This study is aimed to investigate the
inflammation and neurological dysfunction induced by tetrachloro-
p-benzoquinone (TCBQ) through
Toll-like receptor 4 (TLR4) signaling. We also investigated the protective role of
melatonin as an
antioxidant and
anti-inflammatory agent. In vitro model was established by rat
pheochromocytoma PC12 cells, meanwhile, TLR4 wild-type (C57BL/6) and knockout mice (C57BL/10ScNJ TLR4-/-) were used as in vivo model. In vitro study showed TCBQ exposure enhanced the expression of TLR4,
myeloid differentiation factor 88 (MyD88) at both transcriptional and post-transcriptional levels. By contrast,
melatonin decreased TLR4 and MyD88 expressions. Moreover, our result indicated that
melatonin disrupted the formation of TLR4/MyD88/MD2/CD14 complex. In addition,
melatonin terminated TCBQ-mediated phosphorylation of
c-Jun N-terminal kinase (JNK), p38, and extracellular regulated
protein kinase (ERK) signaling and hampered its downstream pro-inflammatory
cytokine releases. In vivo result also indicated TLR4 deficiency partially protected against TCBQ-induced morphological and neuropathological changes in mice brain, suggested the role of TLR4. In conclusion,
melatonin modulates TCBQ-mediated inflammatory genes through TLR4/MyD88-dependent signaling pathway. Our current study, to the best of our knowledge, is the first time show
melatonin not only disrupt the binding of TLR4 and MyD88, but also restricted the formation of TLR4/MD2/CD14 complex, suggesting that
melatonin supplementary may represent a valuable therapeutic strategy for inflammatory neurological dysfunction.