Natural Xanthone α-Mangostin Inhibits LPS-Induced Microglial Inflammatory Responses and Memory Impairment by Blocking the TAK1/NF-κB Signaling Pathway

Abstract

Scope: The effect of α-mangostin (α-M), a polyphenolic xanthone isolated from mangostin, on lipopolysaccharide (LPS)-induced microglial activation and memory impairment is explored. The possible underlying mechanisms are also investigated.

Methods and results: Cytokine production and activation of transforming growth factor activated kinase-1 (TAK1) and nuclear factor-κB (NF-κB) are detected by enzyme-linked immunosorbent assay (ELISA) or Western blot. Microglial migration and phagocytosis are evaluated with scratch wound-healing assay and phagocytosis of fluorescent latex beads, respectively. Learning and memory abilities of mice are evaluated with the Morris water maze test. The nanomolar (100-500 nm) α-M suppresses LPS-induced pro-inflammatory cytokine production and inducible nitric oxide synthase (iNOS) expression in microglia. It also inhibits LPS-induced microglial migration and phagocytosis. α-M rescues LPS-caused, microglia-mediated neuronal dendritic damage. Moreover, α-M represses LPS-induced toll-like receptor 4 (TLR4) expression and activation of TAK1 and NF-κB. In a mouse neuroinflammation model, α-M (50 mg kg^-1 day^-1 ) shows obvious anti-neuroinflammatory, neuroprotective, and memory-improving effects in vivo.

Conclusion: α-M inhibits microglia-mediated neuroinflammation and prevents neurotoxicity and memory impairment from inflammatory damage. These results indicate that α-M has great potential to be used as a nutritional preventive strategy for neuroinflammation-related neurodegenerative disorders such as Alzheimer's disease.

Keywords: TLR4; memory; microglia; neuroinflammation; α-mangostin.