title: Acrolein acts as a neurotoxin in the nigrostriatal dopaminergic system of rat: involvement of α-synuclein aggregation and programmed cell death.
abstract: Clinical studies report significant increases in acrolein (an α,β-unsaturated aldehyde) in the substantia nigra (SN) of patients with Parkinson's disease (PD). In the present study, acrolein-induced neurotoxicity in the nigrostriatal dopaminergic system was investigated by local infusion of acrolein (15, 50, 150 nmoles/0.5 μl) in the SN of Sprague-Dawley rats. Acrolein-induced neurodegeneration of nigrostriatal dopaminergic system was delineated by reductions in tyrosine hydroxylase (TH) levels, dopamine transporter levels and TH-positive neurons in the infused SN as well as in striatal dopamine content. At the same time, apomorphine-induced turning behavior was evident in rats subjected to a unilateral infusion of acrolein in SN. Acrolein was pro-oxidative by increasing 4-hydroxy-2-nonenal and heme oxygenase-1 levels. Furthermore, acrolein conjugated with proteins at lysine residue and induced α-synuclein aggregation in the infused SN. Acrolein was pro-inflammatory by activating astrocytes and microglia. In addition, acrolein activated caspase 1 in the infused SN, suggesting acrolein-induced inflammasome formation. The neurotoxic mechanisms underlying acrolein-induced neurotoxicity involved programmed cell death, including apoptosis and necroptosis. Compared with well-known Parkinsonian neurotoxins, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and rotenone which do not exist in the SN of PD patients, our in vivo study shows that acrolein acts as a Parkinsonian neurotoxin in the nigrostriatal dopaminergic system of rat brain.
authors.affiliation: Institute of Physiology, National Yang Ming University, Taipei, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Institute of Physiology, National Yang Ming University, Taipei, Taiwan.
authors.forename: Hui-Ching
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Institute of Pharmacology, National Yang Ming University, Taipei, Taiwan.
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Zhao
authors.affiliation: Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Huang
authors.affiliation: Institute of Pharmacology, National Yang Ming University, Taipei, Taiwan.
authors.forename: Yu-Li
authors.initials: YL
authors.lastname: Lo
authors.affiliation: Institute of Pharmacology, National Yang Ming University, Taipei, Taiwan.
authors.forename: Hsiang-Tsui
authors.initials: HT
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology, National Yang Ming University, Taipei, Taiwan.|Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Pharmacy, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Anya Maan-Yuh
authors.initials: AM
authors.lastname: Lin
mesh_terms: D000171:Acrolein / Q000633:toxicity*; D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004660:Encephalitis / Q000139:chemically induced; D008297:Male; D018384:Oxidative Stress; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000139:chemically induced; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D000171:Acrolein