Tryptamine-Gallic Acid Hybrid Prevents Non-steroidal Anti-inflammatory Drug-induced Gastropathy

• Published in: The Journal of biological chemistry 2012-01, Vol.287 (5), p.3495-3509
• Main Authors: Pal, Chinmay, Bindu, Samik, Dey, Sumanta, Alam, Athar, Goyal, Manish, Iqbal, Mohd. Shameel, Sarkar, Souvik, Kumar, Rahul, Halder, Kamal Krishna, Debnath, Mita Chatterjee, Adhikari, Susanta, Bandyopadhyay, Uday
• Format: Article
• Language: English
• Subjects: Dysfunction; Gastropathy; Mitochondria; Mitochondrial Apoptosis; Oxidative Stress; Radiolabeling; Reactive Oxygen Species (ROS); Small Molecules
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.307199

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O2̇̄) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled (99mTc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy. Background: Non-steroidal anti-inflammatory drugs (NSAIDs) induce gastropathy by promoting mitochondrial pathology, oxidative stress, and apoptosis in gastric mucosal cells. Results: We have synthesized SEGA (3a), a tryptamine-gallic acid hybrid, which prevents NSAID-induced gastropathy by preventing mitochondrial oxidative stress, dysfunction, and apoptosis. Conclusion: SEGA (3a) bears an immense therapeutic potential against NSAID-induced gastropathy. Significance: This novel molecule is a significant addition in the discovery of gastroprotective drugs.