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Ferulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4 Receptor in the Mouse Hippocampus.
- Source :
-
Molecular neurobiology [Mol Neurobiol] 2019 Apr; Vol. 56 (4), pp. 2774-2790. Date of Electronic Publication: 2018 Jul 30. - Publication Year :
- 2019
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Abstract
- Microglia play a crucial role in the inflammatory brain response to infection. However, overactivation of microglia is neurotoxic. Toll-like receptor 4 (TLR4) is involved in microglial activation via lipopolysaccharide (LPS), which triggers a variety of cytotoxic pro-inflammatory markers that produce deleterious effects on neuronal cells. Ferulic acid (FA) is a phenolic compound that exerts antioxidant and anti-inflammatory effects in neurodegenerative disease. However, the manner in which FA inhibits neuroinflammation-induced neurodegeneration is poorly understood. Therefore, we investigated the anti-inflammatory effects of FA against LPS-induced neuroinflammation in the mouse brain. First, we provide evidence that FA interferes with TLR4 interaction sites, which are required for the activation of microglia-induced neuroinflammation, and further examined the potential mechanism of its neuroprotective effects in the mouse hippocampus using molecular docking simulation and immunoblot analysis. Our results indicated that FA treatment inhibited glial cell activation, p-JNK, p-NF <subscript>K</subscript> B, and downstream signaling molecules, such as iNOS, COX-2, TNF-α, and IL-1β, in the mouse hippocampus and BV2 microglial cells. FA treatment strongly inhibited mitochondrial apoptotic signaling molecules, such as Bax, cytochrome C, caspase-3, and PARP-1, and reversed deregulated synaptic proteins, including PSD-95, synaptophysin, SNAP-25, and SNAP-23, and synaptic dysfunction in LPS-treated mice. These findings demonstrated that FA treatment interfered with the TLR4/MD2 complex binding site, which is crucial for evoking neuroinflammation via microglia activation and inhibited NF <subscript>K</subscript> B likely via a JNK-dependent mechanism, which suggests a therapeutic implication for neuroinflammation-induced neurodegeneration.
- Subjects :
- Animals
Apoptosis drug effects
Astrocytes drug effects
Astrocytes metabolism
Biomarkers metabolism
Cell Line
Cognition drug effects
Coumaric Acids pharmacology
Hippocampus drug effects
Inflammation pathology
Inflammation Mediators metabolism
JNK Mitogen-Activated Protein Kinases metabolism
Lipopolysaccharides
Male
Mice, Inbred C57BL
Microglia drug effects
Microglia metabolism
Mitochondria drug effects
Mitochondria metabolism
NF-kappa B metabolism
Nerve Degeneration pathology
Neurotoxicity Syndromes pathology
Oxidative Stress drug effects
Signal Transduction drug effects
Synapses drug effects
Synapses metabolism
Toll-Like Receptor 4 metabolism
Up-Regulation drug effects
Coumaric Acids therapeutic use
Hippocampus metabolism
Neurotoxicity Syndromes drug therapy
Neurotoxicity Syndromes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1559-1182
- Volume :
- 56
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 30058023
- Full Text :
- https://doi.org/10.1007/s12035-018-1280-9