Neuroprotective effect of chicoric acid-loaded liposome nanoparticles against AlCl3-induced neurotoxicity in rats: Insights into the role of AMPK/AKT/Nrf-2 signaling pathway

Aluminum (Al) is the primary hazardous metal that individuals are exposed to in their daily lives via food, drinking water, and pharmaceuticals. The aim of this study was to evaluate the potential neuroprotective effect of chicoric acid-loaded liposome nanoparticles (CA nanoparticles) on aluminum chloride (AlCl3)-induced neurotoxicity in rats. CA nanoparticles were prepared using the thin-film hydration method, yielding nanoparticles with an average size of 146.3 nm, a polydispersity index (PDI) of 0.377, and a zeta potential of −41.8 mV, ensuring good stability. Thirty-two male Sprague-Dawley rats were allocated into four groups. The control group received saline, the control positive group was given AlCl3 (70 mg/kg/day p.o.) for 5 weeks, and the CA nanoparticle groups were given 2 doses (5 and 10 mg/kg/day p.o.) for 5 weeks, one hour after the injection of AlCl3. Behavioral tests, including open field and novel object tests, were conducted, and brain tissues were analysed for biochemical, molecular, histological and immune-histochemical changes at the end of the experiment. Compared with AlCl3, CA nanoparticles (10 mg/kg) improved the behavioral impairments and reduced the brain levels of acetylcholine esterase activity, glutamine, malondialdehyde, tumor necrosis factor-alpha, and interleukin-6 and increased the brain glutathione, nuclear factor erythroid 2-related factor 2 (Nrf-2), AKT signaling pathway, and AMP-activated kinase (AMPK) expression levels. Additionally, CA nanoparticles (10 mg/kg) improved histopathological changes and restored the immune-histochemical scores of glial fibrillary acidic proteins and the expression of Beclin. These findings revealed that CA nanoparticles (10 mg/kg) play a crucial role in the AMPK/AKT/Nrf-2 pathway, which is responsible for their antioxidant and anti-inflammatory effects against AlCl3-induced neurotoxicity in rats. These findings are paving the way for future investigations exploring the potential of CA nanoparticles in other neurodegenerative models, optimizing their formulation for enhanced brain targeting, and advancing their clinical translation as a therapeutic strategy.