Journal
NEUROTOXICITY RESEARCH
Volume 36, Issue 3, Pages 551-562Publisher
SPRINGER
DOI: 10.1007/s12640-019-00044-8
Keywords
Carnosic acid; Glutamate; Excitotoxicity; Mitochondria; Nrf2; Antioxidant
Categories
Funding
- CNPq (Edital Universal 2016)
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) (Brazil) [001]
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Mitochondria are the major site of adenosine triphosphate (ATP) production in mammalian cells. Moreover, mitochondria produce most of the reactive oxygen species (ROS) in nucleated cells. Redox and bioenergetic abnormalities have been seen in mitochondria during the onset and progression of neurodegenerative diseases. In that context, excitotoxicity induced by glutamate (GLU) plays an important role in mediating neurotoxicity. Several drugs have been used in the treatment of diseases involving excitotoxicity. Nonetheless, some patients (20-30%) present drug resistance. Thus, it is necessary to find chemicals able to attenuate mitochondrial dysfunction in the case of excitotoxicity. In this work, we treated the human neuroblastoma SH-SY5Y cell line with the diterpene carnosic acid (CA) at 1 mu M for 12 h prior to the exposure to GLU for further 24 h. We found that CA prevented the GLU-induced mitochondrion-related redox impairment and bioenergetic decline in SH-SY5Y cells. CA also downregulated the pro-apoptotic stimulus elicited by GLU in this experimental model. CA exerted mitochondrial protection by a mechanism associated with the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), since silencing of this protein with small interfering RNA (siRNA) suppressed the CA-induced protective effects. Future directions include investigating whether CA would be able to modulate mitochondrial function and/or dynamics in in vivo experimental models of excitotoxicity.
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