 1 summarizes the 0 0 sources of plant cytopro- Veh 1,2 2,5 5,0 tection and their known physi- L-NNA (50 mg/kg i.v.) ological actions on GIT. Data + CAPSAICIN (0,5 mg/kg i.v.) on the composition of these Fig. 4. Mean area of 100% ethanol-induced gastric lesions and the gastric blood sources include different flow (expressed as percent of control) in rats without (vehicle only) and with chemical compounds with dif- pretreatment with graded doses of capsaicin (upper panel) without and with addition of L-NNA, a NO synthase inhibitor (lower panel). Each column is a ferent molecular structures. mean (± SEM) of 5-8 rats. Asterisk indicates significant (P<0.05) change as They are represented in compared to the vehicle (control) values. Table 2.

ISSN 0201-8489 Ô³ç³îë. æóðí., 2004, Ò. 50, ¹ 6 123 Influence of plant-originated gastroprotective

Table 1. Pharmacological actions and plant-originated Table 2. Active constituents in plant gastroprotectors cytoprotectors Active substances Sources Physiological actions Origins Polysacchrides Opunta ficus indica cla- Gastroprotective Grapefruit (Citrus dodes and antiulcer paradisi) seeds Flavonoids Erica andevalensis Cabe- Panax ginseng zudo-Rivera Induced changes in amount Erica andevalensis Cabe Garcinia kola seeds (kola- and glycoprotein content zudo-Rivera viron) of gastric mucus UL-409, herbal formula- Achyrocline satureioides tion Silydum marianum Scutellaria baicalensis Preventive and curative Sea buckthorn (Hippo- effects phae rhammoides L.) Proanthocyanidins Grape seeds extract Grape skin extract Inhibition the basal and Azadirachta indica histamine-induced Chinese cinnamon Polyphenolic natural Neem (Azadiracta indica) gastric acid secretion Phellodendron amurense compound Curcumin Ruprecht Diterpnes Tasmannia Lanceolata NO-induced rise in Gingi biloba Egletes viscosa mucosal blood flow Silybum marianum Sesquiterpenes Petasites hybridus Grapefruit seeds Emblica officinalis Bacopa monniera Grape seeds Saponins Hippocrata excelsa Mucus and alkaline Tasmannia lanceolata Scvalen Amaranth secretion Bacopa monniera Sitosterol Egletes viscosaless Azadirachta indica Mikania cordata Ternatin Horse chestnuts Solon (Sophoradin) Escins Cinnamonum cassia Prostaglandin release Tamannia lanceolata Petasites hybridus Berberine Phellodendron amureuse Ruta chalepensis L. (Ru- Ruprecht taceae) Hepatoprotective Tinospora bakis (Menisoer- 2. The mechanism of this protection is maceae) closely related to the increase in gastric mi- Premma tomentosa (L. Ver- crocirculation probably caused by stimulation banacae) of afferent nerves and release of NO in the Anticancerogenic Grapefruit seeds mucosa because the protection and gastric Garsinia kola hyperemia could be significantly attenuated Grape seeds following the inactivation of neurotoxic dose CONCLUSIONS of capsaicin and the application of NOS in- hibitor, L-NNA; 1. We demonstrated that plant-originated sub- 3. This study provides evidence that ex- stances such as Solon – Sophoradin root orig- tracts originating from the plants used in inated flavonoid, seed extract of Amaranth, ancient herbal medicine appear to contain extract of grapefruit seeds - Citro kvapky, and highly effective, but unfortunately little capsaicin present in chilly pepper, all exerted studied in humans substances, most likely beneficial and dose-dependent reduction in flavonoids, that are capable of protecting acute gastric lesions induced by corrosive gastric mucosa from necrotizing substances concentration (100%) of ethanol and this re- and possibly are useful in the therapy of duction was accompanied by dose-dependent acute and chronic gastric ulcerations. Only rise in gastric blood flow; Solon is now widely used in gastritis and

124 ISSN 0201-8489 Ô³ç³îë. æóðí., 2004, Ò. 50, ¹ 6 Zayachkivska O. S., Konturek S.J., Drozdowicz D., Brzozowski T., Gzhegotsky M.R. peptic ulcer therapy in certain countries. 3. Bagchi D. , Bagchi M. , Stohs S. et al. Cellular protec- Acknowledgement: To Prof. W. Pawlik for invalu- tion with proanthocyanidins derived from grape seeds able assistance with research in Jagiellonian Uni- // Ann N. Y. Acad. Sci. – 2002. – 957. – P. 260–270. 4. Bagchi D., Ray S.D., Bagchi M., Preuss H.G., Stohs versity. S.J. Mechanistic pathways of antioxidant cyto- Source of support: Department resources/ protection by a novel IH636 grape seed proantho- cyanidin extract // Indian J. Exp. Biol. – 2002.– 40(6). – O.S. Zayachkivska, S.J. Konturek, D. Drozdowicz, P. 717–726. 5. Bagchi D., Sen C.K., Ray S.D. et al. Molecular mecha- T. Brzozowski, M.R. Gzhegotsky nisms of cardioprotection by novel grape seed INFLUENCE OF PLANT-ORIGINATED proanthoceanidin extract // Mutat Res. – 2003. – 523– GASTROPROTECTIVE AND ANTIULCER 524. – P. 87–97.92. SUBSTANCES ON GASTRIC MUCOSAL REPAIR 6. Bandyopadhyay U., Biswas K., Chatterjee R. et al. Gastroprotective effects of Neem (Azadirachta indica) Fundamental basis of cellular and molecular mechanisms bark extract: possible involment of H(+)–K(+)–AT- involved in mucosal injury and repair in gastrointestinal tract Pase inhibition and scavenging of hydroxyl radical // helps to develop new therapeutic approaches to various gut Life Sci.– 2002.– 71(24).–P. 2845–2865. mucosal injury- related diseases. The study was aimed to as- 7. Bickel D., Roder T., Bestman H.J., Brune K. Identifi- sess the relations between plant-originated substances and cation and characterization of inhibitiors of peptido- their bioactivity measured in terms of antioxidant, cyto- leukotrienes syntesis from Petasites hybridus// Planta protective and antiulceric activities and to determinate if these Med. – 1994. – 60(4). – P. 318–322. effects are capable of affecting the gastric mucosal lesions 8. Blankson H., Grotterod E.M., Seglen P.O. Prevention induced by absolute ethanol applied intragastrically. The fol- of toxin-induced cytoskeletal disruption and apoptotic lowing plant-originated substances were considered: Solon, liver cell death by the grapefruit flavonoid, naringin // capsaicin, grapefruit-seed extract and amaranth. The area of Cell Death Differ. – 2000. – 7. – P. 739–746. gastric mucosa lesions and gastric blood flow were measured 9. Brzozowski T., Konturek P.C., ²liwowski Z. et al. in rats with ethanol-induced lesions without (control) and with Importance of nitric oxide and capsaicin-sensitive af- one of the tested substances without and with capsaicin dene- ferent nerves in healing of stress lesions induced by rvation of afferent nerves or administration of L-nitro-arginine epidermal growth factor // J. Clin Gastroenterol. – (L-NNA), an inhibitor of nitric oxide synthase (NOS). 1997. – 25 (1). – P. 28–38. Material/Methods: male Wistar rats, weighing 180-220 g fasted 10. Chao J.C., Hung H.C., Chen S.H., Fang C.L. Effects of for 24 h before the study, 100% ethanol was applied ig to Ginkgo biloba extract on cytoprotective factors in rats induced gastric lesions, whose area was determined by with duodenal ulcer // World J. Gastroenterol. – 2004. – planimetry. Gastric blood flow was assessed using electro- 10(4). – P. 560–566. lytic regional blood flowmeter. 11. Dorababu M., Prabha T., Priyambada S., Agrawal V.K., Results: All tested plant-originated substances afforded Aryya N.C., Goel R.K. Effect of Bacopa monniera gastroprotection against ethanol-induced damage and this was and Azadirachta indica on gastric ulceration and heal- accompanied by an increase in gastric microcirculation, both ing in experimental NIDDM rats // Indian J. Exp. Biol. – changes being reversed by pretreatment with neurotoxic dose 2004. – 42(4). – P.389–397. of capsaicin or by pretreatment with L-NNA. 12. Farombi E.O., Alabi M.C., Akuru T.O. Kolaviron Conclusions: Plant-originated substances are highly modulates cellular redox status and impairment of gastroprotective probably due to enhancement of the expres- membrane protein activities induced by potassium bro- sion of NOS I, NO release and an increase in gastric microcir- mate (KbrO(3)) in rats // Pharmacol Res. – 2002. – culation. 45(1). – P. 63–68. 13. Farombi E.O., Hansen M., Ravn-Haren G. et al. 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DepartmLviv National Medical University, Ukraine; Paper vas submited Jagiellonian University College of Medicine, Cracow, Poland 21.10.2004

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