title: Heat shock proteins reduce toxicity of 1-methyl-4-phenylpyridinium ion in SK-N-SH cells.
abstract: The pathology of Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, the pathogenesis of PD remains unclear. Heat shock proteins (HSPs) have many functions, including inhibition of apoptosis and necrosis, protection from oxidative stress, and maintenance of the mitochondrial membrane potential, that are related to neurodegenerative diseases. 1-Methyl-4-phenylpyridinium ion (MPP(+)) is a neurotoxin that selectively inhibits the mitochondrial functions of DA neurons in the substantia nigra. MPP(+) administration is accepted as a model for PD. In the present study, we found that MPP(+) induced a concentration- and time-dependent decrease in cell viability. Lower concentrations of MPP(+) induced mainly early apoptosis, and, as the concentration increased, the number of late apoptotic and necrotic cells significantly increased. However, treated by heat shock preconditioning or transfection with HDJ-1, a homologue of human Hsp40, cells showed marked improvement in viability after exposure to the same concentrations of MPP(+). Compared with heat shock, HDJ-1 appeared to improve cell viability obviously. Similarly, HDJ-1 elicited significantly stronger protective effects against apoptosis and necrosis. In addition, HDJ-1 transfection maintained more injured cells in early apoptotic stages and inhibited the occurrence of late apoptotic/necrotic events. Heat shock and HDJ-1 both ameliorated MPP(+)-induced cytotoxicity by maintaining the mitochondrial membrane potential and reducing reactive oxygen species (ROS). Therefore, the effects of HSPs, such as reducing apoptosis and necrosis, preserving mitochondrial functions and decreasing oxidative stress, may bring a novel approach for PD therapy.
authors.affiliation: Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Second Medical University, China.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fan
authors.forename: Chen
authors.initials: C
authors.lastname: Qi
authors.forename: Sheng-Di
authors.initials: SD
authors.lastname: Chen
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001562:Benzimidazoles / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002232:Carbocyanines / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D006360:Heat-Shock Proteins / Q000145:classification / Q000502:physiology*; D006358:Hot Temperature; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism; D009447:Neuroblastoma; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D001562:Benzimidazoles; D002232:Carbocyanines; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D015655:1-Methyl-4-phenylpyridinium