5-Lipoxygenase and cysteinyl leukotriene receptors in neuroinflammation and neuronal injury  

作　　者：LI Cheng-tan ZHANG Si-ran WANG Yu-xi ZHAO Jian-bo ZHENG Wei WANG Yan-fang ZHANG Li-hui 

机构地区：[1]Department of Pharmacology,Hangzhou Key Laboratory of Medical Neurobiology,School of Medicine,Hangzhou Normal University [2]Department of Neurology,Zhejiang Hospital

出　　处：《中国药理学与毒理学杂志》2018年第9期709-710,共2页Chinese Journal of Pharmacology and Toxicology

基　　金：The project supported by National Natural Science Foundation of China(81671188);Zhejiang Provincial Natural Science Foundation of China(LY12H31010);Key Laboratory of Hangzhou City Project(20090233T12)

摘　　要：Brian ischemic injury and central neurodegenerative diseases as leading contributors to disability and death have become a majorclinical and public health concern worldwide.Neuroinflammation plays a pivotal role in the pathological progression of cerebral ischemia and neurodegenerative diseases including Parkinson disease(PD).Therefore,it is important to find effective therapeutic targets to attenuate inflammation and delay the progression of brain injury.Cysteinyl leukotrienes(CysLTs) are potent inflammatory mediators synthesized from arachidonic acid by 5-lipoxygenase(5-LOX) in the central nervous system.Two distinct G-protein-coupled receptors,CysLT1 R and CysLT2 R,mediate most of the known CysLTs biological responses.Accumulating evidence has demonstrated that postischemic inflammation and neuronal loss are mediated by 5-LOX and CysLTRs fol owing focal cerebral ischemia.We recently reported that the expression of 5-LOX,CysLT1R and inflammatory vascular cell adhesion molecule-1(VCAM-1) was upregulated in the hippocampus of rats with transient global cerebral ischemia,which was closely associated with delayed neuronal death in the hippocampal CA1 area.5-LOX inhibitor zileuton,CysLT1R antagonist ONO-1078 and montelukast dose-dependently reduced hippocampal CA1 neuronal death and inhibited the increased expression of 5-LOX and VCAM-1.In vitro ischemia-like injury in 5-LOXtransfected PC12 cells,oxygen-glucose deprivation(OGD) induced cell death mediated by5-LOX via ROS/P38 MAPK pathway.The nonselective 5-LOX inhibitor caffeic acid inhibited OGDstimulated activation of 5-LOX and ROS/P38 MAPK signaling and improved neuronal survival.In PD model,high concentrations of rotenone caused directly PC12 neurotoxicity,which was modulated by 5-LOX and abolished by suppression of 5-LOX.It is well known that microglia is major modulators of inflammatory response after brain injury.Overactivated microglia and production of proinflammatory cytokine IL-1β,IL-6 and TNF-α contribute to the neuroinflammation and brain injury.5-LOXBrian ischemic injury and central neurodegenerative diseases as leading contributors to disability and death have become a majorclinical and public health concern worldwide.Neuroinflammation plays a pivotal role in the pathological progression of cerebral ischemia and neurodegenerative diseases including Parkinson disease(PD).Therefore,it is important to find effective therapeutic targets to attenuate inflammation and delay the progression of brain injury.Cysteinyl leukotrienes(CysLTs) are potent inflammatory mediators synthesized from arachidonic acid by 5-lipoxygenase(5-LOX) in the central nervous system.Two distinct G-protein-coupled receptors,CysLT1 R and CysLT2 R,mediate most of the known CysLTs biological responses.Accumulating evidence has demonstrated that postischemic inflammation and neuronal loss are mediated by 5-LOX and CysLTRs fol owing focal cerebral ischemia.We recently reported that the expression of 5-LOX,CysLT1R and inflammatory vascular cell adhesion molecule-1(VCAM-1) was upregulated in the hippocampus of rats with transient global cerebral ischemia,which was closely associated with delayed neuronal death in the hippocampal CA1 area.5-LOX inhibitor zileuton,CysLT1R antagonist ONO-1078 and montelukast dose-dependently reduced hippocampal CA1 neuronal death and inhibited the increased expression of 5-LOX and VCAM-1.In vitro ischemia-like injury in 5-LOXtransfected PC12 cells,oxygen-glucose deprivation(OGD) induced cell death mediated by5-LOX via ROS/P38 MAPK pathway.The nonselective 5-LOX inhibitor caffeic acid inhibited OGDstimulated activation of 5-LOX and ROS/P38 MAPK signaling and improved neuronal survival.In PD model,high concentrations of rotenone caused directly PC12 neurotoxicity,which was modulated by 5-LOX and abolished by suppression of 5-LOX.It is well known that microglia is major modulators of inflammatory response after brain injury.Overactivated microglia and production of proinflammatory cytokine IL-1β,IL-6 and TNF-α contribute to the neuroinflammation and brain injury.5-LOX

关 键 词：5-LIPOXYGENASE cysteinyl leukotrienereceptor INFLAMMATION NEURONS 

分 类 号：R[医药卫生]