Oxidative stress induced by realgar in neurons: p38 MAPK and ERK1/2 perturb autophagy and induce the p62-Keap1-Nrf2 feedback loop to activate the Nrf2 signalling pathway.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:

Due to the modernization of traditional Chinese medicine (TCM) and the influence of traditional medication habits (TCM has no toxicity or side effects), arsenic poisoning incidents caused by the abuse of realgar and realgar-containing Chinese patent medicines have occurred occasionally. However, the potential mechanism of central nervous system toxicity of realgar remains unclear.

AIM OF THE STUDY:

This study aimed to clarify the specific mechanism of realgar-induced neurotoxicity.

MATERIALS AND METHODS:

In this study, the roles of ERK1/2 and p38 MAPK in realgar-induced neuronal autophagy and overactivation of the nuclear factor erythroid-derived factor 2-related factor (Nrf2) signalling pathways was investigated in vivo and in vitro.

RESULTS:

The arsenic in realgar passed through the blood-brain barrier and accumulated in the brain, resulting in damage to neurons, synapses and myelin sheaths in the cerebral cortex and a decrease in the total antioxidant capacity. The specific mechanism is that the excessive activation of Nrf2 is regulated by the upstream signalling molecules ERK1/2 and p38MAPK. At the same time, p38 MAPK and ERK1/2 interfere with autophagy, thereby promoting autophagy initiation but causing subsequent dysfunctional autophagic degradation and inducing the p62-Keap1-Nrf2 feedback loop to promote Nrf2 signalling pathway activation and nerve cell apoptosis.

CONCLUSIONS:

This study confirmed the role of the signalling molecules p38 MAPK and ERK1/2 in perturbing autophagy and inducing the p62-Keap1-Nrf2 feedback loop to activate the Nrf2 signalling pathway in realgar-induced neurotoxicity.

• Authors: Yuan Meng, Rui Feng, Zhao Yang, Tingting Liu, Taoguang Huo, Hong Jiang
• Journal: Journal of ethnopharmacology (J Ethnopharmacol) Vol. 282 Pg. 114582 (Jan 10 2022) ISSN: 1872-7573 [Electronic] Ireland
• PMID: 34492322 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier B.V.

Chemical References

• Arsenicals
• Gtf2h1 protein, mouse
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Sulfides
• Transcription Factor TFIIH
• arsenic disulfide

Topics

• Animals
• Apoptosis (drug effects)
• Arsenic Poisoning (metabolism)
• Arsenicals (pharmacokinetics)
• Autophagy (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Kelch-Like ECH-Associated Protein 1 (metabolism)
• MAP Kinase Signaling System (drug effects)
• Medicine, Chinese Traditional
• Mice
• NF-E2-Related Factor 2 (metabolism)
• Neurons (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Rats
• Sulfides (pharmacokinetics, toxicity)
• Transcription Factor TFIIH (metabolism)