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The Journal of Neuroscience, August 15, 2000, 20(16):6309-6316
Regional Difference in Susceptibility to
Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of
Microglia
Won-Gon
Kim,
Robert P.
Mohney,
Belinda
Wilson,
Gwang-Ho
Jeohn,
Bin
Liu, and
Jau-Shyong
Hong
Neuropharmacology Section, Laboratory of Pharmacology and
Chemistry, National Institute of Environmental Health Sciences,
Research Triangle Park, North Carolina 27709
Inflammation in the brain has been increasingly associated with the
development of a number of neurological diseases. The hallmark of
neuroinflammation is the activation of microglia, the resident brain
immune cells. Injection of bacterial endotoxin lipopolysaccharide (LPS)
into the hippocampus, cortex, or substantia nigra of adult rats
produced neurodegeneration only in the substantia nigra. Although LPS
appeared to impact upon mesencephalic neurons in general, an extensive
loss of dopaminergic neurons was observed. Analysis of the abundance of
microglia revealed that the substantia nigra had the highest density of
microglia. When mixed neuron-glia cultures derived from the rat
hippocampus, cortex, or mesencephalon were treated with LPS,
mesencephalic cultures became sensitive to LPS at a concentration as
low as 10 ng/ml and responded in a dose-dependent manner with the
production of inflammatory factors and a loss of dopaminergic and other
neurons. In contrast, hippocampal or cortical cultures remained
insensitive to LPS treatment at concentrations as high as 10 µg/ml.
Consistent with in vivo observations, mesencephalic
cultures had fourfold to eightfold more microglia than cultures from
other regions. The positive correlation between abundance of microglia
and sensitivity to LPS-induced neurotoxicity was further supported by
the observation that supplementation with enriched microglia derived
from mesencephalon or cortex rendered LPS-insensitive cortical
neuron-glia cultures sensitive to LPS-induced neurotoxicity. These
data indicate that the region-specific differential susceptibility of
neurons to LPS is attributable to differences in the number of
microglia present within the system and may reflect levels of
inflammation-related factors produced by these cells.
Key words:
endotoxin; lipopolysaccharide; inflammation; glia-mediated neurotoxicity; midbrain; microglia; Parkinson's disease
Copyright © 2000 Society for Neuroscience 0270-6474/00/20166309-08$05.00/0
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