Isochlorogenic acid A ameliorated lead-induced anxiety-like behaviors in mice by inhibiting ferroptosis-mediated neuroinflammation via the BDNF/Nrf2/GPX4 pathways

Lead (Pb) is a common environmental neurotoxicant that causes behavioral impairments in both rodents and humans. Isochlorogenic acid A (ICAA), a phenolic acid found in a variety of natural sources such as tea, fruits, vegetables, coffee, plant-based food products, and various medicinal plants, exerts multiple effects, including protective effects on the lungs, livers, and intestines. The objective of this study was to investigate the potential neuroprotective effects of ICAA against Pb-induced neurotoxicity in ICR mice. The results indicate that ICAA attenuates Pb-induced anxiety-like behaviors. ICAA reduced neuroinflammation, ferroptosis, and oxidative stress caused by Pb. ICAA successfully mitigated the Pb-induced deficits in the cholinergic system in the brain through the reduction of ACH levels and the enhancement of AChE and BChE activities. ICAA significantly reduced the levels of ferrous iron and MDA in the brain and prevented decreases in GSH, SOD, and GPx activity. Immunofluorescence analysis demonstrated that ICAA attenuated ferroptosis and upregulated GPx4 expression in the context of Pb-induced nerve damage. Additionally, ICAA downregulated TNF-α and IL-6 expression while concurrently enhancing the activations of Nrf2, HO-1, NQO1, BDNF, and CREB in the brains of mice. The inhibition of BDNF, Nrf2 and GPx4 reversed the protective effects of ICAA on Pb-induced ferroptosis in nerve cells. In general, ICAA ameliorates Pb-induced neuroinflammation, ferroptosis, oxidative stress, and anxiety-like behaviors through the activation of the BDNF/Nrf2/GPx4 pathways.