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.
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.
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白果内酯对脑缺血和再灌注损伤的神经保护作用与抑制促炎介质产生以及下调 JNK1/2 和 p38 MAPK 激活有关
DOI：
10.1186/s12974-014-0167-6
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发表时间：
2014-09-26
影响因子：
9.3
通讯作者：
Mo Z
中科院分区：
文献类型：
--
作者：
Jiang M;Li J;Peng Q;Liu Y;Liu W;Luo C;Peng J;Li J;Yung KK;Mo Z
研究背景丝裂原活化蛋白激酶（MAPK）信号通路参与脑缺血再灌注（I/R）损伤的炎症和凋亡过程。因此，MAPK通路代表了一个有前途的治疗靶点。探索MAPK通路抑制剂的全部潜力是缺血性卒中的有用治疗策略。银杏内酯是银杏叶中主要的倍半萜三内酯成分，具有强大的神经保护作用，与抗炎和抗凋亡途径密切相关。本研究采用大脑中动脉闭塞再灌注（MCAO/R）和氧糖剥夺再给氧（OGD/R）脑缺血再灌注损伤模型，观察白果内酯对脑缺血再灌注损伤的保护作用。此外，我们试图证实这一假设，即其保护作用是通过调节促炎介质和MAPK pathways. MethodsMCAO 2 h，然后再灌注24 h的雄性Sprague-Dawley大鼠。在诱导大脑中动脉闭塞（MCAO）前60分钟腹腔注射白果内酯。再灌注后，评估神经功能缺损评分、梗死体积、梗死重量和脑水肿。收获大脑皮质的缺血半暗带以测定超氧化物歧化酶（SOD）、丙二醛（MDA）、一氧化氮、TNF-Α、白细胞介素1β（IL-1Β）、p-ERK 1/2、p-JNK 1/2和p-p38 MAPK浓度。同样，在OGD/R体外I/R损伤模型中也观察到白果内酯对一氧化氮、TNF-Α、IL-1Β、p-ERK 1/2、p-JNK 1/2和p-p38 MAPK表达的影响。（5、10 mg/kg）显著降低神经功能缺损评分、梗塞体积、梗塞重量、脑水肿和MDA、一氧化氮、TNF-Α、IL-1Β、提高SOD活性。银杏内酯（5、10 mg/kg）预处理可显著下调p-JNK 1/2和p-p38 MAPK的表达，而对缺血半暗带p-ERK 1/2的表达无影响。白果内酯预处理支持这些体内观察结果（50、100 μM）显著下调一氧化氮、TNF-Α、IL-1Β、p-JNK 1/2和p-p38 MAPK表达，结论白果内酯对脑缺血再灌注损伤的保护作用与其抑制脑缺血再灌注损伤后神经元p-ERK 1/2的表达有关。炎症介质的产生和JNK 1/2和p38 MAPK活化的下调。
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 ofGinkgo bilobaleaves, 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/Rin vitromodel 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 observationsin 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.
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影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
影响因子：
8.3
作者：
Jauch, Edward C.;Saver, Jeffrey L.;Yonas, Howard
通讯作者：
Yonas, Howard
影响因子：
8.3
作者：
BEDERSON, JB;PITTS, LH;BARTKOWSKI, H
通讯作者：
BARTKOWSKI, H
影响因子：
1.6
作者：
Goldie, Michelle;Dolan, Sharron
通讯作者：
Dolan, Sharron
影响因子：
4.8
作者：
Iadecola, C;Alexander, M
通讯作者：
Alexander, M