Tryptamine-gallic acid hybrid prevents non-steroidal anti-inflammatory drug-induced gastropathy: correction of mitochondrial dysfunction and inhibition of apoptosis in gastric mucosal cells

Pal, C. ; Bindu, S. ; Dey, S. ; Alam, A. ; Goyal, M. ; Iqbal, M. S. ; Sarkar, S. ; Kumar, R. ; Halder, K. K. ; Debnath, M. C. ; Adhikari, S. ; Bandyopadhyay, U. (2012) Tryptamine-gallic acid hybrid prevents non-steroidal anti-inflammatory drug-induced gastropathy: correction of mitochondrial dysfunction and inhibition of apoptosis in gastric mucosal cells Journal of Biological Chemistry, 287 (5). pp. 3495-3509. ISSN 0021-9258

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Official URL: http://www.jbc.org/content/287/5/3495.full

Related URL: http://dx.doi.org/10.1074/jbc.M111.307199

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 (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.

Item Type:Article
Source:Copyright of this article belongs to American Society for Biochemistry and Molecular Biology.
Keywords:Mitochondria; Mitochondrial Apoptosis; Oxidative Stress; Reactive Oxygen Species (ROS); Small Molecules; Gastropathy; Dysfunction; Radiolabeling
ID Code:98494
Deposited On:12 Aug 2014 10:37
Last Modified:12 Aug 2014 10:37

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