Kim Won-Gon. Mohney Robert P. Wilson Belinda. Jeohn Gwang-Ho. Liu Bin.
Hong Jau-Shyong [a].
Regional difference in susceptibility to lipopolysaccharide-induced
neurotoxicity in the rat brain: Role of microglia, Journal of Neuroscience 20(16) :6309-6316, 2000.
Abstract
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 mug/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.
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