Microglial NADPH oxidase mediates leucine enkephalin dopaminergic neuroprotection

Liya Qin, Yuxin Liu, Xun Qian, Jau Shyong Hong, Michelle L. Block

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Here, we report that leucine enkephalin (LE) is neuroprotective to dopaminergic (DA) neurons at femtomolar concentrations through anti-inflammatory properties. Mesencephalic nearon-glia cultures pretreated with femtomolar concentrations of LE (10-15-10-13 M) protected DA neurons from lipopolysaccharide (LPS)-induced DA neerotoxicity, as determined by DA uptake assay and tyrosine hydroxylase (TH) immunocytochemistry (ICC). However, des-tyrosine leucine enkephalin (DTLE), an LE analogue that is missing the tyrosine residue required for binding to the kappa opioid receptor, was also neuroprotective (10-15-10-13 M), as determined by DA uptake assay and TH ICC. Both LE and DTLE (10-15-10-13 M) reduced LPS-induced superoxide production from microglia-enriched cultures. Further, both LE and DTLE (10-14, 10-13 M) reduced the LPS-induced tumor necrosis factor-alpha (TNFα) mRNA and TNFα protein from PHOX+/+ microglia, as determined by quantitative real-time RT-PCR and ELISA analysis in mesencephalic neuron-glia cultures, respectively. However, both peptides failed to inhibit TNFα expression in PHOX -/- cultures, which are unable to produce extracellular superoxide in response to LPS. Additionally, LE and DTLE (10-14, 10-13 M) failed to show any neuroprotection against LPS in PHOX-/- cultures. Together, these data indicate that LE and DTLE are neuroprotective at femtomolar concentrations through the inhibition of oxidative insult associated with microglial NADPH oxidase and the attenuation of the ROS-mediated amplification of TNFα gene expression in microglia.

Original languageEnglish (US)
Pages (from-to)107-120
Number of pages14
JournalAnnals of the New York Academy of Sciences
Volume1053
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

Keywords

  • Des-tyrosine leucine enkephalin (DTLE)
  • Leucine enkephalin (LE)
  • Lipopolysaccharide (LPS)
  • Microglial NADPH oxidase
  • Neuroprotection
  • Neurotoxicity
  • Tumor necrosis factor-alpha (TNFα)

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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