PMID- 18470306
OWN - NLM
STAT- MEDLINE
DCOM- 20080925
LR  - 20220223
IS  - 0091-6765 (Print)
IS  - 1552-9924 (Electronic)
IS  - 0091-6765 (Linking)
VI  - 116
IP  - 5
DP  - 2008 May
TI  - Formyl-methionyl-leucyl-phenylalanine-induced dopaminergic neurotoxicity via 
      microglial activation: a mediator between peripheral infection and 
      neurodegeneration?
PG  - 593-8
LID - 10.1289/ehp.11031 [doi]
AB  - BACKGROUND: Parkinson disease (PD), a chronic neurodegenerative disease, has been 
      proposed to be a multifactorial disorder resulting from a combination of 
      environmental mechanisms (chemical, infectious, and traumatic), aging, and 
      genetic deficits. Microglial activation is important in the pathogenesis of PD. 
      OBJECTIVES: We investigated dopaminergic (DA) neurotoxicity and the underlying 
      mechanisms of formyl-methionyl-leucyl-phenylalanine (fMLP), a bacteria-derived 
      peptide, in relation to PD. METHODS: We measured DA neurotoxicity using a DA 
      uptake assay and immunocytochemical staining (ICC) in primary mesencephalic 
      cultures from rodents. Microglial activation was observed via ICC, flow 
      cytometry, and superoxide measurement. RESULTS: fMLP can cause selective DA 
      neuronal loss at concentrations as low as 10(-13) M. Further, fMLP (10(-13) M) 
      led to a significant reduction in DA uptake capacity in neuron/glia (N/G) 
      cultures, but not in microglia-depleted cultures, indicating an indispensable 
      role of microglia in fMLP-induced neurotoxicity. Using ICC of a specific 
      microglial marker, OX42, we observed morphologic changes in activated microglia 
      after fMLP treatment. Microglial activation after fMLP treatment was confirmed by 
      flow cytometry analysis of major histocompatibility antigen class II expression 
      on a microglia HAPI cell line. Mechanistic studies revealed that fMLP (10(-13) 
      M)-induced increase in the production of extracellular superoxide from microglia 
      is critical in mediating fMLP-elicited neurotoxicity. Pharmacologic inhibition of 
      NADPH oxidase (PHOX) with diphenylene-iodonium or apocynin abolished the DA 
      neurotoxicity of fMLP. N/G cultures from PHOX-deficient (gp91PHOX-/ -) mice were 
      also insensitive to fMLP-induced DA neurotoxicity. CONCLUSION: fMLP (10(-13) M) 
      induces DA neurotoxicity through activation of microglial PHOX and subsequent 
      production of superoxide, suggesting a role of fMLP in the central nervous system 
      inflammatory process.
FAU - Gao, Xi
AU  - Gao X
AD  - Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National 
      Institute of Environmental Health Sciences, National Institutes of Health, 
      Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
FAU - Hu, Xiaoming
AU  - Hu X
FAU - Qian, Li
AU  - Qian L
FAU - Yang, Sufen
AU  - Yang S
FAU - Zhang, Wei
AU  - Zhang W
FAU - Zhang, Dan
AU  - Zhang D
FAU - Wu, Xuefei
AU  - Wu X
FAU - Fraser, Alison
AU  - Fraser A
FAU - Wilson, Belinda
AU  - Wilson B
FAU - Flood, Patrick M
AU  - Flood PM
FAU - Block, Michelle
AU  - Block M
FAU - Hong, Jau-Shyong
AU  - Hong JS
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PL  - United States
TA  - Environ Health Perspect
JT  - Environmental health perspectives
JID - 0330411
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Central Nervous System Infections/*etiology/metabolism/pathology
MH  - Dopamine/*metabolism
MH  - Enzyme Activation
MH  - Female
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microglia/*drug effects/enzymology/metabolism
MH  - N-Formylmethionine Leucyl-Phenylalanine/*toxicity
MH  - NADPH Oxidases/metabolism
MH  - Neurodegenerative Diseases/*chemically induced/metabolism/pathology
MH  - Neurons/drug effects/metabolism
MH  - Oxidative Stress
MH  - Parkinson Disease/*etiology
MH  - Pregnancy
MH  - Rats
MH  - Rats, Inbred F344
PMC - PMC2367670
OTO - NOTNLM
OT  - NADPH oxidase
OT  - fMLP
OT  - inflammation
OT  - microglia
OT  - neurotoxicity
EDAT- 2008/05/13 09:00
MHDA- 2008/09/26 09:00
PMCR- 2008/05/01
CRDT- 2008/05/13 09:00
PHST- 2007/10/30 00:00 [received]
PHST- 2008/01/28 00:00 [accepted]
PHST- 2008/05/13 09:00 [pubmed]
PHST- 2008/09/26 09:00 [medline]
PHST- 2008/05/13 09:00 [entrez]
PHST- 2008/05/01 00:00 [pmc-release]
AID - ehp0116-000593 [pii]
AID - 10.1289/ehp.11031 [doi]
PST - ppublish
SO  - Environ Health Perspect. 2008 May;116(5):593-8. doi: 10.1289/ehp.11031.