title: Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage.
abstract: Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease (PD). Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. We previously showed that micromolar concentrations of dextromethorphan (DM), a major ingredient of widely used antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through the inhibition of microglial activation. In this study, we report that femto- and micromolar concentrations of DM (both pre- and post-treatment) showed equal efficacy in protecting lipopolysaccharide (LPS) -induced dopaminergic neuron death in midbrain neuron-glia cultures. Both concentrations of DM decreased LPS-induced release of nitric oxide, tumor necrosis factor-alpha, prostaglandin E2 and superoxide from microglia in comparable degrees. The important role of superoxide was demonstrated by DM's failure to show a neuroprotective effect in neuron-glia cultures from NADPH oxidase-deficient mice. These results suggest that the neuroprotective effect elicited by femtomolar concentrations of DM is mediated through the inhibition of LPS-induced proinflammatory factors, especially superoxide. These findings suggest a novel therapeutic concept of using "ultra-low" drug concentrations for the intervention of inflammation-related neurodegenerative diseases.
authors.affiliation: Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. guorongl@med.unc.edu
authors.forename: Guorong
authors.initials: G
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Cui
authors.forename: Nian-Ssheng
authors.initials: NS
authors.lastname: Tzeng
authors.forename: Sung-Jen
authors.initials: SJ
authors.lastname: Wei
authors.forename: Tongguang
authors.initials: T
authors.lastname: Wang
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Block
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003915:Dextromethorphan / Q000008:administration & dosage*; D015232:Dinoprostone / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D007249:Inflammation / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008636:Mesencephalon / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000502:physiology; D009410:Nerve Degeneration / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000032:analysis; D010300:Parkinson Disease; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014316:Tritium; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
chemical_list: D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D009573:Nitrites; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014316:Tritium; D013481:Superoxides; D009569:Nitric Oxide; D003915:Dextromethorphan; D014446:Tyrosine 3-Monooxygenase; D019255:NADPH Oxidases; D015232:Dinoprostone; D004298:Dopamine