Regional Difference in Susceptibility to Lipopolysaccharide-Induced Neurotoxicity in the Rat Brain: Role of Microglia

By Won-Gon Kim, R. Mohney, B. Wilson, G. Jeohn, Bin Liu, Jau-Shyong Hong. Journal of Neuroscience, 2000

898 citations recorded by the source corpus.

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.

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/fdab91f6ebccc12f53816f89147f4d907ed7fbff

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. P. Whitton
2. S. Rivest
3. M. Block
4. Jau-Shyong Hong
5. M. Tan
6. L. Tan
7. T. Wyss‐Coray
8. Neil A. Harrison

In Neurology

1. M. Block
2. Jau-Shyong Hong
3. P. Whitton
4. S. Rivest
5. Bin Liu
6. S. Przedborski
7. M. Tan
8. L. Tan

Citations in the corpus

• Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease (2002, background): “Consistent with this is the demonstration that direct injection of the known microglial activator lipopolysaccharide into the rat SNpc causes a strong microglial response associated with significant dopaminergic neuronal death (Castano et al., 1998; Herrera et al., 2000; Kim et al., 2000).”
• Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. (2005, background): “Additionally, the SN contains 4.5 times as many microglia when compared to the cortex and other regions of the brain (Kim et al., 2000), suggesting that the localization of microglia in the SN predisposes them to vulnerability to immunological insult.”
• Mechanisms Underlying Inflammation in Neurodegeneration (2010, neutral): “TLR4, the main receptor for LPS, is preferentially expressed on microglia compared to astrocytes (Kim et al., 2000), but it is present at very low or undetectable levels on neurons.”
• Microglia in Alzheimer's Disease (2014, background): “In recent years, the study found that microglia cells (MG) play a core role in the pathogenesis of AD, which is currently one of the hot topics in the study of the nervous system degenerative disease.”
• Inflammation as a causative factor in the aetiology of Parkinson's disease (2007, background): “LPS is a Gram-negative bacterial endotoxin and is a potent microglial cell activator (Lieberman et al., 1989; Kim et al., 2000).”
• Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains (2003, background): “Many studies indicate the vulnerability of neurons to the potential toxicity of microglia that produce neurotoxic substances including superoxide anion, nitric oxide (NO), glutamate and pro-inflammatory cytokines [10, 11, 19, 26, 27, 30, 38].”
• Innate immunity: the missing link in neuroprotection and neurodegeneration? (2002, background): “LPS-induced pro-inflammatory signal-transduction pathways are generally not associated with neurodegeneration, although a few studies have provided evidence of LPS-induced neurotoxicit”
• Aggregated α‐synuclein activates microglia: a process leading to disease progression in Parkinson's disease (2005, background): “What makes dopaminergic neurons more susceptible to aggregated -synuclein-induced neurotoxicity is not completely understood at this time, although the neurotransmitter DA and the oxidative stress associated with its metabolism (43, 44), as well as the higher density of microglia in the SN than in t”
• Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease (2011, result): “Rodent nigral neurons have been shown to be more vulnerable than either hippocampal or cortical neurons to LPS-induced degeneration in vivo and in vitro, and this was shown to be due to the higher number of activated microglia per unit area in the SNpc compared with the other brain regions [39].”
• Role of Microglia in Inflammation-Mediated Neurodegenerative Diseases: Mechanisms and Strategies for Therapeutic Intervention (2003, background): “The SN region of the brain is particularly rich in microglia (Lawson et al., 1990; Kim et al., 2000).”
• Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration (2007, background): “…Inflammation Induces a Delayed and Progressive Loss of Dopaminergic Neurons in the Substantia Nigra The substantia nigra (SN) is densely populated with microglia (Kim et al., 2000; Lawson et al., 1990) and it is hypothesized that this brain region is particularly susceptible to inflammatory insult.”
• Microglia-mediated neurotoxicity: uncovering the molecular mechanisms (2007, background): “(redox active elements) and increased numbers of microglia in the substantia nigr”