Modulation of Oxidative Stress and Apoptosis by Antrodia cinnamomea–Loaded Citrate-Stabilized Silver Nanoparticles in Experimental Parkinsonism

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra pars compacta, accompanied by oxidative stress and neuroinflammation. Novel multitarget neuroprotective strategies are required to overcome the limitations of current symptomatic treatments. The neuroprotective effects of Antrodia cinnamomea (AC) and citrate-stabilized silver nanoparticles (AgNPs), alone and in combination, were evaluated using a 6-hydroxydopamine (6-OHDA)–induced SH-SY5Y cell model and a unilateral 6-OHDA rat model. Sixty-three rats were divided into nine experimental groups. Cell viability, behavioral tests, LC–MS/MS analysis of dopamine and acetylcholine, oxidative stress and inflammatory biomarkers, histopathological assessment, immunohistochemistry, and Western blot analyses of TH, α-synuclein, PI3K, Bcl-2, Caspase-3, and agmatinase were performed. 6-OHDA significantly reduced cell viability, impaired motor performance, and induced dopaminergic neuronal degeneration. AC treatment, particularly in combination with AgNPs, markedly improved cell survival, ameliorated behavioral deficits, and preserved neuronal architecture. Combined treatment significantly decreased MDA, TNF-α, and IL-1β levels, while restoring GSH and SOD activities. LC–MS/MS analysis demonstrated partial recovery of dopamine and acetylcholine levels. Increased TH and PI3K expression, reduced α-synuclein and Caspase-3 levels, and normalization of Bcl-2 and agmatinase were observed following AC + AgNP treatment. AC conjugated with citrate-stabilized AgNPs exerts significant neuroprotective effects in experimental PD by concurrently modulating oxidative stress, neuroinflammation, and apoptotic pathways, highlighting its potential as a multitarget therapeutic strategy. Graphical Abstract The graphical abstract contains some schematic illustrations created using BioRender. This information was inadvertently omitted and should be added accordingly