Combined exposure to lead and high-fat diet induced neuronal deficits in rats: Anti-neuroinflammatory role of SIRT1.

Abstract

Lead (Pb) exposure and high-fat diet (HFD) trigger neurotoxicity, which may involve neuroinflammation. However, the mechanism by which combined Pb and HFD exposure induces nucleotide oligomerization domain-like receptor family pyrin domain 3 (NLRP3) inflammasome activation has not been fully elucidated. The Sprague-Dawley (SD) rat model of exposure to Pb and HFD was established to reveal the influence of co-exposure on cognition and identify signaling clues that mediate neuroinflammation and synaptic dysregulation. PC12 cells was treated with Pb and PA in vitro. Silent information regulator 1 (SIRT1) agonist (SRT 1720) was employed as intervention agent. Our results showed that Pb and HFD exposure induced cognitive impairment and lead to neurological damage in rats. Meanwhile, Pb and HFD could stimulate the NLRP3 inflammasome assembly and activate caspase 1, releasing proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18), further promoting neuronal cell activation and amplifying neuroinflammatory responses. Additionally, our findings suggest that SIRT1 plays a role in Pb and HFD induced neuroinflammation. However, the use of SRT 1720 agonists showed some potential in alleviating these impairments. Pb exposure and HFD intake could induce neuronal damage through activation of the NLRP3 inflammasome pathway and synaptic dysregulation, while the NLRP3 inflammasome pathway may be rescued via activating SIRT1.