Combating Lead/HFD Neurotoxicity in Rats: The Synergistic Effect of 10-Hydroxydecanoic Acid and Zinc Oxide Nanoparticles.

Exposure to heavy metals and unbalanced diets poses significant global health concerns. This study investigated the neurotoxic effect of chronic lead acetate and high-fat diet (Pb/HFD) co-exposure in rats and the neuroprotective potential of 10-hydroxydecanoic acid (HDA) and zinc oxide nanoparticles (ZnO-NPs). Rats were allocated into naive, HDA, ZnO-NPs, MIX (HDA/ZnO-NPs), Pb/HFD, Pb/HFD + HDA, Pb/HFD + ZnO-NPs, and Pb/HFD + MIX, with 10 rats per group. For 12 weeks, rats received a daily oral dose of PbAc (30 mg/kg) alongside a 40% fat HFD. Following this induction period, groups continued the Pb/HFD exposure for an additional 4 weeks while also receiving a daily dose of either HDA (5 mg/kg), ZnO-NPs (5 mg/kg), or a combination of both. Spatial learning and memory, brain lead content, and key markers of oxidative stress, neuroinflammation, amyloidogenesis, and apoptosis were evaluated. Pb/HFD co-exposure significantly increased brain lead levels, leading to cognitive impairment as evidenced by the Morris water maze test. This was attributed to a rise in oxidative stress, inflammatory responses, and amyloidogenesis, alongside a reduction in antioxidant markers and a proliferation of glial cells. In contrast, HDA effectively mitigated both the cognitive deficits and the underlying neuroinflammation and oxidative stress. Conversely, ZnO-NPs alone were linked to detrimental cognitive effects, primarily through oxidative stress and neuroinflammation. Our findings support a neuroprotective role for HDA and highlight the need for caution regarding ZnO-NPs monotherapy. Critically, the combination of HDA and ZnO-NPs exhibited a synergistic neuroprotective effect, offering a promising and enhanced therapeutic strategy against environmental and dietary neurotoxic stressors.