Green-Synthesized Silver Nanoparticles Improve Cognitive Function and Modulate Nrf2/HO-1-BDNF-Related Gene Expression in Experimental Chronic Toxoplasmosis.

Abstract

BACKGROUND AND AIMS: This study aimed to evaluate the neuroprotective effects of silver nanoparticles (AgNPs) green-synthesized using the ethanolic extract of Muscari neglectum against Toxoplasma gondii-induced cognitive impairment and to explore the underlying Nrf2/BDNF and oxidative stress-related mechanisms. METHODS: Chronic toxoplasmosis was experimentally induced in mice using the Tehran strain of T. gondii. Forty-eight mice were randomly allocated into six experimental groups, including a noninfected control group, an infected untreated control group, and four treatment groups receiving pyrimethamine (PYM, 20 mg/kg), donepezil (DON, 2 mg/kg), AgNPs (10 mg/kg), or AgNPs (20 mg/kg). Spatial learning and memory capabilities were assessed using the Morris water maze test. Post-treatment, brain cyst number and size were determined via microscopic examination. Additionally, quantitative real-time PCR was employed to evaluate the expression levels of genes associated with oxidative stress and neuroprotection, including brain-derived neurotrophic factor (Bdnf), NADPH oxidase 2 (Nox2), superoxide dismutase 2 (Sod2), catalase (Cat), glutathione peroxidase 1 (Gpx1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (Hmox1). RESULTS: Treatment with AgNP resulted in a significant, dose-dependent improvement in behavioral performance, evidenced by reduced escape latency and enhanced exploration of the target quadrant (p < 0.001). Moreover, AgNP administration markedly decreased both the number and size of brain Toxoplasma cysts, with the 20 mg/kg dose demonstrating superior efficacy compared to PYM (p < 0.01). Molecular analyses indicated significant upregulation of Nrf2, Hmox1, Bdnf, Sod2, Cat, and Gpx1, accompanied by downregulation of Nox2 expression in mice treated with AgNP (p < 0.001). CONCLUSION: These findings suggest that green-synthesized AgNP exert significant, dose-dependent antiparasitic and neuroprotective effects in the context of chronic toxoplasmosis. AgNP notably reduced brain cyst burden, enhanced spatial learning and memory, and normalized oxidative stress-related gene expression. Importantly, AgNP exhibited greater efficacy than both PYM and DON, indicating their potential as a promising therapeutic approach for neurotoxoplasmosis.

Key Findings

• Green-synthesized silver nanoparticles (AgNPs) improved cognitive function in mice with chronic toxoplasmosis in a dose-dependent manner.
• AgNP treatment significantly reduced the number and size of brain Toxoplasma cysts, outperforming pyrimethamine at the higher dose.
• AgNP administration upregulated neuroprotective and antioxidant genes including Nrf2, Hmox1, Bdnf, Sod2, Cat, and Gpx1, while downregulating the oxidative stress-related gene Nox2.

Clinical Significance

Citation

Khaksarian Mojtaba, Khalaf Amal Khudair, Shojaee Saeedehet al.. Green-Synthesized Silver Nanoparticles Improve Cognitive Function and Modulate Nrf2/HO-1-BDNF-Related Gene Expression in Experimental Chronic Toxoplasmosis. Journal of tropical medicine. 2026.