Acetaminophen attenuates dopamine neuron degeneration in animal models of Parkinson's disease.
Parkinson's disease (PD) is the second most common neurodegenerative disorder with approximately 2% of people over age 65 suffering from this disease. Risk factors for PD involve interplay between still poorly defined genetic and non-genetic contributors, but appear to converge upon cellular pathways that mediate protein misfolding and oxidative stress that lead to dopaminergic neuron loss. The identification of either new or repurposed drugs that exhibit benefit in slowing the age-dependent neuronal damage that occurs in PD is a significant goal of much ongoing research. We have exploited the nematode Caenorhabditis elegans as a model system by which the neuroprotective capacity of acetaminophen could be rapidly evaluated for efficacy in attenuating dopamine (DA) neurodegeneration. Using three independent and established neurodegenerative models in C. elegans, we assayed for acetaminophen-dependent rescue in response to: (1) over-expression of the PD-associated protein, alpha-synuclein; (2) acute exposure to 6-hydroxydopamine (6-OHDA); (3) excess intracellular DA production due to over-expression of the DA biosynthetic enzyme, tyrosine hydroxylase (TH). These data suggest that acetaminophen significantly protected C. elegans DA neurons from stressors related to oxidative damage, but not protein misfolding. Taken together, these studies imply an activity for acetaminophen in the attenuation of DA neuron loss that, following essential corroborative analyses in mammalian systems, may represent a potential benefit for PD.
Locke
Cody J
CJ
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA.
Fox
Stacey A
SA
Caldwell
Guy A
GA
Caldwell
Kim A
KA
D000082:Acetaminophen / Q000494:pharmacology*; D018663:Adrenergic Agents / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000473:pathology*; D009474:Neurons / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications / Q000209:etiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
D018663:Adrenergic Agents; D018712:Analgesics, Non-Narcotic; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D000082:Acetaminophen; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine