Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats

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• 作者：Ting-Lin Yen^a ; ^b ; Ray-Jade Chen^c ; ^d ; ^e ; Thanasekaran Jayakumar^a ; ^b ; Wan-Jung Lu^a ; ^b ; ^d ; ^e ; Cheng-Ying Hsieh^b ; Ming-Jen Hsu^b ; Chih-Hao Yang^b ; Chao-Chien Chang^b ; ^f ; Yen-Kuang Lin^g ; Kuan-Hung Lin^b ; ^h ; ^{d102092002@tmu.edu.tw" class="auth_mail" title="E-mail the corresponding author} ; Joen-Rong Sheu^a ; ^b ; ^{sheujr@tmu.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BBB ; blood-brain barrier ; CEC ; cerebral endothelial cell ; HO-1 ; heme oxygenase 1 ; MAPK ; mitogen-activated protein kinase ; MCAO ; middle cerebral artery occlusion ; ROS ; reactive oxygen species
• 刊名：Translational Research
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：170
• 期：Complete
• 页码：57-72
• 全文大小：2075 K

文摘

Stroke pathogenesis involves complex oxidative stress-related pathways. The nuclear factor erythroid-2–related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) pathways have been considered molecular targets in pharmacologic intervention for ischemic diseases. Andrographolide, a labdane diterpene, has received increasing attention in recent years because of its various pharmacologic activities. We determined that andrographolide modulates the mitogen-activated protein kinase (MAPK)-Nrf2-HO-1 signaling cascade in primary cerebral endothelial cells (CECs) to provide positive protection against middle cerebral artery occlusion (MCAO)-induced ischemic stroke in rats. In the present study, andrographolide (10 μM) increased HO-1 protein and messenger RNA expressions, Nrf2 phosphorylation, and nuclear translocation in CECs, and these activities were disrupted by a p38 MAPK inhibitor, SB203580, but not by the extracellular signal-regulated kinase inhibitor PD98059 or c-Jun amino-terminal kinase inhibitor SP600125. Similar results were observed in confocal microscopy analysis. Moreover, andrographolide-induced Nrf2 and HO-1 protein expressions were significantly inhibited by Nrf2 small interfering RNA. Moreover, HO-1 knockdown attenuated the protective effect of andrographolide against oxygen-glucose deprivation-induced CEC death. Andrographolide (0.1 mg/kg) significantly suppressed free radical formation, blood-brain barrier disruption, and brain infarction in MCAO-insulted rats, and these effects were reversed by the HO-1 inhibitor zinc protoporphyrin IX. The mechanism is attributable to HO-1 activation, as directly evidenced by andrographolide-induced pronounced HO-1 expression in brain tissues, which was highly localized in the cerebral capillary. In conclusion, andrographolide increased Nrf2-HO-1 expression through p38 MAPK regulation, confirming that it provides protection against MCAO-induced brain injury. These findings provide strong evidence that andrographolide could be a therapeutic agent for treating ischemic stroke or neurodegenerative diseases.