ABSTRACT
Oxidative stress has been confirmed as a contribution to the pathogenesis and pathophysiology of many neurological disorders such as Alzheimer's disease and Parkinson's disease. Caffeoylquinic acids (CQAs) are considered to have anti-oxidative stress ability in a previous study, but the structure-activity relationships (SARs) of CQAs in neuroprotective effects are still unclear. In the present study, we primarily expound the SARs of CQAs in counteracting H2O2-induced injury in SH-SY5Y cells. We found that CQAs (1-10) represented the protection of SH-SY5Y cells against H2O2-induced injury in varying degrees and malonyl groups could obviously increase the anti-oxidative stress ability of CQAs. Intensive studies of 4,5-O-dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid (MDCQA) indicated that the mechanisms could potentially involve activation of endogenous antioxidant enzymes and the regulation of the phosphorylation of MAPKs and AKT. In conclusion, MDCQA could serve as a neuroprotective agent with a potential to attenuate oxidative stress.
Subject(s)
Hydrogen Peroxide/toxicity , Neuroblastoma/pathology , Neuroprotection/drug effects , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Quinic Acid/analogs & derivatives , Apoptosis/drug effects , Cell Line, Tumor , Extracellular Signal-Regulated MAP Kinases/metabolism , Glutathione Peroxidase/metabolism , Humans , Malondialdehyde/metabolism , Membrane Potential, Mitochondrial/drug effects , Neuroblastoma/enzymology , Neuroprotective Agents/chemistry , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Quinic Acid/chemistry , Quinic Acid/pharmacology , Superoxide Dismutase/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
AIMS: Compound MQA (1,5-O-dicaffeoyl-3-O-[4-malic acid methyl ester]-quinic acid) is a natural derivative of caffeoylquinic acid isolated from Arctium lappa L. roots. However, we know little about the effects of MQA on the central nervous system. This study aims to investigate the neuroprotective effects and underlying mechanisms of MQA against the neurotoxicity of N-methyl-d-aspartate (NMDA). METHODS AND RESULTS: Pretreatment with MQA attenuated the loss of cell viability after SH-SY5Y cells treated with 1 mM NMDA for 30 min by MTT assay. Hoechst 33342 and Annexin V-PI double staining showed that MQA inhibited NMDA-induced apoptosis. In addition to preventing Ca(2+) influx, the potential mechanisms are associated with increases in the Bcl-2/Bax ratio, attenuation of cytochrome c release, caspase-3, caspase-9 activities, and expressions. Also, MQA inhibited NMDA-induced phosphorylation of ERK1/2, p38, and JNK1/2. Furthermore, deactivation of CREB, AKT, and GSK-3ß, upregulation of GluN2B-containing NMDA receptors (NMDARs), and downregulation of GluN2A-containing NMDARs were significantly reversed by MQA treatment. Computational docking simulation indicates that MQA possesses a well affinity for NMDARs. CONCLUSION: The protective effects of MQA against NMDA-induced cell injury may be mediated by blocking NMDARs. The potential mechanisms are related with mitochondrial apoptosis, ERK-CREB, AKT/GSK-3ß, p38, and JNK1/2 pathway.
Subject(s)
Apoptosis/drug effects , Caffeic Acids/pharmacology , Excitatory Amino Acid Agonists/toxicity , Malates/pharmacology , N-Methylaspartate/toxicity , Neuroprotective Agents/pharmacology , Annexin A5/metabolism , Calcium/metabolism , Caspase 3/metabolism , Caspase 9/metabolism , Cell Line, Tumor , Chlorogenic Acid/analogs & derivatives , Chlorogenic Acid/pharmacology , Dizocilpine Maleate/pharmacology , Dose-Response Relationship, Drug , Flow Cytometry , Gene Expression Regulation/drug effects , Glycogen Synthase Kinase 3/genetics , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Humans , L-Lactate Dehydrogenase/metabolism , Neuroblastoma/pathology , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction/drug effectsABSTRACT
Many studies have shown that glutamate-induced oxidative stress can lead to neuronal cell death involved in the development of neurodegenerative diseases. In this work, protective effects of ethyl acetate extract (EAE) of Arctium lappa L. roots against glutamate-induced oxidative stress in PC12 cells were evaluated. Also, the effects of EAE on antioxidant system, mitochondrial pathway, and signal transduction pathway were explored. Pretreatment with EAE significantly increased cell viability, activities of GSH-Px and SOD, mitochondrial membrane potential and reduced LDH leakage, ROS formation, and nuclear condensation in a dose-dependent manner. Furthermore, western blot results revealed that EAE increased the Bcl-2/Bax ratio, and inhibited the up-regulation of caspase-3, release of cytochrome c, phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). Therefore, our results indicate that EAE may be a promising neuroprotective agent for the prevention and treatment of neurodegenerative diseases implicated with oxidative stress.
