Melatonin reduces indomethacin‐induced gastric mucosal cell apoptosis by preventing mitochondrial oxidative stress and the activation of mitochondrial pathway of apoptosis

Abstract

Augmentation of gastric mucosal cell apoptosis due to development of oxidative stress is one of the main pathogenic events in the development of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. Identification of a nontoxic, anti-apoptotic molecule is warranted for therapy against NSAID-induced gastropathy. The objective of the present study was to define the mechanism of the anti-apoptotic effect of melatonin, a nontoxic molecule which scavenges reactive oxygen species. Using an array of experimental approaches, we have shown that melatonin prevents the development of mitochondrial oxidative stress and activation of mitochondrial pathway of apoptosis induced by indomethacin (a NSAID) in the gastric mucosa. Melatonin inhibits the important steps of indomethacin-induced activation of mitochondrial pathway of apoptosis such as upregulation of the expression of Bax and Bak, and the downregulation of Bcl-2 and BclxL. Melatonin also prevents indomethacin-induced mitochondrial translocation of Bax and prevents the collapse of mitochondrial membrane potential. Moreover, melatonin reduces indomethacin-mediated activation of caspase-9 and caspase-3 by blocking the release of cytochrome c and finally rescues gastric mucosal cells from indomethacin-induced apoptosis as measured by the TUNEL assay. Histologic studies of gastric mucosa further document that melatonin almost completely protects against gastric damage induced by indomethacin. Thus, melatonin has significant anti-apoptotic effects to protect gastric mucosa from NSAID-induced apoptosis and gastropathy, which makes its use as potential therapy against gastric damage during NSAID treatment.

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

“…The animals, which were not treated with SEGA (3a) and received only indomethacin, served as the autohealing group. Starting from 0 h, the stomach was dissected out from all groups at intervals of 2, 4, 8, and 24 h, respectively, for measuring injury index as described (6,12) and histological studies.…”

Melatonin: A pleiotropic molecule regulating inflammation

“…Indeed, many studies have demonstrated that its anti-apoptotic effect involves the down-regulation of Bax [110][111][112][113] and /or the up-regulation of Bcl-2 [110,114,115] that occurs via activation of NF-B [115]. Besides altering their abundance, melatonin could alter Bax and Bcl-2 activity in other ways.…”

Melatonin modulates the expression of BCL-xl and improve the development of vitrified embryos obtained by IVF in mice

“…In the response to oxidative stress, the functional balance of Pro-apoptotic (Bax, Bak, Bad) and anti-apoptotic (Bcl-2, Bclw, Bcl-xl) mitochondrial proteins are altered which eventually lead to apoptosis [9].…”