Geraniin Attenuates Lipopolysaccharide-Induced Cognitive Impairment in Mice by Inhibiting Toll-Like Receptor 4 Activation

摘要

Geraniin has been reported to possess potent anti-inflammatory properties and to modulate the macrophage polarization. This study sought to evaluate the protective effects and underlying mechanisms of geraniin on lipopolysaccharide (LPS)-induced neuroinflammation and neurobiological alternations as well as cognitive impairment. Daily intragastrical administration with geraniin (20 mg kg(-1) day(-1)) for 14 days significantly prolonged the duration in the target quadrant (26.53 +/- 2.03 versus 37.09 +/- 3.27%; p < 0.05) and increased crossing-target number (1.93 +/- 0.22 versus 3.08 +/- 0.17; p < 0.01) in the probe test of LPS-treated mice. Geraniin also ameliorated LPS-elicited neural/synaptic impairments and decreased levels of LPS-induced A beta generation (p < 0.05), amyloid precursor protein (APP) (p < 0.05) and beta-site amyloid precursor protein cleavage enzyme 1 (BACE1) (p < 0.05). Furthermore, geraniin suppressed the production of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) (9.85 +/- 0.58 versus 5.20 +/- 0.52 pg/mg of protein; p < 0.01), interleukin (IL)-1 beta (16.31 +/- 0.67 versus 8.62 +/- 0.46 pg/mg of protein; p < 0.01), and IL-6 (12.12 +/- 0.45 versus 7.43 +/- 0.32 pg/mg of protein; p < 0.05), and inhibited glial cell activation. Moreover, geraniin effectively polarized the microglia toward an anti-inflammatory M2 phenotype. Further study revealed that geraniin targeted toll-like receptor 4 (TLR4)-mediated signaling and decreased the production of pro-inflammatory cytokines in BV-2 microglial cells. These results indicate that geraniin mitigates LPS-elicited neural/synaptic neurodegeneration, amyloidogenesis, neuroinflammation, and cognitive impairment and suggest geraniin as a therapeutic option for neuroinflammation-associated neurological disorders, such as Alzheimer's disease.