Neuroprotective Effects of the Nonsteroidal Anti-inflammatory Drug Celecoxib Against Caspase-1-dependent Pyroptosis Partially by Suppressing the HMGB1/TLR4 Pathway
Abstract
This study evaluated the protective effects of celecoxib on epilepsy and explore its potential involvement in regulating pyroptosis and the high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4) signaling pathway. Adult male Sprague-Dawley rats were injected with ferrous chloride (FeCl2) with or without celecoxib for 7 consecutive days. After sacrifice, tissues were collected for neurological function assessments, magnetic resonance imaging, and multiple tissue analyses. Intracerebral injection of FeCl2 in rats induced severe seizures, microglial recruitment and polarization, ferroptosis, pyroptosis, and inflammation in the frontal cortex. In the hippocampus, FeCl2 injection led to neuronal loss, reduced synaptic complexity, and aberrant HMGB1 expression. Celecoxib treatment delayed seizure onset and significantly reduced the severity and duration of seizures, the extent of injury, and neurological impairments caused by FeCl2 exposure. These effects were mediated through the suppression of HMGB1/TLR4 signaling and inhibition of key pro-inflammatory cytokines. Celecoxib treatment mitigated neuronal loss, improved synaptic complexity, stabilized microglial activity, inhibited astrocyte proliferation, and modulated HMGB1 expression. In conclusion, celecoxib effectively attenuated FeCl2-induced inflammation and neural injury partially by inhibiting the HMGB1/TLR4 pathway, thereby suppressing pyroptosis and reactive gliosis. These effects improved seizure, highlighting the…
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