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

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

Research output: Contribution to journalArticle

71 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Dynorphins
substance P
Oxidative stress
Dopaminergic Neurons
neuroglia
Microglia
Substance P
Neurons
Oxidative Stress
oxidative stress
neurons
Neuroglia
NADPH Oxidase
reactive oxygen species
Reactive Oxygen Species
Chemical activation
neurotoxicity
Parkinson disease
Poisons
mice

Keywords

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

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival : Substance P vs. dynorphin. / Block, Michelle; Li, G.; Qin, L.; Wu, X.; Pei, Z.; Wang, T.; Wilson, B.; Yang, J.; Hong, J. S.

In: FASEB Journal, Vol. 20, No. 2, 02.2006, p. 251-258.

Research output: Contribution to journalArticle

Block, Michelle ; Li, G. ; Qin, L. ; Wu, X. ; Pei, Z. ; Wang, T. ; Wilson, B. ; Yang, J. ; Hong, J. S. / Potent regulation of microglia-derived oxidative stress and dopaminergic neuron survival : Substance P vs. dynorphin. In: FASEB Journal. 2006 ; Vol. 20, No. 2. pp. 251-258.
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