title: Tryptamine-gallic acid hybrid prevents non-steroidal anti-inflammatory drug-induced gastropathy: correction of mitochondrial dysfunction and inhibition of apoptosis in gastric mucosal cells.
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.
authors.affiliation: Division of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata-700032, West Bengal, India.
authors.forename: Chinmay
authors.initials: C
authors.lastname: Pal
authors.forename: Samik
authors.initials: S
authors.lastname: Bindu
authors.forename: Sumanta
authors.initials: S
authors.lastname: Dey
authors.forename: Athar
authors.initials: A
authors.lastname: Alam
authors.forename: Manish
authors.initials: M
authors.lastname: Goyal
authors.forename: Mohd Shameel
authors.initials: MS
authors.lastname: Iqbal
authors.forename: Souvik
authors.initials: S
authors.lastname: Sarkar
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.forename: Kamal Krishna
authors.initials: KK
authors.lastname: Halder
authors.forename: Mita Chatterjee
authors.initials: MC
authors.lastname: Debnath
authors.forename: Susanta
authors.initials: S
authors.lastname: Adhikari
authors.forename: Uday
authors.initials: U
authors.lastname: Bandyopadhyay
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005707:Gallic Acid / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013272:Stomach Diseases / Q000139:chemically induced* / Q000188:drug therapy*; D013481:Superoxides / Q000378:metabolism; D014363:Tryptamines / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C494828:Bax protein, rat; D045222:Electron Transport Chain Complex Proteins; D014363:Tryptamines; D051028:bcl-2-Associated X Protein; D013481:Superoxides; C030820:tryptamine; D005707:Gallic Acid; D007213:Indomethacin