Celastrol exerts a neuroprotective effect by inhibiting necroptosis and inflammation in intracerebral hemorrhage-induced brain injury

BACKGROUND: Celastrol, a natural plant-derived compound with potent antioxidant and anti-inflammatory properties, demonstrates neuroprotective effects in various central nervous system disorders, though its impact on intracerebral hemorrhage (ICH) remains unexplored. This study examines whether celastrol modulates inflammation and necroptosis following ICH. METHODS: We established an ICH model in male C57BL/6 mice using collagenase IV and administered celastrol via intraperitoneal injection postinjury. Neurological function, Evans blue extravasation, brain water content, propidium iodide labeling, quantitative reverse transcription PCR, immunofluorescence staining, and Western blotting were employed to assess outcomes. RESULTS: Celastrol treatment markedly reduced cerebral edema and vascular leakage while improving neurological function post-ICH. The compound suppressed M1 microglial activation, evidenced by decreased Iba1 expression and reduced mRNA levels of tumor necrosis factor alpha, interleukin 1β, and inducible nitric oxide synthase. In addition, celastrol downregulated key necroptosis mediators receptor-interacting protein 3 and mixed lineage kinase domain-like protein, after ICH. CONCLUSION: These findings suggest that celastrol mitigates ICH-induced injury by concurrently inhibiting necroptotic pathways and inflammatory responses.