Abstract
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 (O(2)(·-)) 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 ((99m)Tc-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.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) induce gastropathy by promoting mitochondrial pathology, oxidative stress, and apoptosis in gastric mucosal cells
The results clearly indicate that SEGA (3a) shows a reducing ability (Fe(III) to Fe(II)) that is much better than GASE (4d) (Table 1)
The results indicate that SEGA (3a) shows greater DPPH scavenging potency compared with GASE (4d) (Table 1)
Summary
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. Significance: This novel molecule is a significant addition in the discovery of gastroprotective drugs. We have investigated the gastroprotective effect of SEGA (3a), NSAIDs2 are the most popular drugs commonly used a newly synthesized tryptamine-gallic acid hybrid molecule throughout the world for the treatment of pain, inflammation, against non-steroidal anti-inflammatory drug (NSAID)-in- rheumatic disorders, and osteoarthritis [1, 2]. Howindomethacin (NSAID)-induced mitochondrial oxidative stress ever, NSAIDs have limitations; they induces gastropathy, and (MOS) and dysfunctions in gastric mucosal cells, which play a ϳ107,000 patients are hospitalized every year due to NSAID-
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