Honokiol, an inducer of Sirtuin 3, protects against NSAID-induced gastric mucosal mitochondrial pathology, apoptosis and inflammatory tissue injury.

BACKGROUND AND PURPOSE: Mitochondrial oxidative stress, inflammation and apoptosis primarily underlies gastric mucosal injury by non-steroidal anti-inflammatory drugs (NSAIDs), the most unavoidable and widely used anti-inflammatory medicines. Alternative gastroprotective strategy is therefore warranted. Sirtuin-3 pivotally maintains mitochondrial structural integrity and metabolism while preventing oxidative stress; however never explored in gastric injury. We investigated whether and how Sirtuin-3 stimulation by a phytochemical, 'honokiol' (HKL), rescued NSAID-induced gastric injury.

EXPERIMENTAL APPROACH: Indomethacin (representative NSAID) was administered in rats to induce gastric injury in presence/absence of HKL. Next generation sequencing-based transcriptomics followed by functional validation identified the gastroprotective function of Sirtuin-3. Effect of HKL on oxidative stress, mitochondrial dynamics, electron transport chain function and inflammatory as well as apoptotic markers were checked by flowcytometry, immunoblotting, qRT-PCR and immunohistochemistry. Effect of indomethacin on sirtuin-3 deacetylase activity was estimated. Gastric luminal pH was measured.

KEY RESULTS: Indomethacin downregulated Sirtuin-3 to induce oxidative stress, mitochondrial hyperacetylation, OGG1 depletion, mitochondrial DNA damage, respiratory chain defect and mitochondrial fragmentation leading to severe mucosal injury. Indomethacin dose-dependently inhibited Sirtuin-3 deacetylase activity. HKL prevented mitochondrial oxidative damage and inflammatory tissue injury by attenuating indomethacin-induced depletion of both Sirtuin-3 and its transcriptional regulators PGC1α and ERRα. HKL significantly accelerated gastric wound healing and bypassed acid suppression unlike lansoprazole.

CONCLUSION AND IMPLICATIONS: Sirtuin-3 stimulation by HKL prevented as well as restored NSAID-induced gastric injury through maintaining mitochondrial integrity. HKL did not affect gastric acid secretion. Sirtuin-3 stimulation by HKL may be capitalized as a mitochondria-based, acid-independent novel gastroprotective strategy against NSAIDs.