ABSTRACT
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN), and oxidative stress is thought to contribute to the pathogenesis. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway, which is a cellular defense system against oxidative stress, is a promising target for therapeutics aimed at reducing neuronal death in PD. Previously, we have isolated 2',3'-dihydroxy-4',6'-dimethoxychalcone (DDC) from green perilla leaves as an activator of the Nrf2-ARE pathway. The present study showed the protective effect of DDC on PD models in vivo and in vitro. In a 6-hydroxydopamine (6-OHDA)-induced hemiparkinson's disease mouse model, intracerebral administration of DDC suppressed the dopaminergic neuronal loss and behavioral dysfunction. DDC upregulated the expression of heme oxygenase-1 (HO-1), one of the ARE-driven antioxidant enzymes, in astrocytes and microglia of the SN. In primary mesencephalic cultures, treatment with DDC also increased the HO-1 expression in astrocytes and microglia. DDC showed a protective effect against 6-OHDA-induced dopaminergic neuronal death, and the effect was suppressed by an HO-1 inhibitor. These results suggest that DDC prevents dopaminergic neurons from oxidative stress by upregulation of glial expression of HO-1.
Subject(s)
Antioxidants/metabolism , Dopaminergic Neurons/drug effects , NF-E2-Related Factor 2/metabolism , Parkinson Disease/pathology , Perilla/chemistry , Plant Extracts/pharmacology , Plant Leaves/chemistry , Animals , Cell Death/drug effects , Disease Models, Animal , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/pathology , Gene Expression Regulation, Enzymologic/drug effects , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Male , Mice , NAD(P)H Dehydrogenase (Quinone)/genetics , NAD(P)H Dehydrogenase (Quinone)/metabolism , Neuroglia/drug effects , Neuroglia/metabolism , Neuroprotective Agents/pharmacology , Oxidopamine/toxicity , Response Elements/drug effectsABSTRACT
The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a cellular defense system against oxidative stress. Activation of this pathway increases expression of antioxidant enzymes. Epidemiological studies have demonstrated that the consumption of fruits and vegetables is associated with reduced risk of contracting a variety of human diseases. The aim of this study is to find Nrf2-ARE activators in dietary fruits and vegetables. We first attempted to compare the potency of ARE activation in six fruit and six vegetables extracts. Green perilla (Perilla frutescens var. crispa f. viridis) extract exhibited high ARE activity. We isolated the active fraction from green perilla extract through bioactivity-guided fractionation. Based on nuclear magnetic resonance and mass spectrometric analysis, the active ingredient responsible for the ARE activity was identified as 2',3'-dihydroxy-4',6'-dimethoxychalcone (DDC). DDC induced the expression of antioxidant enzymes, such as γ-glutamylcysteine synthetase (γ-GCS), NAD(P)H: quinone oxidoreductase-1 (NQO1), and heme oxygenase-1. DDC inhibited the formation of intracellular reactive oxygen species and the cytotoxicity induced by 6-hydroxydopamine. Inhibition of the p38 mitogen-activated protein kinase pathway abolished ARE activation, the induction of γ-GCS and NQO1, and the cytoprotective effect brought about by DDC. Thus, this study demonstrated that DDC contained in green perilla enhanced cellular resistance to oxidative damage through activation of the Nrf2-ARE pathway.
Subject(s)
Antioxidant Response Elements , Chalcones/isolation & purification , NF-E2-Related Factor 2/genetics , Perilla frutescens/chemistry , Plant Extracts/isolation & purification , Plant Leaves/chemistry , Transcriptional Activation/drug effects , Animals , Cell Survival/drug effects , Chalcones/pharmacology , Cytoprotection , Enzyme Induction/drug effects , Fruit/chemistry , Genes, Reporter , Glutathione/metabolism , Luciferases, Firefly/biosynthesis , Luciferases, Firefly/genetics , Molecular Structure , NAD(P)H Dehydrogenase (Quinone)/genetics , NAD(P)H Dehydrogenase (Quinone)/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress , PC12 Cells , Plant Extracts/pharmacology , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Rats , Reactive Oxygen Species/metabolism , Transcription, Genetic , Vegetables/chemistry , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
OBJECTIVE: The purpose of this study was to assess relationships between life satisfaction and lifestyle in residents of the city of Kyoto, Japan, by addressing their subjective evaluation of their own health status. METHODS: The subjects comprised 4746 men and women (15-97 years old) who had completed a questionnaire on life style in the 1998 Kyoto Citizen's Health and Nutrition Study. Stratified by their responses to subjective health, the relationship between life-satisfaction and lifestyle was evaluated by odds ratios and chi-square tests of the subjects classified by age and gender. RESULTS: The proportion of respondents who felt their subjective health was good decreased with age, while the proportion of respondents who considered their life satisfaction good increased with age. Whether the residents had good or poor subjective health, the proportion of respondents who had a healthy lifestyle, as exemplified by having breakfast everyday, having dinner with their family regularly and having a good intake of greeny-ellow vegetables increased with age in both men and women. This healthy lifestyle was also positively associated with good life satisfaction. CONCLUSION: Whether the residents had good or poor subjective health, these results suggest that thos with a healthy lifestyle feel good life satisfaction.
