Silybin attenuates PERK/IRE1α ER-stress signaling, neuroinflammation, and restores CDNF levels in an MPTP-induced Parkinson's disease model.

Parkinson's disease (PD) is a progressive neurodegenerative disorder in which dopaminergic dysfunction is associated with oxidative stress, chronic neuroinflammation, and endoplasmic reticulum (ER)-stress-related signaling. ER-resident neurotrophic factors, cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF), have emerged as potential modulators of neuronal stress responses. Silybin, a flavonolignan derived from S. marianum, has antioxidant, anti-inflammatory, and neuroprotective effects in experimental PD models, although the molecular pathways underlying these effects remain incompletely defined. In this study, we evaluated whether silybin was associated with changes in CDNF/MANF levels, unfolded protein response-related markers, inflammatory mediators, and antioxidant enzyme activities in a subchronic MPTP mouse model. Silybin improved survival, reduced motor impairment, and partially preserved tyrosine hydroxylase content in the nigrostriatal pathway. Also, silybin selectively increased CDNF levels, whereas MANF remained unchanged. In parallel, silybin modulated PERK/eIF2α/ATF4- and IRE1α/XBP1-associated markers, lowered total NF-κB p65 and pro-inflammatory cytokine levels, and normalized several endogenous antioxidant enzyme activities. Correlation analyses identified CDNF as a prominent correlate of the protective phenotype, and in silico docking and molecular dynamics analyses further suggested that silybin may interact with PERK and IRE1α domains, providing a structural hypothesis compatible with the experimental findings. Overall, these results indicate that silybin modulates convergent changes in stress-, inflammatory-, and redox-related pathways in the MPTP model, together with selective CDNF upregulation and improved behavioral outcomes.