Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Ethanol extract of Periploca forrestii Schltr. and chlorogenic acid alleviate ischemic stroke by inhibiting TLR4-mediated neuroinflammation.
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Wu Wenze, Xu Libin, Sun Lu, Xue Juan, Wang Feng, Guo Hua, Lei Ning, Liu Dongyao, Liu Yueyang, Liang Dong, Wang Yan, Mi Yan, Chai Huifang, Hou Yue
Аннотация
BACKGROUND: Neuroinflammation is a major factor in the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). Periploca forrestii Schltr., commonly known as Heiguteng (HGT) in China, is a traditional anti-inflammatory herb that has been found effective in treating cardiovascular and cerebrovascular diseases. However, its potential protective effects against CIRI remain unclear.
PURPOSE: This study aimed to investigate the pharmacological actions and underlying mechanisms of ethanol extract of HGT (EEHGT) on CIRI.
METHODS: The middle cerebral artery occlusion-reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models were used to evaluate the protective effects of EEHGT on CIRI. Additionally, comprehensive metabolomics and systems pharmacology analyses were performed to elucidate the mechanisms of EEHGT.
RESULTS: The results demonstrated that EEHGT effectively alleviated CIRI in MCAO/R rats and reduced neuronal damage in OGD/R-treated SH-SY5Y cells. Notably, EEHGT mitigated the secretion of pro-inflammatory cytokines and restored the levels of key inflammation-related metabolites, including arginine, lactate, and L-tyrosine. Network pharmacology analysis indicated that the PI3K-Akt and NF-κB signaling pathways are involved in mediating the neuroprotective and anti-inflammatory activities of EEHGT. Consistent with this result, EEHGT activated PI3K-Akt pathway and inhibited NF-κB signaling in both MCAO/R rats and OGD/R-treated BV2 cells. The results indicated that TLR4 serves as a key mediator of EEHGT on CIRI, and TLR4 knockdown abolished its anti-neuroinflammatory effects. In addition, chlorogenic acid (CGA), an active compound of EEHGT, exhibited strong binding affinity to TLR4, and its anti-inflammatory activity was abolished upon TLR4 knockdown.
CONCLUSIONS: Collectively, this study provides the first evidence that EEHGT protects against CIRI by attenuating TLR4-mediated neuroinflammation. Mechanistically, EEHGT exerts its anti-inflammatory effects by activating the PI3K-Akt pathway and inhibiting NF-κB signaling. Notably, TLR4 was identified as a shared therapeutic target of both EEHGT and its active component, CGA, highlighting a novel mechanism underlying their neuroprotective effects.
PURPOSE: This study aimed to investigate the pharmacological actions and underlying mechanisms of ethanol extract of HGT (EEHGT) on CIRI.
METHODS: The middle cerebral artery occlusion-reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models were used to evaluate the protective effects of EEHGT on CIRI. Additionally, comprehensive metabolomics and systems pharmacology analyses were performed to elucidate the mechanisms of EEHGT.
RESULTS: The results demonstrated that EEHGT effectively alleviated CIRI in MCAO/R rats and reduced neuronal damage in OGD/R-treated SH-SY5Y cells. Notably, EEHGT mitigated the secretion of pro-inflammatory cytokines and restored the levels of key inflammation-related metabolites, including arginine, lactate, and L-tyrosine. Network pharmacology analysis indicated that the PI3K-Akt and NF-κB signaling pathways are involved in mediating the neuroprotective and anti-inflammatory activities of EEHGT. Consistent with this result, EEHGT activated PI3K-Akt pathway and inhibited NF-κB signaling in both MCAO/R rats and OGD/R-treated BV2 cells. The results indicated that TLR4 serves as a key mediator of EEHGT on CIRI, and TLR4 knockdown abolished its anti-neuroinflammatory effects. In addition, chlorogenic acid (CGA), an active compound of EEHGT, exhibited strong binding affinity to TLR4, and its anti-inflammatory activity was abolished upon TLR4 knockdown.
CONCLUSIONS: Collectively, this study provides the first evidence that EEHGT protects against CIRI by attenuating TLR4-mediated neuroinflammation. Mechanistically, EEHGT exerts its anti-inflammatory effects by activating the PI3K-Akt pathway and inhibiting NF-κB signaling. Notably, TLR4 was identified as a shared therapeutic target of both EEHGT and its active component, CGA, highlighting a novel mechanism underlying their neuroprotective effects.