International immunopharmacology · 2026
Anacardic acid mitigates traumatic brain injury-induced inflammatory damage: involvement of TLR4/MyD88/NF-κB pathway regulation and inhibition of P300 HAT activity on NF-κB acetylation.
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Yang Chenguang, Ru Junnan, Zhang Xingxing, Kong Xiaobin, Zhu Chaoran, Gao Zhuqi, Chen Fatao, Zheng Kaiwei, Jin Kunlin, Zhuge Qichuan, Yang Su, Huang Lijie
Аннотация
INTRODUCTION: Traumatic brain injury (TBI) triggers neuroinflammation and NLRP3 inflammasome-dependent pyroptosis, causing substantial neuronal damage. Anacardic acid (AA), a natural histone acetyltransferase (HAT) inhibitor, has anti-inflammatory properties related to TBI. This study explored AA's effects on pyroptosis and its neuroprotective potential after TBI.
METHODS: A controlled cortical impact (CCI) mouse model was employed. Neurological recovery was evaluated by mNSS and rotarod tests, lesion volume by H&E staining, and neuronal survival by NeuN/TUNEL immunofluorescence. Inflammatory cytokines were measured via ELISA, and inflammatory-related proteins by western blotting. Pyroptosis was assessed through LDH release, GSDMD cleavage, and microglial IBA-1/cleaved Caspase-1 (p20) immunostaining. The role of P300 in NF-κB acetylation was determined using CTB (an activator of HAT) and P300 knockdown via siRNA.
RESULTS: AA treatment reduced brain lesion volume, improved neurological function, and promoted cortical neuronal survival. It significantly decreased pro-inflammatory cytokine levels (IL-1β, IL-6, IL-18, TNF-α), inhibited NLRP3 inflammasome assembly, and blocked microglial pyroptosis. AA also suppressed the TLR4/MyD88/NF-κB pathway and upstream NF-κB activation. Remarkably, p300 knockdown exacerbated NF-κB acetylation and NLRP3 inflammasome assembly, while CTB administration reversed these effects.
CONCLUSIONS: AA confers neuroprotection in TBI by alleviating neuroinflammation and NLRP3-dependent pyroptosis. This is achieved by inhibiting the TLR4/MyD88/NF-κB pathway and suppressing p300-mediated NF-κB acetylation, suggesting AA's therapeutic potential for TBI.
METHODS: A controlled cortical impact (CCI) mouse model was employed. Neurological recovery was evaluated by mNSS and rotarod tests, lesion volume by H&E staining, and neuronal survival by NeuN/TUNEL immunofluorescence. Inflammatory cytokines were measured via ELISA, and inflammatory-related proteins by western blotting. Pyroptosis was assessed through LDH release, GSDMD cleavage, and microglial IBA-1/cleaved Caspase-1 (p20) immunostaining. The role of P300 in NF-κB acetylation was determined using CTB (an activator of HAT) and P300 knockdown via siRNA.
RESULTS: AA treatment reduced brain lesion volume, improved neurological function, and promoted cortical neuronal survival. It significantly decreased pro-inflammatory cytokine levels (IL-1β, IL-6, IL-18, TNF-α), inhibited NLRP3 inflammasome assembly, and blocked microglial pyroptosis. AA also suppressed the TLR4/MyD88/NF-κB pathway and upstream NF-κB activation. Remarkably, p300 knockdown exacerbated NF-κB acetylation and NLRP3 inflammasome assembly, while CTB administration reversed these effects.
CONCLUSIONS: AA confers neuroprotection in TBI by alleviating neuroinflammation and NLRP3-dependent pyroptosis. This is achieved by inhibiting the TLR4/MyD88/NF-κB pathway and suppressing p300-mediated NF-κB acetylation, suggesting AA's therapeutic potential for TBI.