Lycopene mitigates atrazine-induced hypothalamic neural stem cell senescence by modulating the integrated stress...

Atrazine, a widely used herbicide, has become a major pollutant in agricultural water bodies. Pesticide contamination, including atrazine, is linked to a high incidence of age-related neurodegenerative diseases, suggesting its neurotoxic potential. Lycopene, a potent antioxidant, is renowned for its diverse pharmacological effects, especially its neuroprotective properties. However, the underlying pharmacological mechanisms of lycopene and its impact on potential pathways against atrazine-induced hypothalamic damage have not been elucidated.

Our study aimed to elucidate how lycopene ameliorates hypothalamic injury triggered by atrazine exposure, with a special focus on the pluripotency of neural stem cells (NSCs) and pathways involved in cell senescence.

Mice were administered lycopene and/or atrazine via gavage for 21 days. The C17.2 NSC cell line and specific molecular inhibitors were utilized to examine the potential protective effects of lycopene in vitro. Morphological changes and ultrastructural damage in the hypothalamus were observed by hematoxylin-eosin staining and transmission electron microscopy, respectively. The mechanisms of action of lycopene were explored through various methods, including senescence β-galactosidase staining, multiplex immunofluorescence, Western blotting and qRT‒PCR.

Our results indicated that lycopene notably ameliorated atrazine-induced histological and ultrastructural damage, as well as the loss of intact and mature neurons in mouse hypothalami. Additionally, hypothalamic NSCs (HtNSCs) and microglia were recruited to areas of neuronal injury after atrazine exposure; intriguingly, lycopene treatment reduced this recruitment. Through in vivo and in vitro assays, we elucidated the outcomes of atrazine-induced HtNSC recruitment and neuronal loss, along with the neuroprotective mechanisms of lycopene. Mechanistically, lycopene prevents atrazine-induced senescence in HtNSCs and enhances their proliferation and differentiation by inhibiting the integrated stress response (ISR) signaling pathway, thus promoting the renewal of damaged neurons in the hypothalamus.

Collectively, the results of the present study reveal, for the first time, that lycopene mitigates atrazine-induced HtNSC senescence by modulating the ISR signaling pathway. These findings offer novel insights into the role of lycopene in preventing and alleviating NSC senescence and suggest its potential development as a new therapy for neurodegenerative diseases.