title: Prostaglandin A1 inhibits rotenone-induced apoptosis in SH-SY5Y cells.
abstract: The degeneration of nigral dopamine neurons in Parkinson's disease (PD) reportedly involves a defect in brain mitochondrial complex I in association with the activation of nuclear factor-kappaB (NF-kappaB) and caspase-3. To elucidate molecular mechanisms possibly linking these events, as well as to evaluate the neuroprotective potential of the cyclopentenone prostaglandin A1 (PGA1), an inducer of heat shock proteins (HSPs), we exposed human dopaminergic SH-SY5Y cells to the complex I inhibitor rotenone. Dose-dependent apoptosis was preceded by the nuclear translocation of NF-kappaB and then the activation of caspase-3 over the ensuing 24 h. PGA1 increased the expression of HSP70 and HSP27 and protected against rotenone-induced apoptosis, without increasing necrotic death. PGA1 blocked the rotenone-induced nuclear translocation of NF-kappaB and attenuated, but did not abolish, the caspase-3 elevation. Unexpectedly, the caspase-3 inhibitor, Ac-DEVD.CHO (DEVD), at a concentration that completely prevented the caspase-3 elevation produced by rotenone, failed to protect against apoptosis. These results suggest that complex I deficiency in dopamine cells can induce apoptosis by a process involving early NF-kappaB nuclear translocation and caspase-3 activation. PGA1 appears to protect against rotenone-induced cell death by inducing HSPs and blocking nuclear translocation of NF-kappaB in a process that attenuates caspase-3 activation, but is not mediated by its inhibition.
authors.affiliation: National Institute of Neurological Disorders and Stroke, Experimental Therapeutics Branch, Bethesda, Maryland, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Wang
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Qin
authors.forename: Yan
authors.initials: Y
authors.lastname: Leng
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiannu
authors.initials: X
authors.lastname: Jin
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Chase
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Bennett
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D018832:Molecular Chaperones; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011454:Prostaglandins A / Q000494:pharmacology*; D012402:Rotenone / Q000633:toxicity*; D014475:Uncoupling Agents / Q000633:toxicity
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; D011454:Prostaglandins A; D014475:Uncoupling Agents; D012402:Rotenone; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C100573:prostaglandin A1