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.
Highlights
Ischemic stroke, known as cerebral infarction, is one of the leading causes of death with substantial morbidity and mortality worldwide
All of these results indicated that the protective effects of patients. Notoginseng leaf triterpenes (PNGL) against cerebral ischemia and reperfusion (I/R) injury could be associated with inhibiting high mobility group box-1 protein (HMGB1)-triggered inflammation, suppressing the activation of mitogen-activated protein kinase (MAPK) and NF-κB, and improved cerebral I/R-induced neuropathological changes
To assess the neuroprotective effects of PNGL on focal brain ischemic injury, SD rats were subjected to 2 h of MCAO and 24 h of reperfusion
Summary
Known as cerebral infarction, is one of the leading causes of death with substantial morbidity and mortality worldwide. 6.2 million people die from stroke each year, and it is estimated that the lifetime risk for stroke is 8% to 10%. Of all strokes [1]. The subsequent reperfusion phase results in brain injury, including BBB disruption, hemorrhagic transformation, and massive brain edema, which is involved in a wide range of neuropathic alteration and processes including oxidative stress, inflammatory stress [2] and cytokine damage glutamate toxicity, Ca2+ overload, excessive nitric oxide synthesis, and apoptosis [1,3,4]. The mechanisms of cerebral ischemia and reperfusion
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