Neuroprotective effects of bilobalide on cerebral ischemia and reperfusion injury are associated with inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation

Abstract

BackgroundMitogen-activated protein kinase (MAPK) signaling pathways are implicated in inflammatory and apoptotic processes of cerebral ischemia and reperfusion (I/R) injury. Hence, MAPK pathways represent a promising therapeutic target. Exploring the full potential of inhibitors of MAPK pathways is a useful therapeutic strategy for ischemic stroke. Bilobalide, a predominant sesquiterpene trilactone constituent of Ginkgo biloba leaves, has been shown to exert powerful neuroprotective properties, which are closely related to both anti-inflammatory and anti-apoptotic pathways. We investigated the neuroprotective roles of bilobalide in the models of middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen-glucose deprivation and reoxygenation (OGD/R) of cerebral I/R injury. Moreover, we attempted to confirm the hypothesis that its protection effect is via modulation of pro-inflammatory mediators and MAPK pathways.MethodsMale Sprague-Dawley rats were subjected to MCAO for 2 h followed by reperfusion for 24 h. Bilobalide was administered intraperitoneally 60 min before induction of middle cerebral artery occlusion (MCAO). After reperfusion, neurological deficit scores, infarct volume, infarct weight, and brain edema were assessed. Ischemic penumbrae of the cerebral cortex were harvested to determine superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide, TNF-α, interleukin 1β (IL-1β), p-ERK1/2, p-JNK1/2, and p-p38 MAPK concentration. Similarly, the influence of bilobalide on the expression of nitric oxide, TNF-α, IL-1β, p-ERK1/2, p-JNK1/2, and p-p38 MAPK was also observed in an OGD/R in vitro model of I/R injury.ResultsPretreatment with bilobalide (5, 10 mg/kg) significantly decreased neurological deficit scores, infarct volume, infarct weight, brain edema, and concentrations of MDA, nitric oxide, TNF-α, IL-1β, and increased SOD activity. Furthermore, bilobalide (5, 10 mg/kg) pretreatment significantly down-regulated both p-JNK1/2 and p-p38 MAPK expression, whereas they had no effect on p-ERK1/2 expression in the ischemic penumbra. Supporting these observations in vivo, pretreatment with bilobalide (50, 100 μM) significantly down-regulated nitric oxide, TNF-α, IL-1β, p-JNK1/2, and p-p38 MAPK expression, but did not change p-ERK1/2 expression in rat cortical neurons after OGD/R injury.ConclusionsThese data indicate that the neuroprotective effects of bilobalide on cerebral I/R injury are associated with its inhibition of pro-inflammatory mediator production and down-regulation of JNK1/2 and p38 MAPK activation.

By Activating Akt/eNOS Bilobalide B Inhibits Autophagy and Promotes Angiogenesis Following Focal Cerebral Ischemia Reperfusion

“…Bilobalide, a sesquiterpene lactone that constitutes 2.9-3.2% of the Ginkgo extract EGb761, has been shown to have a wide variety of therapeutic applications on neurodegenerative disease and dementia [7]. Other studies found that bilobalide may improve the outcome of ischemic dementia by promoting the mitochondrial respiratory chain function [8,9] and down-regulaing nitric oxide [10]. However, the specific molecular mechanism underlying bilobalide mediated dementia protection needs to be further invesitgated.…”

Gypenoside attenuates renal ischemia/reperfusion injury in mice by inhibition of ERK signaling

“…MAPK compounds, including ERK, stress-activated protein kinases/c-Jun NH 2 -terminal kinases and p38 MAPKs have been implicated in inflammatory signaling mechanisms in I/R injury (30,31). Additionally, ERK signaling serves a crucial function in I/R-induced cell apoptosis (32,33).…”

Activation of cerebral sodium-glucose transporter type 1 function mediated by post-ischemic hyperglycemia exacerbates the development of cerebral ischemia

“…Cerebral ischemic stress or hyperglycemia activates p-38 and ERK1/2, and these substances regulate the activation of SP1 that eventually resulted in the increased transcription of Sp1-dependent genes (Grell et al, 2014;Jiang et al, 2014;Chen et al, 2015;Kiss et al, 2015). Moreover, Sp1 binding activity is 23 increased by phosphorylation by AMPK (Hahn et al, 2014).…”