Cadmium (Cd) is an important environmental and industrial pollutant that induces neurotoxicity and neurobehavioral disorders in animals. Urolithin A (UA), a gut microbial-derived metabolite from polyphenolic compounds, exhibits potent neuroprotective effects in neurological disorders. Herein, we evaluated the ameliorative impact of UA on Cd exposure-evoked hippocampal injury and cognitive deficits in mice and disclosed the underlying molecular mechanisms. C57BL/6J mice were randomly divided into four groups: Control, CdCl₂, CdCl₂ + UA, and UA. CdCl₂ (1 mg/kg) was administered intraperitoneally for 8 weeks. UA (200 mg/kg) was given by gavage 2 h prior to CdCl₂ treatment. SH-SY5Y cells were pretreated with UA followed by 20 μM CdCl₂ exposure. Behavioral tests (Morris water maze, Y-maze, Novel object recognition), Nissl staining, Immunofluorescence, Western blot, transmission electron microscopy, mitochondrial reactive oxygen species (mtROS) detection, and Flow cytometry were used to assess cognitive function, neuronal/synaptic damage, and molecular signaling. The results demonstrated that UA administration markedly mitigated hippocampal neuronal/synaptic injury and cognitive impairments in Cd-exposed mice. Mechanically, UA administration suppressed Cd exposure-triggered activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and subsequent neuronal pyroptosis in mice hippocampi and SH-SY5Y cells. Moreover, UA administration inhibited Cd-induced AhR activation and reduced the expression of CYP1A1, leading to mtROS elimination in vivo and in vitro. In conclusion, our findings revealed that UA mitigated Cd stress-driven aberrant NLRP3 inflammasome activation and its-mediated neuronal pyroptosis by promoting mtROS clearance, partly via the inhibition of the AhR-CYP1A1 signaling pathway, which ultimately contributed to the attenuation of neuronal/synaptic damage and cognitive deficits.
Zhu et al. (Tue,) studied this question.