Characterization of the role of glutathione in repin-induced mitochondrial dysfunction, oxidative stress and dopaminergic neurotoxicity in rat pheochromocytoma (PC12) cells.

Abstract

Repin, a major constituent in extracts of the plant Centaurea repens is thought to be the active principal responsible for the development of equine nigropallidal encephalomalacia (ENE), a fatal Parkinson-like neurodegenerative disorder in horses. Although the exact mechanism by which ingestion of this weed causes ENE is uncertain, a limited body of experimental evidence suggests a critical role for the glutathione redox system. In the present study, the mechanism of repin neurotoxicity was examined in PC12 cells with a focus on determining the role of glutathione (GSH) in repin-induced mitochondrial dysfunction, oxidative stress and dopaminergic toxicity. The results demonstrate that repin reduced both cellular GSH levels and mitochondrial function in a manner that was time- and concentration-dependent. The repin-induced changes in GSH levels were found to precede the changes in mitochondrial function. Depletion of GSH with a potent GSH depletor (ethacrynic acid (EA)) and a GSH synthesis inhibitor (buthionine sulfoximine (BSO)) prior to repin treatment enhanced the repin-induced mitochondrial change. In addition, repin caused a concentration-dependent decrease in cellular dopamine levels in NGF-differentiated PC12 cells. Increases in intracellular GSH levels induced by pre-treatment with reducing agents (N-acetyl-L-cysteine or reduced glutathione) completely protected the cells from repin-induced mitochondrial and dopaminergic toxicity. Antioxidants, coenzyme-Q and ascorbic acid completely blocked repin-induced dopaminergic toxicity. These data suggest that GSH plays a critical role in repin-induced neurotoxicity and that the maintenance of neuronal redox status may prove to be a useful strategy for the prevention and/or treatment of ENE. The results support the view that GSH depletion, leading to oxidative damage and subsequent mitochondrial dysfunction, may serve as a trigger for neuronal cell death.

• Authors: Francis F Tukov, John M Rimoldi, John C Matthews
• Journal: Neurotoxicology (Neurotoxicology) Vol. 25 Issue 6 Pg. 989-99 (Dec 2004) ISSN: 0161-813X [Print] Netherlands
• PMID: 15474617 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Sesquiterpenes
• repin
• Glutathione
• Dopamine

Topics

• Animals
• Dopamine (metabolism)
• Dose-Response Relationship, Drug
• Glutathione (physiology)
• Mitochondria (drug effects, metabolism)
• Neurons (drug effects, metabolism)
• Oxidative Stress (drug effects, physiology)
• PC12 Cells
• Rats
• Sesquiterpenes (toxicity)