Malabaricone C Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Ulceration by Decreasing Oxidative/Nitrative Stress and Inflammation and Promoting Angiogenic Autohealing.

Abstract

Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs), among the most commonly used drugs worldwide, are associated with gastrointestinal (GI) complications that severely limit the clinical utility of this essential class of pain medications. Here, we mechanistically dissect the protective impact of a natural product, malabaricone C (Mal C), on NSAID-induced gastropathy. Results: Mal C dose dependently diminished erosion of the stomach lining and inflammation in mice treated with NSAIDs with the protective impact translating to improvement in survival. By decreasing oxidative and nitrative stress, Mal C treatment prevented NSAID-induced mitochondrial dysfunction and cell death; nuclear factor κ-light-chain enhancer of activated B cell induction, release of proinflammatory cytokines and neutrophil infiltration; and disruptions in the vascular endothelial growth factor/endostatin balance that contributes to mucosal autohealing. Importantly, Mal C failed to impact the therapeutic anti-inflammatory properties of multiple NSAIDs in a model of acute inflammation. In all assays tested, Mal C proved as or more efficacious than the current first-line therapy for NSAID-dependent GI complications, the proton pump inhibitor omeprazole. Innovation: Given that omeprazole-mediated prophylaxis is, itself, associated with a shift in NSAID-driven GI complications from the upper GI to the lower GI system, there is a clear and present need for novel therapeutics aimed at ameliorating NSAID-induced gastropathy. Mal C provided significant protection against NSAID-induced gastric ulcerations impacting multiple critical signaling cascades contributing to inflammation, cell loss, extracellular matrix degradation, and angiogenic autohealing. Conclusion: Thus, Mal C represents a viable lead compound for the development of novel gastroprotective agents.

• Authors: Madhuri Basak, Tarun Mahata, Sreemoyee Chakraborti, Pranesh Kumar, Bolay Bhattacharya, Sandip Kumar Bandyopadhyay, Madhusudan Das, Adele Stewart, Sudipta Saha, Biswanath Maity
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 32 Issue 11 Pg. 766-784 (04 10 2020) ISSN: 1557-7716 [Electronic] United States
• PMID: 31830804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Protective Agents
• Resorcinols
• malabaricone C
• Indomethacin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage)
• Cell Death (drug effects)
• Dose-Response Relationship, Drug
• Indomethacin (administration & dosage, antagonists & inhibitors)
• Inflammation (chemically induced, drug therapy, pathology)
• Male
• Mice
• Mitochondria (drug effects, metabolism)
• Molecular Structure
• Neovascularization, Pathologic (chemically induced, drug therapy, pathology)
• Oxidative Stress (drug effects)
• Protective Agents (administration & dosage, metabolism, pharmacology)
• Resorcinols (administration & dosage, metabolism, pharmacology)
• Stomach Ulcer (chemically induced, drug therapy, pathology)
• Wound Healing (drug effects)