Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway

Food Chem Toxicol. 2019 Dec:134:110824. doi: 10.1016/j.fct.2019.110824. Epub 2019 Sep 17.


Fisetin, a natural flavonoid found in plants, fruits and vegetables, exerts anti-cancer, anti-oxidant, anti-inflammatory and anti-mitotic effects. The current study instigates the protective effect of fisetin against lead-induced synaptic dysfunction, neuroinflammation and neurodegeneration in mice, and explores its underlying mechanisms. The results indicated fisetin can significantly ameliorated behavioral impairments in Pb-treated mice. Fisetin inhibited Pb-induced the apoptotic neurodegeneration, as indicated by the decreased levels of Bax and cleaved caspase-3. Fisetin suppressed activations of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), NF-κB and subsequently inactivate pro-inflammatory factor including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). It can also decrease the accumulation of p-tau and amyloid-beta (Aβ) and increased the expression of the Aβ remover neprilysin (NEP) in brains of mice. Fisetin also reversed Pb-induced synaptic dysfunction by increasing the levels of synaptosomal associated protein-25 (SNAP-25), postsynaptic density-95 (PSD-95), cyclic-AMP-response element-binding protein (CREB) phosphorylation and calcium/calmodulin kinase II (CaMKII) phosphorylation. Fisetin promoted Pb-induced autophagy in the brains of mice. Moreover, fisetin can increase levels of the denosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation and SIRT1. Fisetin may be developed as a potential nutritional target for the prevention of Pb-induced neurotoxicity.

Keywords: Apoptosis; Autophagy; Fisetin; Inflammation; Lead; Synaptic dysfunctions.

MeSH terms

  • Adenylate Kinase / metabolism*
  • Animals
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Brain / drug effects
  • Brain / physiopathology
  • Flavonoids / pharmacology
  • Flavonoids / therapeutic use*
  • Flavonols
  • Inflammation / drug therapy*
  • Lead / toxicity*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Phosphorylation
  • Sirtuin 1 / metabolism*
  • Synapses / drug effects*
  • Synapses / physiology


  • Flavonoids
  • Flavonols
  • Lead
  • Adenylate Kinase
  • Sirt1 protein, mouse
  • Sirtuin 1
  • fisetin