Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage Guorong Li * ,1 , Gang Cui † , Nian-Ssheng Tzeng ‡ , Sung-Jen Wei § , Tongguang Wang * , Michelle L. Block * and Jau-Shyong Hong * * Neuropharmacology Section, Laboratory of Pharmacology and Chemistry and § the National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; † Pathology & Lab Medicine, University of North Carolina at Chapel Hill, North Carolina, USA; and ‡ Departments of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 1 Correspondence: Neuropharmacology Section NIEHS/NIH, PO BOX 12233, MD: F1-01 111 Alexander Dr., Research Triangle Park, NC 27709, USA. E-mail: hong3@niehs.nih.gov; guorongl@med.unc.edu 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-α, prostaglandin E 2 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.—Li, G., Cui, G., Tzeng, N.-S., Wei, S,.-J., Wang, T., Block, M. L., Hong, J.-S. Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage. Key Words: DM • femtomolar • inflammation • microglia • neuroprotection • Parkinson’s disease
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Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage
Li, Guorong; Cui, Gang; Tzeng, Nian-Ssheng; Wei, Sung-Jen; Wang, Tongguang; Block, Michelle L.; Hong, Jau-Shyong
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, Volume 19 (6): 489
Fed of American Socs for Experimental Biology – Apr 1, 2005
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