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Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration.
- Source :
-
Molecular medicine (Cambridge, Mass.) [Mol Med] 2012 Sep 07; Vol. 18, pp. 971-81. Date of Electronic Publication: 2012 Sep 07. - Publication Year :
- 2012
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Abstract
- Sustained inflammatory reactions are common pathological events associated with neuron loss in neurodegenerative diseases. Reported evidence suggests that Toll-like receptor 4 (TLR4) is a key player of neuroinflammation in several neurodegenerative diseases. However, the mechanisms by which TLR4 mediates neurotoxic signals remain poorly understood. We investigated the role of TLR4 in in vitro and in vivo settings of motor neuron degeneration. Using primary cultures from mouse spinal cords, we characterized both the proinflammatory and neurotoxic effects of TLR4 activation with lipopolysaccharide (activation of microglial cells, release of proinflammatory cytokines and motor neuron death) and the protective effects of a cyanobacteria-derived TLR4 antagonist (VB3323). With the use of TLR4-deficient cells, a critical role of the microglial component with functionally active TLR4 emerged in this setting. The in vivo experiments were carried out in a mouse model of spontaneous motor neuron degeneration, the wobbler mouse, where we preliminarily confirmed a protective effect of TLR4 antagonism. Compared with vehicle- and riluzole-treated mice, those chronically treated with VB3323 showed a decrease in microglial activation and morphological alterations of spinal cord neurons and a better performance in the paw abnormality and grip-strength tests. Taken together, our data add new understanding of the role of TLR4 in mediating neurotoxicity in the spinal cord and suggest that TLR4 antagonists could be considered in future studies as candidate protective agents for motor neurons in degenerative diseases.
- Subjects :
- Animals
Cell Culture Techniques
Cell Shape drug effects
Cell Survival drug effects
Disease Models, Animal
Ligands
Lipopolysaccharides toxicity
Mice
Mice, Inbred C57BL
Mice, Neurologic Mutants
Microglia drug effects
Microglia metabolism
Microglia pathology
Motor Neurons drug effects
Muscles drug effects
Muscles pathology
Neurotoxins toxicity
Spinal Cord drug effects
Spinal Cord metabolism
Toll-Like Receptor 4 metabolism
Tumor Necrosis Factor-alpha metabolism
Motor Neurons metabolism
Motor Neurons pathology
Nerve Degeneration metabolism
Nerve Degeneration pathology
Neuroprotective Agents metabolism
Spinal Cord pathology
Toll-Like Receptor 4 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1528-3658
- Volume :
- 18
- Database :
- MEDLINE
- Journal :
- Molecular medicine (Cambridge, Mass.)
- Publication Type :
- Academic Journal
- Accession number :
- 22562723
- Full Text :
- https://doi.org/10.2119/molmed.2012.00020