title: Protective effects of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-hydroxydopamine-induced neuronal cell death.
abstract: 6-Hydroxydopamine (6-OHDA) is a neurotoxin and is commonly used to generate experimental models of Parkinson's disease (PD). In this study, we investigated the signaling molecules involved in the 6-OHDA-induced cell death using a neuronal catecholaminergic cell line (SK-N-SH cells), and the protective effect of fustin, a flavonoid from Rhus verniciflua Stokes, on 6-OHDA-induced neuronal death. 6-OHDA significantly increased levels of reactive oxygen species (ROS), intracellular Ca(2+) ([Ca(2+)](i)), and p38 phosphorylation. In addition, this ROS increase by 6-OHDA was reduced by pretreatment with N-acetylcysteine (NAC), a free radical scavenger, but not by bis-(o-aminophenoxy)-ethane-N,N,N,N-tetraacetic acid (BAPTA), a Ca(2+) chelator. However, the [Ca(2+)](i) increase induced by 6-OHDA was suppressed by NAC. Moreover, pretreatment with NAC or BAPTA significantly prevented the 6-OHDA-induced increases in p38 phosphorylation, Bax/Bcl-2 ratio, and caspase-3 activity. Although 6-OHDA-increased phosphorylation of p38 was prevented by NAC or BAPTA, inhibition of p38 by SB203580 did not suppress ROS, Bax/Bcl-2 ratio, or caspase-3 activity increases, and only partially prevented 6-OHDA-induced cell death, thus demonstrating that p38 activation is a component of a signaling pathway leading to the initiation of 6-OHDA-induced cell death, which acts in parallel with an ROS-Ca(2+)-Bcl-2-caspase-3 pathway. Moreover, fustin not only suppressed 6-OHDA-induced cell death in a concentration-dependent manner but also blocked 6-OHDA-induced increases in ROS, [Ca(2+)](i), Bax/Bcl-2 ratio, caspase-3 activity, and p38 phosphorylation. These results suggest that fustin exerts neuroprotection against 6-OHDA-induced cell death.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea.
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Park
authors.forename: Yong Soo
authors.initials: YS
authors.lastname: Lee
authors.forename: Hee-Juhn
authors.initials: HJ
authors.lastname: Park
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Kwak
authors.forename: Bong Kyu
authors.initials: BK
authors.lastname: Yoo
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004789:Enzyme Activation; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D029045:Rhus / Q000737:chemistry*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D005419:Flavonoids; D007093:Imidazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D017382:Reactive Oxygen Species; C522894:fustin; D004533:Egtazic Acid; D016627:Oxidopamine; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C093642:SB 203580; D002118:Calcium; D000111:Acetylcysteine