Silica nanoparticles trigger striatal oxidative stress, apoptosis, and histopathological alterations: in vivo and in silico molecular docking insights.

Abstract

Humans are increasingly exposed to silica nanoparticles (SiNPs) from environmental and occupational sources, raising significant concerns about their safety. Despite growing applications, data on their neurotoxic effects, particularly those involving oxidative/nitrosative imbalance and striatal damage, remain limited. This study aimed to elucidate the mechanisms of SiNP-induced neurotoxicity in the striatum, a brain region crucial for motor control and learning, using a rat model. Subacute intraperitoneal administration of SiNPs (25 and 100 mg/kg bw/day for 28 days) resulted in a marked increase in lipid peroxidation (LPO), reactive oxygen species (ROS), nitrite (NO), and protein carbonyl content, alongside a significant reduction in the activity of antioxidant enzymes, viz. superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as glutathione (GSH). Additionally, cholinergic [acetylcholinesterase (AChE) and b1utyrylcholinesterase (BChE)] and membrane-bound adenosine triphosphate (ATP)ase (Na⁺/K⁺, Mg²⁺, and Ca²⁺ ATPase) activities were significantly reduced in the striatum. Immunofluorescence and immunohistochemistry revealed elevated expression of antioxidant markers, particularly nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Quantitative reverse-transcriptase real-time polymerase chain reaction (qRT-PCR) analysis demonstrated upregulation of pro-apoptotic genes (Bax, p53, caspase-9/3) and downregulation of the anti-apoptotic gene Bcl-2, leading to an increased Bax/Bcl-2 ratio. Complementary in silico molecular docking studies showed that SiNPs exhibit notable binding affinities toward Nrf2, HO-1, AChE, and BChE. Collectively, these findings indicate that SiNPs induce striatal neurotoxicity via oxidative/nitrosative stress-mediated apoptosis, involving activation of Nrf2/HO-1, cholinergic disruption, and apoptotic signaling pathways.