Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences on mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts

ABSTRACT

Introduction

Carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) are extensively used worldwide due to their antipyretic, analgesic, and anti-inflammatory effects. CBA-NSAIDs have reasonable margin of safety at therapeutic doses, and in the current climate, do not possess addiction potential like opioid drugs. Studies have revealed that various adverse events of CBA-NSAIDs are related mitochondrial dysfunction and oxidative stress.

Areas covered

This review article summarizes adverse events induced by CBA-NSAIDs, mechanisms of mitochondrial damage, oxidative stress, and metabolic interactions. Meanwhile, this review discusses the treatment and prevention of CBA-NSAIDs damage by natural plant extracts based on antioxidant effects.

Expert opinion

CBA-NSAIDs can induce reactive oxygen species (ROS) production, mediate DNA, protein and lipid damage, lead to imbalance of cell antioxidant status, change of mitochondrial membrane potential, activate oxidative stress signal pathway, thus leading to oxidative stress and cell damage. Adverse events caused by CBA-NSAIDs often exhibit dose and time dependence. In order to avoid adverse events caused by CBA-NSAIDs, it is necessary to provide detailed patient consultation and eliminate influencing factors. Moreover, constructive research studies on the organ-specific toxicity and mechanism of natural plant extracts in preventing and treating metabolic abnormalities of CBA-NSAIDs, will provide important value for warning and guidance for use of CBA-NSAIDs.

KEYWORDS:

• Carboxylic acid NSAIDs
• oxidative stress
• mitochondrial dysfunction
• adverse events
• metabolism

Article highlights

• Non-steroidal drugs (NSAIDs) have been widely recognized worldwide for their antipyretic, analgesic, and anti-inflammatory effects, with carboxylic acid NSAIDs (CBA-NSAIDs) being the most commonly used. CBA-NSAIDs typically have reasonable safety at therapeutic doses. However, high doses and residual CBA-NSAIDs in the environment may cause damage to animals and even non-target organisms.

• Some CBA-NSAIDs can produce reactive oxygen species (ROS), reactive nitrogen species (RNS), and other substances during the metabolic process, leading to the production of oxidative stress and related toxicity. The generation of ROS and RNS plays a very important role in the oxidative stress and related toxicity induced by CBA-NSAIDs.

• CBA-NSAIDs can cause significant changes in antioxidant status in both in vivo and in vitro models, including the expression of major antioxidant enzymes CAT, SOD, GSH, GPx, GR, and GST, antioxidant pathways, and related genes. Causing oxidative stress, this may lead to damage to cellular macromolecules, causing damage to DNA, lipids, proteins, and other toxic effects, resulting in cell apoptosis.

• Currently, there are various compounds available to combat the toxicity caused by CBA-NSAIDs. Although most of these compounds are antioxidants, there are also some natural plant extracts with antioxidant properties.

• The enzymes that metabolize CBA-NSAIDs mainly include CYP1A2, CYP3A4, CYP2E1, and CYP2C9. The metabolites half-life, of CBA-NSAIDs may vary in different animals, and the metabolites of CBA-NSAIDs can also lead to oxidative stress.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (NSFC) (32072925) and Major Special Science and Technology Plan (202302AA310020) and Project Ref. PID 2020-115979RR-C33 from the Ministerio de Ciencia e Innovación, Spain (Project/AEI/10.13039/501100011033).

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.