title: Involvement of the Nrf2/HO-1 signaling pathway in sulfuretin-induced protection against amyloid beta25-35 neurotoxicity.
abstract: Sulfuretin, one of the major flavonoid glycosides found in the stem bark of Albizzia julibrissin and heartwood of Rhus verniciflua, is a known anti-oxidant. We previously demonstrated that sulfuretin inhibits neuronal death via reactive oxygen species (ROS)-dependent mechanisms in human SH-SY5Y cells, although other relevant mechanisms of action of this compound remain largely uncharacterized. As part of our ongoing exploration of the pharmacological actions of sulfuretin, we studied the neuroprotective effects of sulfuretin against amyloid beta (Aβ)-induced neurotoxicity in human SH-SY5Y and primary hippocampal neuron cells and investigated the possible mechanisms involved. Specifically, we found in the present study that sulfuretin significantly attenuates the decrease in cell viability, release of lactate dehydrogenase, and accumulation of ROS associated with Aβ25-35-induced neurotoxicity in neuronal cells. Furthermore, sulfuretin stimulated the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a downstream target of phosphatidylinositol 3-kinases (PI3K)/Akt. We demonstrated that sulfuretin induces the expression of heme oxygenase-1 (HO-1), an anti-oxidant response gene. Notably, we found that the neuroprotective effects of sulfuretin were diminished by an Nrf2 small interfering RNA (siRNA), the HO-1 inhibitor zinc protoporphyrin IX (ZnPP), as well as the PI3K/Akt inhibitor LY294002. Taken together, these results indicated that sulfuretin protects neuronal cells from Aβ25-35-induced neurotoxicity through activation of Nrf/HO-1 and PI3K/Akt signaling pathways. Our results also indicate that sulfuretin-induced induction of Nrf2-dependent HO-1 expression via the PI3K/Akt signaling pathway has preventive and/or therapeutic potential for the management of Alzheimer's disease.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: S-X
authors.initials: SX
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: jang@skku.edu.
authors.forename: C-G
authors.initials: CG
authors.lastname: Jang
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D001572:Benzofurans; D005419:Flavonoids; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; C495635:NFE2L2 protein, human; C495637:Nfe2l2 protein, rat; C074636:amyloid beta-protein (25-35); C496541:HMOX1 protein, human; C491523:Hmox1 protein, rat; C054989:sulfuretin
keywords: Alzheimer’s disease; amyloid beta(25–35); heme oxygenase-1; neurotoxicity; nuclear factor erythroid 2-related factor 2; sulfuretin