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Vol. 302, Issue 3, 1212-1219, September 2002
-Amyloid Peptide
(1-42)-induced Superoxide Production in Microglia and Degeneration of
Cortical and Mesencephalic Neurons
Neuropharmacology Section, Laboratory of Pharmacology and
Chemistry, National Institute of Environmental Health Sciences/National
Institutes of Health, Research Triangle Park, North Carolina (Y.L.,
L.Q., B.C.W., J.-S.H., B.L.), and Department of Bioengineering, Dalian
University of Technology, Dalian, China (Y.L., L.A.)
Previously we reported that naloxone stereoisomers, in an opioid
receptor-independent manner, attenuated the inflammation-mediated degeneration of dopaminergic neurons by inhibition of the activation of
microglia, the resident immune cells in the brain. Recently we
discovered that 
-amyloid peptide A (1-42) exhibited enhanced neurotoxicity toward both cortical and mesencephalic neurons through the activation of microglia and production of superoxide. The purpose
of this study was to determine whether naloxone isomers had any effect
on A (1-42)-induced neurodegeneration. Pretreatment of either
cortical or mesencephalic neuron-glia cultures with 1 to 10 µM
(
)-naloxone, prior to treatment for up to 11 days with 0.1 to 3 µM
A (1-42), afforded significant neuroprotection as judged by
neurotransmitter uptake, immunocytochemical analysis, and cell
counting. More importantly, (+)-naloxone, the ineffective enantiomer of
()-naloxone in binding opioid receptors, was equally effective in
affording neuroprotection. Mechanistically, inhibition of A
(1-42)-induced production of superoxide in microglia underlay the
neuroprotective effect of naloxone stereoisomers. Moreover, neuroprotection and inhibition of A (1-42)-induced superoxide production was also achieved with naloxone methiodide, a charged analog
with quaternary amine, suggesting that the site of action for naloxone
isomers is at the cell surface of microglia. These results demonstrated
that naloxone isomers, through mechanisms unrelated to the opioid
receptors, were capable of inhibiting A (1-42)-induced microglial
activation and degeneration of both cortical and mesencephalic neurons.
Combined with our previous observations with inflammagen-induced
neurodegeneration, naloxone analogs, especially (+)-naloxone, may have
potential therapeutic efficacy for the treatment of Alzheimer's and
Parkinson's disease.
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