HMGB1-triggered inflammation inhibition of notoginseng leaf triterpenes against cerebral ischemia and reperfusion injury via MAPK and NF-κB signaling pathways.

Abstract

Ischemic stroke is a clinically common cerebrovascular disease whose main risks include necrosis, apoptosis and cerebral infarction, all caused by cerebral ischemia and reperfusion (I/R) injury. This process has particular significance for the treatment of stroke patients. Notoginseng leaf triterpenes (PNGL), as a valuable medicine, have been discovered to have neuroprotective effects. However, it was not confirmed that whether PNGL may possess neuroprotective effects against cerebral I/R injury. To explore the neuroprotective effects of PNGL and their underlying mechanisms, a middle cerebral artery occlusion/reperfusion (MCAO/R) model was established. In vivo results suggested that in MCAO/R model rats, PNGL pretreatment (73.0, 146, 292 mg/kg) remarkably decreased infarct volume, reduced brain water content, and improved neurological functions; moreover, PNGL (73.0, 146, 292 mg/kg) significantly alleviated blood-brain barrier (BBB) disruption and inhibited neuronal apoptosis and neuronal loss caused by cerebral I/R injury, while PNGL with a different concertation (146, 292 mg/kg) significantly reduced the concentrations of IL-6, TNF-α, IL-1 β, and HMGB1 in serums in a dose-dependent way, which indicated that inflammation inhibition could be involved in the neuroprotective effects of PNGL. The immunofluorescence and western blot analysis showed PNGL decreased HMGB1 expression, suppressed the HMGB1-triggered inflammation, and inhibited microglia activation (IBA1) in hippocampus and cortex, thus dose-dependently downregulating inflammatory cytokines including VCAM-1, MMP-9, MMP-2, and ICAM-1 concentrations in ischemic brains. Interestingly, PNGL administration (146 mg/kg) significantly downregulated the levels of p-P44/42, p-JNK1/2 and p-P38 MAPK, and also inhibited expressions of the total NF-κB and phosphorylated NF-κB in ischemic brains, which was the downstream pathway triggered by HMGB1. All of these results indicated that the protective effects of PNGL against cerebral I/R injury could be associated with inhibiting HMGB1-triggered inflammation, suppressing the activation of MAPKs and NF-κB, and thus improved cerebral I/R-induced neuropathological changes. This study may offer insight into discovering new active compounds for the treatment of ischemic stroke.

• Authors: Weijie Xie, Ting Zhu, Xi Dong, Fengwei Nan, Xiangbao Meng, Ping Zhou, Guibo Sun, Xiaobo Sun
• Journal: Biomolecules (Biomolecules) Vol. 9 Issue 10 (09 20 2019) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 31547018 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• HMGB1 Protein
• Hbp1 protein, rat
• NF-kappa B
• Triterpenes
• Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Blood-Brain Barrier (drug effects)
• Brain Infarction (metabolism, prevention & control)
• Cytokines (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• HMGB1 Protein (metabolism)
• Infarction, Middle Cerebral Artery (complications, drug therapy, etiology)
• Male
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (metabolism)
• Panax notoginseng (chemistry)
• Plant Leaves (chemistry)
• Rats
• Reperfusion Injury (complications, drug therapy, etiology)
• Signal Transduction (drug effects)
• Triterpenes (administration & dosage, pharmacology)