Mechanism of Action of Multi–Potent Ulcer Blockers in In Vitro and In Vivo Models

Ulcer is a common global problem with increasing incidence and prevalence.
Worldwide 14.5 million people have ulcers with a mortality of 4.08 million.
The increasing incidence and prevalence of ulcers have been attributed to
several factors encountered during day-to-day life, such as stress, exposure
to bacterial infection, use of non-steroidal anti-inflammatory drugs (NSAIDs)
etc. Ulcers are resulted from excess secretion of hydrochloric acid from
gastric parietal cells via activation of H+, K+ -ATPase enzyme, which releases
H+ into the lumen of the stomach leading to acidity. Released acid act on
gastric mucosa leading to loss of mucosal damage and hence impaired
mucosal protection. Gastric lesions thus develop due to loss of the delicate
balance between gastroprotective and aggressive factors. Reduction in
gastric mucin, enhanced the secretion of gastric and susceptibility to
Helicobacter pylori infection adding to the severity of the disease.
Sustainable efforts and constant research in the area lead to the
development of several drugs that can act at multi-steps during ulcer
pathogenicity such as proton pump blockers (Lansoprazole, Omeprazole),
histamine receptor blockers (Ranitidine, Cimitidine, Famotidine) and H.
pylori inhibitors (Amoxicillin, Erythromycin, Metronidazole). However,
majority of them have been documented to pose problems of adverse effects.
In the light of the above, it was pertinent to study natural products from
dietary sources as potential antiulcer compounds. In the current thesis
therefore dietary components have been explored as a potential effective and
safer antiulcer compounds. Series of commonly used dietary sources were
examined for inhibition of H+, K+ -ATPase, inhibition of H. pylori growth and
antioxidant activity. The Antiulcer index (AUI) was calculated based on the
results. Highest AUI sources – Swallow root (Decalepis hamiltonii) and Black
cumin (Nigella Sativa) were selected for further studies. Pectic polysaccharide
Abstract
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and one of the abundant Swallow root components (2-hydroxy-4-methoxy
benzaldehyde) was examined for anti-H. pylori, ulcer preventive or ulcer
healing properties. Structure - function analysis of pectic polysaccharides of
Swallow root (SRPP) and Black cumin (BCPP) revealed that galacturonan;
either arabino or rhamnogalacturonan may be responsible for the antiulcer
activity. The in vivo efficacy of these indicated that they are potent in
inhibiting 73 to 85% of either swim/ethanol stress induced ulcers.
Besides, 80 to 90% ulcer healing together with normalization of H+, K+ -
ATPase, oxidative stress, antioxidant levels were also observed. Further, the
selected components were also effective against multi-steps of H. pylori
induced pathogenicity such as colonization on gastric mucin, invasion and
cytotoxicity.
Overall, the current study for the first time provided evidence for the ability
of dietary pectic polysaccharides to elicit the signaling cascade of ulcer
prevention and healing including the multi-step inhibition of potential ulcer
pathogenic steps as indicated in scheme 1. Outcome of this study thus may
result in the potential use of dietary compounds as better gastroprotective
compounds that are safer with no side effects. Further, the ability of these
dietary factors in eliciting the signaling cascade of ulcer healing process is
quite intriguing and throws insights into the use of such compounds for
designing of gastroprotective nutraceutical for gastric ulcer patients.