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Pharmacological correction of stress-induced gastric ulceration by novel small-molecule agents with antioxidant profile.

Kudryavtsev KV, Markevich AO, Virchenko OV, Falalyeyeva TM, Beregova TV, Ostapchenko LI, Zabolotnev DV, Zefirov NS - ScientificWorldJournal (2014)

Bottom Line: Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats.Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions.Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline at least partially depends on the correction of gastric mucosa oxidative balance.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow 119991, Russia ; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Russia.

ABSTRACT
This study was designed to determine novel small-molecule agents influencing the pathogenesis of gastric lesions induced by stress. To achieve this goal, four novel organic compounds containing structural fragments with known antioxidant activity were synthesized, characterized by physicochemical methods, and evaluated in vivo at water immersion restraint conditions. The levels of lipid peroxidation products and activities of antioxidative system enzymes were measured in gastric mucosa and correlated with the observed gastroprotective activity of the active compounds. Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats. Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions. Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline at least partially depends on the correction of gastric mucosa oxidative balance.

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Related in: MedlinePlus

Structural formula of small-molecule agents synthesized and studied in the present work. Substructures with known antioxidant activity are shown in red.
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Related In: Results  -  Collection


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fig1: Structural formula of small-molecule agents synthesized and studied in the present work. Substructures with known antioxidant activity are shown in red.

Mentions: The relationship between severe physiological stress and gastrointestinal (GI) ulceration is well recognized. Different types of GI injuries ranging from superficial to focal deep mucosal damages are considered as stress-related mucosal disease (SRMD) [1]. Stress ulcers differ from ordinary peptic ulcers in risk factors and symptoms. Usually SRMD is not associated with abdominal pain as in the case of peptic ulcers and induced lesions remit after the patient recovers. Common antiulcer medicines like histamine2-receptor antagonists (H2RAs) and proton pump inhibitors (PPI) have several drug interactions and adverse effects that limits their usage for the prevention of SRMD [1, 2]. There are strong suggestions that not only physical but also psychological stress is an important pathogenic factor for gastric ulceration [3]. Accordingly, development of novel agents influenced stress-related GI lesions is highly desired. Typically, primary mucosal erosions are referred to as stress-related injury (SRI) and, namely, stress ulcers represent focal deep mucosal damages with a high risk for bleeding. The main risk factors of SRMD bleedings are respiratory failure and coagulopathy [1]. Insufficient blood microcirculation in the upper GI tissues is considered as the major cause of mucosal defense reduction leading to the ulcer formation. Reactive oxygen species (ROS), such as superoxide anion O2•−, hydrogen peroxide H2O2, and hydroxyl radical HO•, accompany ischemic tissue events and are suggested as mediators of GI injuries of different etiology including stress-induced lesions [4]. ROS trigger lipid peroxidation (LPO) with subsequent loss of membrane fluidity, weakened ion transport and membrane integrity, and finally loss of cellular functions. Attenuating of ROS has been detected for several gastroprotective small-molecule drugs, such as rebamipide [5], melatonin [6], and omeprazole [7], and could be considered as an approach for the treatment of ulcerative GI pathologies. To determine correlations between oxidative and ulcerogenic factors, we studied effects of novel small-molecule organic compounds 1–4 (Figure 1) on SRI and ulceration progress in rats subjected to water immersion restraint as a stress conditions model.


Pharmacological correction of stress-induced gastric ulceration by novel small-molecule agents with antioxidant profile.

Kudryavtsev KV, Markevich AO, Virchenko OV, Falalyeyeva TM, Beregova TV, Ostapchenko LI, Zabolotnev DV, Zefirov NS - ScientificWorldJournal (2014)

Structural formula of small-molecule agents synthesized and studied in the present work. Substructures with known antioxidant activity are shown in red.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3934458&req=5

fig1: Structural formula of small-molecule agents synthesized and studied in the present work. Substructures with known antioxidant activity are shown in red.
Mentions: The relationship between severe physiological stress and gastrointestinal (GI) ulceration is well recognized. Different types of GI injuries ranging from superficial to focal deep mucosal damages are considered as stress-related mucosal disease (SRMD) [1]. Stress ulcers differ from ordinary peptic ulcers in risk factors and symptoms. Usually SRMD is not associated with abdominal pain as in the case of peptic ulcers and induced lesions remit after the patient recovers. Common antiulcer medicines like histamine2-receptor antagonists (H2RAs) and proton pump inhibitors (PPI) have several drug interactions and adverse effects that limits their usage for the prevention of SRMD [1, 2]. There are strong suggestions that not only physical but also psychological stress is an important pathogenic factor for gastric ulceration [3]. Accordingly, development of novel agents influenced stress-related GI lesions is highly desired. Typically, primary mucosal erosions are referred to as stress-related injury (SRI) and, namely, stress ulcers represent focal deep mucosal damages with a high risk for bleeding. The main risk factors of SRMD bleedings are respiratory failure and coagulopathy [1]. Insufficient blood microcirculation in the upper GI tissues is considered as the major cause of mucosal defense reduction leading to the ulcer formation. Reactive oxygen species (ROS), such as superoxide anion O2•−, hydrogen peroxide H2O2, and hydroxyl radical HO•, accompany ischemic tissue events and are suggested as mediators of GI injuries of different etiology including stress-induced lesions [4]. ROS trigger lipid peroxidation (LPO) with subsequent loss of membrane fluidity, weakened ion transport and membrane integrity, and finally loss of cellular functions. Attenuating of ROS has been detected for several gastroprotective small-molecule drugs, such as rebamipide [5], melatonin [6], and omeprazole [7], and could be considered as an approach for the treatment of ulcerative GI pathologies. To determine correlations between oxidative and ulcerogenic factors, we studied effects of novel small-molecule organic compounds 1–4 (Figure 1) on SRI and ulceration progress in rats subjected to water immersion restraint as a stress conditions model.

Bottom Line: Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats.Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions.Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline at least partially depends on the correction of gastric mucosa oxidative balance.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, M.V. Lomonosov Moscow State University, Moscow 119991, Russia ; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Russia.

ABSTRACT
This study was designed to determine novel small-molecule agents influencing the pathogenesis of gastric lesions induced by stress. To achieve this goal, four novel organic compounds containing structural fragments with known antioxidant activity were synthesized, characterized by physicochemical methods, and evaluated in vivo at water immersion restraint conditions. The levels of lipid peroxidation products and activities of antioxidative system enzymes were measured in gastric mucosa and correlated with the observed gastroprotective activity of the active compounds. Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats. Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions. Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline at least partially depends on the correction of gastric mucosa oxidative balance.

Show MeSH
Related in: MedlinePlus