Green-Synthesized Silver Nanoparticles with <i>Nigella sativa</i>: A Multifaceted Approach against Parkinson’s Disease in Rats via MicroRNA Modulation

Parkinson's disease (PD) is a prevalent neurodegenerative disease. As the disease advances, patients become less receptive to levodopa and disease progression continues. So, there is a need for alternative treatment. Green synthesis of silver nanoparticles using <i>Nigella sativa</i> (NS-AgNPs) gives AgNPs additional pharmacological properties. We aimed to explore the possible therapeutic and/or protective effects of NS-AgNPs on PD-like model rats at different levels: histological, behavioral, α-synuclein (α-syn) aggregation, redox, neurotransmitters, apoptosis, and microRNAs (miR-34c and miR-124). The PD-like model was induced in rats by subcutaneous injection of rotenone (2 mg/kg) daily for 30 days. Then, PD-like rats were divided into the Nanotreated group, receiving NS-AgNPs (orally, 10 mg/kg daily for 30 days); Sinemet-treated group, receiving Sinemet 25 mg/250 mg (orally 10 mg/kg daily for 30 days); and Nanoprotected group, receiving rotenone and NS-AgNPs (10 mg/kg daily for 30 days) simultaneously. The PD-like rats disturbed the striatal histoarchitecture, increased α-syn content, oxidative stress, inflammation, and apoptosis, and decreased neurotransmission and microRNAs (miRs) levels. The Sinemet-treated group showed moderate histoarchitectural improvement and partially enhanced behavioral performance, neurotransmission, inflammation, and oxidative stress. In contrast, the NS-AgNPs ameliorated these effects and targeted multiple key pathways in the development and progression of PD, mainly through the modulation of miR-34a and miR-124 expression and significant elevation in dopamine content. It also decreased α-syn aggregation, inhibited microglial activation and apoptosis, decreased oxidative stress levels, and upregulated vesicular monoamine transporter 2 (VMAT2). This goes accordingly with the histopathological examination of the striatum and improvement in the behavioral performance of the PD-like rats. All of these effects, together with no adverse effects of NS-AgNPs, make it a promising therapeutic and neuroprotective agent for PD management.