Suppression of 6-Hydroxydopamine-Induced Oxidative Stress by Hyperoside Via Activation of Nrf2/HO-1 Signaling in Dopaminergic Neurons

• Published in: International journal of molecular sciences Vol. 20; no. 23; p. 5832
• Main Authors: Kwon, Seung-Hwan, Lee, Seoung Rak, Park, Yong Joo, Ra, Moonjin, Lee, Yongjun, Pang, Changhyun, Kim, Ki Hyun
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20-11-2019; MDPI
• Subjects: 6-Hydroxydopamine; Acer - chemistry; acer tegmentosum; Acids; Antioxidants; Antioxidants - pharmacology; Apoptosis; Cell Line, Tumor; Cell viability; Chromatography; Cytotoxicity; Death; Dementia; Dopamine receptors; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Enzymes; Galactosides; Heme; Heme oxygenase (decyclizing); heme oxygenase-1; Heme Oxygenase-1 - metabolism; Humans; hyperoside; Investigations; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Liver diseases; Membrane potential; Metabolites; Mitochondria; Natural products; Neuroblastoma; Neurons; Neuroprotection; Neuroprotective Agents - pharmacology; Neurotoxicity; NF-E2-Related Factor 2 - metabolism; NMR; NRF2 protein; nuclear factor erythroid 2-related factor 2; Nuclear magnetic resonance; Oxidative Stress; Oxidopamine - toxicity; Oxygenase; parkinson′s disease; Pathogenesis; Quercetin; Quercetin - analogs & derivatives; Quercetin - pharmacology; Signal Transduction; siRNA; Therapeutic targets; Acer tegmentosum; 6-hydroxydopamine; Parkinson′s disease; heme oxygenase-1; hyperoside; nuclear factor erythroid 2-related factor 2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20235832

In our ongoing research to discover natural products with neuroprotective effects, hyperoside (quercetin 3-O-galactoside) was isolated from Acer tegmentosum, which has been used in Korean traditional medicine to treat liver-related disorders. Here, we demonstrated that hyperoside protects cultured dopaminergic neurons from death via reactive oxygen species (ROS)-dependent mechanisms, although other relevant mechanisms of hyperoside activity remain largely uncharacterized. For the first time, we investigated the neuroprotective effects of hyperoside on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in neurons, and the possible underlying mechanisms. Hyperoside significantly ameliorated the loss of neuronal cell viability, lactate dehydrogenase release, excessive ROS accumulation and mitochondrial membrane potential dysfunction associated with 6-OHDA-induced neurotoxicity. Furthermore, hyperoside treatment activated the nuclear erythroid 2-related factor 2 (Nrf2), an upstream molecule of heme oxygenase-1 (HO-1). Hyperoside also induced the expression of HO-1, an antioxidant response gene. Remarkably, we found that the neuroprotective effects of hyperoside were weakened by an Nrf2 small interfering RNA, which blocked the ability of hyperoside to inhibit neuronal death, indicating the vital role of HO-1. Overall, we show that hyperoside, via the induction of Nrf2-dependent HO-1 activation, suppresses neuronal death caused by 6-OHDA-induced oxidative stress. Moreover, Nrf2-dependent HO-1 signaling activation represents a potential preventive and therapeutic target in Parkinson's disease management.