TY - JOUR
T1 - Ferulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4 Receptor in the Mouse Hippocampus
AU - Rehman, Shafiq Ur
AU - Ali, Tahir
AU - Alam, Sayed Ibrar
AU - Ullah, Rahat
AU - Zeb, Amir
AU - Lee, Keun Woo
AU - Rutten, Bart P. F.
AU - Kim, Myeong Ok
N1 - Funding Information:
This research work was supported by the Brain Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT (2016M3C7A1904391).
Funding Information:
Acknowledgments This research work was supported by the Brain Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT (2016M3C7A1904391).
Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/4
Y1 - 2019/4
N2 - 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-NFKB, and downstream signaling molecules, such as iNOS, COX-2, TNF-, and IL-1, 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 NFKB likely via a JNK-dependent mechanism, which suggests a therapeutic implication for neuroinflammation-induced neurodegeneration.
AB - 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-NFKB, and downstream signaling molecules, such as iNOS, COX-2, TNF-, and IL-1, 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 NFKB likely via a JNK-dependent mechanism, which suggests a therapeutic implication for neuroinflammation-induced neurodegeneration.
KW - Microglia
KW - LPS
KW - TLR4
KW - Neuroinflammation
KW - Neurodegeneration
KW - ROS
KW - Synaptic dysfunction
KW - NF-KAPPA-B
KW - LIPOPOLYSACCHARIDE-INDUCED NEUROINFLAMMATION
KW - INDUCED OXIDATIVE STRESS
KW - TOLL-LIKE RECEPTORS
KW - MICROGLIAL ACTIVATION
KW - SIGNALING PATHWAYS
KW - CELL-DEATH
KW - IN-VIVO
KW - INHIBITION
KW - EXPRESSION
U2 - 10.1007/s12035-018-1280-9
DO - 10.1007/s12035-018-1280-9
M3 - Article
SN - 0893-7648
VL - 56
SP - 2774
EP - 2790
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 4
ER -