Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival: Substance P vs. dynorphin

M. L. Block, G. Li, L. Qin, X. Wu, Z. Pei, T. Wang, B. Wilson, J. Yang, J. S. Hong

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

Unregulated microglial activation has been implicated as a pivotal factor contributing to Parkinson's disease. Using mesencephalic neuron-glia cultures, we address the novel possibility that peptides endogenous to the substantia nigra (SN), substance P and dynorphin (10-13-10-14 M), are opposing mediators of microglial activation and consequent DA neurotoxicity. Here, we identify that substance P (10-13-10-14 M) is selectively toxic to DA neurons in a microglia-dependent manner. Mechanistically, substance P (10-13-10-14 M) activated microglial NADPH oxidase to produce extracellular superoxide and intracellular reactive oxygen species (ROS). Neuron-glia cultures from mice lacking a functional NADPH oxidase complex (PHOX-/-) were insensitive to substance P (10-13-10-14 M) -induced loss of DA neuron function. Mixed glia cultures from (PHOX-/-) mice failed to show a significant increase in intracellular ROS in response to substance P compared with control cultures (PHOX+/+). Further, dynorphin (10-14 M) inhibited substance P (10-13 M) -induced loss of [3H] DA uptake. Here we demonstrate a tightly regulated mechanism governing microglia-derived oxidative stress, where the neuropeptide balance of dynorphin and substance P is critical to DA neuron survival.

Original languageEnglish (US)
Pages (from-to)251-258
Number of pages8
JournalFASEB Journal
Volume20
Issue number2
DOIs
StatePublished - Feb 2006

Keywords

  • DA neurotoxicity
  • Femtomolar
  • Microglia
  • NADPH oxidase
  • Oxidative stress
  • Superoxide

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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