Diacerein attenuates cisplatin-induced cerebellar neurotoxicity in rats: modulation of PI3K/AKT signaling and inhibition of NLRP3-mediated pyroptosis

Aim This study investigated Diacerein’s capacity to protect the cerebellum from cisplatin-driven neurotoxicity characterized by oxidative stress, inflammation, and apoptosis and clarified the associated molecular pathways. Methods Forty adult male Wistar rats were assigned to four groups: control, Diacerein (100 mg/kg), cisplatin (10 mg/kg), and cisplatin plus Diacerein. After seven days of treatment, cerebellar tissues were assessed for oxidative, inflammatory, apoptotic, and pyroptotic alterations using biochemical assays, ELISA, and qRT-PCR. Results Cisplatin exposure caused profound cerebellar degeneration, evidenced by heightened lipid peroxidation, depletion of endogenous antioxidant defenses, and marked suppression of the PI3K/AKT survival pathway. These disturbances were accompanied by robust activation of the NF-κB/NLRP3 inflammasome axis, resulting in elevated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and increased pyroptotic mediators (caspase-1, IL-18, GSDMD). Apoptotic imbalance was also apparent, with upregulation of Bax and caspase-3 and reduced Bcl-2 expression. Histopathological examination corroborated these biochemical disruptions. Co-administration of Diacerein significantly mitigated cisplatin-induced cerebellar toxicity by restoring redox homeostasis, reactivating PI3K/AKT signaling, and suppressing NF-κB-driven inflammatory and pyroptotic cascades. Diacerein also normalized apoptotic markers and preserved cerebellar architecture. Conclusion Collectively, these findings indicate that Diacerein affords substantial neuroprotection against cisplatin-induced cerebellar degeneration through coordinated modulation of oxidative stress, inflammation, and programmed cell death pathways, highlighting its promise as an adjuvant strategy to reduce chemotherapy-associated neurotoxicity.