Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells.

Abstract

Glycation, a process that occurs endogenously and generates advanced glycation end products (AGEs), presents an important role in cases of neurodegeneration, as for instance Alzheimer's disease (AD). Methylglyoxal (MG), a dicarbonyl compound, is the most potent inducer of AGEs, whose levels have been found increased in samples obtained from subjects suffering from AD. Moreover, MG induces protein cross-linking and redox impairment in vitro and in vivo. Carnosic acid (CA), a phenolic diterpene isolated from Rosmarinus officinalis, exerts protective effects in neuronal cells by increasing antioxidant defenses and detoxification systems. In the present work, we aimed to investigate whether there is a role for CA against MG-induced neurotoxicity. Data obtained here clearly demonstrate that CA pretreatment (1 μM for 12 h) caused cytoprotective effects and counteracted the damage elicited by MG in SH-SY5Y cells. CA inhibited loss of mitochondrial membrane polarity (MMP) and cytochrome c release from mitochondria, consequently blocking activation of pro-apoptotic caspase enzymes. Furthermore, CA alleviated MG-induced oxidative and nitrosative damage. CA prevented MG-dependent neurotoxicity by activating the PI3K/Akt/Nrf2 signaling pathway and the antioxidant enzymes modulated by Nrf2 transcription factor. Overall, the data presented here show the protective role of CA by its ability to counteract MG negative effects.

• Authors: Marcos Roberto de Oliveira, Gustavo Costa Ferreira, Patrícia Fernanda Schuck, Simone Morelo Dal Bosco
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 242 Pg. 396-406 (Dec 05 2015) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 26577515 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Abietanes
• Antioxidants
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Neurotoxins
• Pyruvaldehyde
• Proto-Oncogene Proteins c-akt
• salvin

Topics

• Abietanes (pharmacology)
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cytoprotection (drug effects)
• Humans
• NF-E2-Related Factor 2 (metabolism)
• Neuroblastoma (pathology)
• Neurons (cytology, drug effects, enzymology, metabolism)
• Neurotoxins (toxicity)
• Oxidation-Reduction (drug effects)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyruvaldehyde (toxicity)
• Signal Transduction (drug effects)
• Time Factors