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Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation.
J Pharmacol Exp Ther. 2003 Apr; 305(1):212-8.JP

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 and Alzheimer's disease. Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells, the microglia, which produce proinflammatory and neurotoxic factors, including cytokines, reactive oxygen intermediates, nitric oxide, and eicosanoids that impact on neurons to induce neurodegeneration. Hence, identification of compounds that prevent microglial activation may be highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases. In this study, we report that dextromethorphan (DM), an ingredient widely used in antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through inhibition of microglial activation. Pretreatment (30 min) of rat mesencephalic neuron-glia cultures with DM (1-10 micro M) reduced, in a dose-dependent manner, the microglia-mediated degeneration of dopaminergic neurons induced by lipopolysaccharide (LPS, 10 ng/ml). Significant neuroprotection by DM was also evident when DM was applied to cultures up to 60 min after the addition of LPS. The neuroprotective effect of DM was attributed to inhibition of LPS-stimulated microglial activation because DM significantly inhibited the LPS-induced production of tumor necrosis factor-alpha, nitric oxide, and superoxide free radicals. This conclusion was further supported by the finding that DM failed to prevent 1-methyl-4-phenylpyridinium- or beta-amyloid peptide (1-42)-induced dopaminergic neurotoxicity in neuron-enriched cultures. In addition, because LPS did not produce any significant increase in the release of excitatory amino acids from neuron-glia cultures and N-methyl-D-aspartate antagonist dizocilpine maleate failed to afford significant neuroprotection, it is unlikely that the neuroprotective effect of DM is mediated through N-methyl-D-aspartate receptors. These results suggest that DM may be a promising therapeutic agent for the treatment of Parkinson's disease.

Authors+Show Affiliations

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

12649371

Citation

Liu, Yuxin, et al. "Dextromethorphan Protects Dopaminergic Neurons Against Inflammation-mediated Degeneration Through Inhibition of Microglial Activation." The Journal of Pharmacology and Experimental Therapeutics, vol. 305, no. 1, 2003, pp. 212-8.
Liu Y, Qin L, Li G, et al. Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. J Pharmacol Exp Ther. 2003;305(1):212-8.
Liu, Y., Qin, L., Li, G., Zhang, W., An, L., Liu, B., & Hong, J. S. (2003). Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. The Journal of Pharmacology and Experimental Therapeutics, 305(1), 212-8.
Liu Y, et al. Dextromethorphan Protects Dopaminergic Neurons Against Inflammation-mediated Degeneration Through Inhibition of Microglial Activation. J Pharmacol Exp Ther. 2003;305(1):212-8. PubMed PMID: 12649371.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dextromethorphan protects dopaminergic neurons against inflammation-mediated degeneration through inhibition of microglial activation. AU - Liu,Yuxin, AU - Qin,Liya, AU - Li,Guorong, AU - Zhang,Wei, AU - An,Lijia, AU - Liu,Bin, AU - Hong,Jau-Shyong, PY - 2003/3/22/pubmed PY - 2003/4/23/medline PY - 2003/3/22/entrez SP - 212 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 305 IS - 1 N2 - Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease. Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells, the microglia, which produce proinflammatory and neurotoxic factors, including cytokines, reactive oxygen intermediates, nitric oxide, and eicosanoids that impact on neurons to induce neurodegeneration. Hence, identification of compounds that prevent microglial activation may be highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases. In this study, we report that dextromethorphan (DM), an ingredient widely used in antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through inhibition of microglial activation. Pretreatment (30 min) of rat mesencephalic neuron-glia cultures with DM (1-10 micro M) reduced, in a dose-dependent manner, the microglia-mediated degeneration of dopaminergic neurons induced by lipopolysaccharide (LPS, 10 ng/ml). Significant neuroprotection by DM was also evident when DM was applied to cultures up to 60 min after the addition of LPS. The neuroprotective effect of DM was attributed to inhibition of LPS-stimulated microglial activation because DM significantly inhibited the LPS-induced production of tumor necrosis factor-alpha, nitric oxide, and superoxide free radicals. This conclusion was further supported by the finding that DM failed to prevent 1-methyl-4-phenylpyridinium- or beta-amyloid peptide (1-42)-induced dopaminergic neurotoxicity in neuron-enriched cultures. In addition, because LPS did not produce any significant increase in the release of excitatory amino acids from neuron-glia cultures and N-methyl-D-aspartate antagonist dizocilpine maleate failed to afford significant neuroprotection, it is unlikely that the neuroprotective effect of DM is mediated through N-methyl-D-aspartate receptors. These results suggest that DM may be a promising therapeutic agent for the treatment of Parkinson's disease. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12649371/Dextromethorphan_protects_dopaminergic_neurons_against_inflammation_mediated_degeneration_through_inhibition_of_microglial_activation_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12649371 DB - PRIME DP - Unbound Medicine ER -