Dose-dependent neurotoxic effects of anastrozole via disrupting NLRP3 inflammasome and α-synuclein pathways.

PMID 42139902 | DOI 10.1016/j.tice.2026.103590 · Tissue & cell · 2026

Anastrozole (ANZ) is a commonly used aromatase inhibitor in the treatment of hormone-dependent breast cancer. Despite its toxicity profile reported in different studies, the neurotoxic effects against this drug have not been explored yet. The present study was aimed at investigating the neurotoxic effects of ANZ in Sprague Dawley rats using comprehensive biochemical, molecular and histopathological analysis. Rats were divided into control and ANZ treated (0.1, 0.2 and 0.5 mg/ kg) doses. It was found that ANZ intoxication promoted the gene expression of NLRP3, PYCARD, CASP1, IL1-β, IL18, TXNIP, SNCA, and LRRK2 while suppressing the expression of PARK2, PINK1, PARK7 and UCHL1 in dose dependent manner. Moreover, ANZ exposure significantly reduced the antioxidant defense systems as shown by reduction in the activities of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GSR), glutathione-peroxidase (GPx) and heme oxygenase-1 (HO-1) coupled with elevated levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Similarly, ANZ administration showed marked reductions in the levels of BDNF, NGF, GDNF PSD-95, and synaptophysin while increasing the levels of NF-κB, COX-2, TNF-α, IL-1β, and IL-6. Nonetheless, ANZ exposure provoked the levels of Caspase-9, Bax, and Caspase-3 while inhibiting the levels of Bcl-2. Histological examination confirmed the dose-dependent neuronal degeneration such as vacuolization, pyknosis and structural disorganization. Collectively, these results showed that ANZ causes significant neurotoxicity due to oxidative stress, inflammation, and apoptosis resulting in neuronal survival and function dysfunction. This study shows the importance of careful therapeutic use of ANZ and laid down the foundation for further research on the neurological safety profile of ANZ.