Hydroxysafflor yellow a confers neuroprotection against acute traumatic brain injury by modulating neuronal autophagy to inhibit NLRP3 inflammasomes

Hydroxysafflor yellow A (HSYA) is the principal bioactive compound isolated from the plant Carthamus tinctorius L. and has been reported to exert neuroprotective effects against various neurological diseases, including traumatic brain injury (TBI). However, the specific molecular and cellular mechan...

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Published in:Journal of ethnopharmacology 2023-05, Vol.308, p.116268-116268, Article 116268
Main Authors: Lai, Zelin, Li, Cong, Ma, Huihan, Hua, Shiting, Liu, Zhizheng, Huang, Sixian, Liu, Kunlin, Li, Jinghuan, Feng, Zhiming, Cai, Yingqian, Zou, Yuxi, Tang, Yanping, Jiang, Xiaodan
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases
AMPK signalling
Animals
Autophagy
Brain Injuries, Traumatic - metabolism
Hydroxysafflor yellow A
Inflammasomes - metabolism
Mice
Neuronal autophagy
Neuroprotection
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
NLRP3 inflammasome
TOR Serine-Threonine Kinases
Traumatic brain injury
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Summary:Hydroxysafflor yellow A (HSYA) is the principal bioactive compound isolated from the plant Carthamus tinctorius L. and has been reported to exert neuroprotective effects against various neurological diseases, including traumatic brain injury (TBI). However, the specific molecular and cellular mechanisms underlying HSYA-mediated neuroprotection against TBI are unclear. This study explored the effects of HSYA on autophagy and the NLRP3 inflammasome in mice with TBI and the related mechanisms. Mice were subjected to TBI and treated with or without HSYA. Neurological severity scoring, LDH assays and apoptosis detection were first performed to assess the effects of HSYA in mice with TBI. RNA-seq was then conducted to explore the mechanisms that contributed to HSYA-mediated neuroprotection. ELISA, western blotting, and immunofluorescence were performed to further investigate the mechanisms of neuroinflammation and autophagy. Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, was applied to determine the connection between autophagy and the NLRP3 inflammasome. HSYA significantly decreased the neurological severity score, serum LDH levels and apoptosis in mice with TBI. A total of 921 differentially expressed genes were identified in the cortices of HSYA-treated mice with TBI and were significantly enriched in the inflammatory response and autophagy. Furthermore, HSYA treatment markedly reduced inflammatory cytokine levels and astrocyte activation. Importantly, HSYA suppressed neuronal NLRP3 inflammasome activation, as indicated by decreased levels of NLRP3, ASC and cleaved caspase-1 and a reduced NLRP3+ neuron number. It increased autophagy and ameliorated autophagic flux dysfunction, as evidenced by increased LC3 II/LC3 I levels and decreased P62 levels. The effects of HSYA on the NLRP3 inflammasome were abolished by 3-MA. Mechanistically, HSYA may enhance autophagy through AMPK/mTOR signalling. HSYA enhanced neuronal autophagy by triggering the AMPK/mTOR signalling pathway, leading to inhibition of the NLRP3 inflammasome to improve neurological recovery after TBI. [Display omitted] •HSYA inhibits neuronal NLRP3 inflammasome activation after TBI.•HSYA augments neuronal autophagy and ameliorates autophagic flux dysfunction.•HSYA induces autophagy to suppress NLRP3 inflammasome.•HSYA may trigger AMPK/mTOR signalling to enhance autophagy.
ISSN:0378-8741
1872-7573
DOI:10.1016/j.jep.2023.116268