外周型苯二氮卓受体转运蛋白（TSPO）在小胶质细胞炎症反应中的作用及机制的探讨
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摘要
背景与意义
小胶质细胞是脑中最重要的免疫效应细胞。小胶质细胞激活介导的脑内慢性炎症反应在许多种神经系统疾病的病理进程中扮演极其重要角色,这些神经系统疾病包括脑肿瘤、脑缺血、脑外伤、脑感染、神经系统变性疾病等等。在神经系统疾病过程中,小胶质细胞扮演的角色不仅仅是“反应性增生”--简单地对死亡细胞的残骸进行清除,而是直接参与了疾病病理过程的启动、进展和最后结局。激活的小胶质细胞会产生过量的对神经元有损害作用细胞因子,如一氧化氮(NO)、肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)和自由基等多种物质,引起各种不同程度的炎症反应和细胞凋亡构成的“病理级联”变化,最终导致神经元的损伤或死亡。基于上述发现,以抑制小胶质细胞的激活过程为靶点,延缓神经变性疾病的进程已经成为防治神经退行性疾病的一个重要策略,是近年来神经生物学和神经病学研究的热点。
外周型苯二氮卓受体转运蛋白[TSPO 18 kDa,即异喹啉结合点,曾称为外周型苯二氮卓受体(PBR)]在中枢神经系统中主要分布在小胶质细胞线粒体外膜,在神经元分布很少。最近研究表明,TSPO在静息小胶质细胞中的表达很低,而在激活的小胶质细胞中,TSPO呈现明显高表达,这说明了TSPO可能具有调节小胶质细胞功能状态的作用。同时,TSPO配体PK 11195和Ro5-4864(PK 11195称为PBR的拮抗剂,Ro5-4864称为PBR激动剂)良好的外周抗炎作用在近年备受关注,初步的研究表明TSPO配体也具有神经保护作用。但TSPO表达与小胶质细胞功能状态的关系目前尚未明确,TSPO表达与小胶质细胞炎症反应关系又是怎样?TSPO配体是否具有抑制中枢神经系统中小胶质细胞的激活作用和减少活化小胶质细胞释放炎症因子?如果有,通过何种机制?等等。这些问题在近年来备受关注,亟待阐明。
研究目的
1.研究TSPO表达与小胶质细胞炎症反应关系。
2.研究TSPO配体对小胶质细胞的激活抑制作用。
3.研究TSPO基因在小胶质细胞炎症反应中的作用。
4.研究TSPO配体抑制小胶质细胞活化的作用机制。
研究内容
1.LPS对小胶质细胞分泌炎症因子的影响。
2.TSPO在LPS诱导小胶质细胞活化中的表达。
3.TSPO配体对LPS诱导小胶质细胞分泌炎症因子的影响。
4.沉默TSPO基因对LPS诱导小胶质细胞分泌炎症因子的影响。
5.在TSPO基因沉默下TSPO配体对LPS诱导小胶质细胞分泌炎症因子的影响。
6.TSPO配体抑制LPS诱导小胶质细胞分泌炎症因子的信号传导通路的研究。
7.TSPO配体对LPS诱导小胶质细胞分泌炎症因子mRNA稳定性的影响。
研究方法
1.在BV-2小胶质细胞培养体系上,加入LPS(l00 ng/ml)分别于30 min,1 h,2 h,4 h,6 h,12 h,24 h后用倒置相差显微镜观察BV-2细胞的生长分布状况及形态学改变,用ELISA测定BV-2细胞释放TNF-α、IL-1β和IL-6三种细胞因子水平。
2.在BV-2细胞培养体系上,加入LPS(l00 ng/ml)分别于分别于4 h,8 h,24 h,48 h后用Real-time PCR检测TSPO在LPS诱导BV-2细胞中的表达。
3.在BV-2细胞培养体系上,加入LPS(l00 ng/ml)造成BV-2细胞活化状态的细胞模型,然后给予不同剂量(10μM、50μM、100μM)TSPO配体(PK 11195和Ro5-4864),用ELISA和Real-time PCR观察不同剂量TSPO配体(PK 11195和Ro5-4864)对LPS诱导BV-2细胞分泌炎症因子的影响。
4.用TSPO siRNA转染BV-2细胞,转染48 h后,用在Real-time PCR和Western blot检测TSPO基因沉默效果;在转染TSPO siRNA BV-2细胞培养培养体系上,加入LPS(l00 ng/ml)于4 h后用ELISA和Real-time PCR检测沉默TSPO基因对LPS诱导BV-2细胞分泌炎症因子(TNF-α、IL-1β和IL-6)的影响。
5.在转染TSPO siRNA BV-2细胞培养体系上,加入LPS(l00 ng/ml)造成转染TSPO siRNA BV-2细胞活化状态的细胞模型,然后给予不同剂量(10μM、50μM、100μM)TSPO配体(PK 11195和Ro5-4864),用ELISA和Real-time PCR观察不同剂量TSPO配体(PK 11195和Ro5-4864)对LPS诱导转染TSPO siRNA BV-2细胞分泌炎症因子的影响。
6.通过Western blot技术检测给予不同剂量(10μM、50μM、100μM)TSPO配体(PK 11195和Ro5-4864)处理经LPS诱导的BV-2细胞内的Erk、JNK及p38的磷酸化程度及IκB的降解程度,从而了解TSPO配体(PK 11195和Ro5-4864)对BV-2细胞内MAPK及NF-κB的激活情况。
7.用流式细胞仪检测在100μM TSPO配体(PK 11195和Ro5-4864)作用24 h时单个VB-2细胞的荧光强度(MFI),分析TSPO配体(PK 11195和Ro5-4864)对单个VB-2细胞内钙离子浓度([Ca2 +]i)的影响情况。
8.在BV-2细胞培养体系上,加入LPS(l00 ng/ml)处理BV-2细胞2 h后,分成3组分别加入ACTD+PK 11195、ACTD+Ro5-48643和ACTD+DMSO(ACTD剂量10μg/ml, PK 11195剂量100μM, Ro5-48643剂量100μM)再作用1 h、2 h后,用Real time-PCR技术检测IL-1β和IL-6 mRNA含量,分析IL-1β和IL-6 mRNA降解情况。
研究结果
1.LPS可诱导BV-2细胞活化,表现为:BV-2细胞形态随着LPS作用时间延长逐渐变成呈现典型的阿米巴样“活化状态小胶质细胞”外观;活化的BV-2细胞合成、释放TNF-α、IL-lβ和IL -6等炎症因子,并与LPS作用时间和剂量呈正相关。
2.TSPO在静息的BV-2细胞中有一定量表达,表达量不多,在LPS诱导BV-2细胞活化中表达增多,并随LPS干预时间延长而呈增多趋势,在LPS作用24 h时才有明显增多,48 h增多更显著(P<0.01)。
3.TSPO配体PK 11195和Ro5-4864有抗炎作用,它们能显著在抑制LPS诱导BV-2细胞分泌IL-1β和IL-6,并与剂量呈正相关,浓度越高,抑制效果越强。但对TNF-α没有抑制作用。对IL-1β,Ro5-4864抑制效果与PK 11195相当,但对IL-6,Ro5-4864抑制效能比PK 11195强,显示Ro5-4864比PK 11195具有更强抗炎作用。
4. BV-2细胞转染TSPO siRNA后TSPO mRNA表达和蛋白含量均比对照组低,两者差异有统计学意义(P <0.01),表明TSPO siRNA能有效沉默TSPO基因表达。沉默TSPO基因后LPS活化BV-2细胞分泌的TNF-α、IL-1β和IL-6并没有减少,表明沉默TSPO基因对LPS活化BV-2细胞分泌的TNF-α、IL-1β和IL-6无抑制作用,提示TSPO基因不直接介导BV-2细胞的炎症反应,或者在BV-2细胞的炎症反应不是处于主导作用。
5.转染TSPO siRNA BV-2细胞在LPS+ PK 11195和LPS+ Ro5-4864处理后IL-lβ和IL-6的分泌量呈现明显下降;转染control siRNA BV-2细胞在同样LPS+ PK 11195和LPS+ Ro5-4864处理后IL-lβ和IL-6的分泌量也呈现明显下降,但它们之间差异无统计学意义(P >0.05)。表明TSPO配体PK 11195和Ro5-4864抑制LPS诱导BV-2细胞分泌IL-1β、IL-6不受TSPO基因的影响,提示TSPO基因不直接调节TSPO配体的抗炎作用,或者在TSPO配体的抗炎作用处于次要作用。
6.PK 11195和Ro5-4864不影响LPS诱导BV-2细胞内Erk,JNK,p38蛋白磷酸化和IκB蛋白的降解,但能影响BV-2细胞内Ca2+浓度,PK 11195能显著地引起BV-2细胞内Ca2+浓度增加,细胞内Ca2+荧光值(MFI)由1.95±0.16升高到3.37±0.14,两者之间差异有统计学意义(P <0.01);Ro5-4864却作用相反,能显著地降低BV-2细胞内Ca2+浓度,细胞内Ca2+荧光值(MFI)由1.95±0.16降低到1.56±0.09,两者之间差异有统计学意义(P <0.01)。
7. TSPO配体PK 11195和Ro5-4864能加快LPS诱导BV-2细胞IL-1β和IL-6 mRNA降解速度,在PK 11195作用1 h、2 h后,LPS诱导BV-2细胞内IL-1β和IL-6 mRNA分别减少60.2 %、64.3 %和69.4 %、74.1 %;在Ro5-4864作用下,IL-1β和IL-6 mRNA分别减少58.2 %、60.2 %和66.9 %、70.0 %。IL-1β和IL-6 mRNA半衰期明显缩短,均由原来2 h缩短到1 h左右。表明PK 1195和Ro5-4864能降低IL-1β和IL-6 mRNA稳定性。
结论
1. LPS可诱导小胶质细胞的应激活化,活化的小胶质细胞形态呈现阿米巴样“活化状态小胶质细胞”外观,并合成、释放TNF-α、IL-lβ和IL -6等炎症因子。LPS是通过MAPKs信号转导通路和NF -κB转录因子转导来诱导小胶质细胞分泌炎症因子。
2.TSPO在小胶质细胞中确有表达,在静息的小胶质细胞中表达较低,在LPS诱导小胶质细胞活化中(在LPS作用24 h以后)呈现高表达,结合第一部分研究结果表明了TSPO表达与BV-2细胞的激活状态呈正相关。TSPO表达升高是小胶质细胞活化状态的后期反应事件,可反映小胶质细胞活化状态,可能参与调节小胶质细胞活化的功能。
3.TSPO配体PK 11195和Ro5-4864有抗炎作用,它们能抑制LPS诱导的小胶质细胞活性,减少LPS活化小胶质细胞分泌IL-1β和IL-6等炎症因子。TSPO配体PK 11195和Ro5-4864抑制LPS活化小胶质细胞分泌IL-1β、IL-6不通过TSPO基因(即不受TSPO基因的影响),说明了TSPO基因不直接介入TSPO配体的抗炎作用,或者在TSPO配体的抗炎作用处于次要作用,起着传递信息作用,把信息传递给PBR另两个亚单位(VDAC和ANT),进一步说明了PBR三个亚单位(TSPO,VDAC和ANT)是相互联系、相互作用形成一个复合体。异喹啉(PK 11195)可单独结合到异喹啉结合点(TSPO)上,但与TSPO特异结合的苯二氮卓类药物(Ro5-4864)则需要这3个亚单位之间的相互作用。因此,Ro5-4864抑制LPS诱导BV-2细胞分泌IL-6的效能比PK 11195强,而在抑制IL-1β上两者效果相当,显示Ro5-4864比PK 11195具有更强抗炎作用。这些研究结果表明了反映了把原先称为PBR的DBI亚单位改称TSPO 18 kDa [translocator protein 18 kDa (转运蛋白18 kDa)]更能确切反应TSPO生理、药物功能,有利于进一步阐明PBR的结构和功能。
4.TSPO配体PK 11195和Ro5-4864不是通过MAPKs信号转导通路和NF -κB转录因子转导来抑制LPS活化小胶质细胞分泌IL-1β、IL-6,而可能通过通过调节小胶质细胞内钙离子浓度,影响钙离子的信号转导通路来抑制炎症因子分泌。另外,PK 11195和Ro5-4864影响IL-1β和IL-6 mRNA的稳定性,加快IL-1β和IL-6 mRNA降解,缩短IL-1β和IL-6 mRNA半衰期,从而减少IL-1β和IL-6蛋白的含量。
5.在影响小胶质细胞细胞内Ca2+浓度方面,PK 11195和Ro5-4864的作用是相反的。PK 11195能显著地增加小胶质细胞细胞内Ca2+浓度,Ro5-4864却能显著地降低小胶质细胞细胞内Ca2+浓度,结合上述TSPO在小胶质细胞炎症反应中作用,认为把PK 11195和Ro5-4864统称为PBR拮抗剂和激动剂是不确切的,可能称为电压依赖性阴离子通道(VDAC)的拮抗剂和激动剂比较确切地反应它们的属性,这方面工作有待进一步研究。
Background and Significance
Chronic inflammatory process in the brain, triggered by microglia,may play a significant role in the pathologies of several neurological disorders,including brain tumors,cerebral ischemia,brain trauma,brain infections,neurodegenerative disorders.Microglia,the primary resident immune surveillance cell in the brain,lie in the core of these pathogensis.In addition to their phagocytic role--clearing died cell debris,activated miroglia can synthesize and secrete potential neurotoxins that may cause neuronal damage or aggravate underlying pathology.These neurotoxins include nitric oxide (NO),tumor necrosis factor-α(TNF-α),interleukin-lβ(IL-lβ),inter- leukin-6 (IL-6) and free radicals etc.Therefore,in recent years,it is a emerging conception that inhibition of microglial activation may be a novel therapeutic target to slow down the progress of these diseases.
Translocator protein (TSPO,18 kDa),an 18 kDa protein,was initially identified as a peripheral binding site for diazepam and previously known as the peripheral-type benzodiazepine receptor (PBR). TSPO is primarily localized at outer mitochondrial membranes.In the normal brain,overall TSPO expression is low,and TSPO is mainly found in glia and at very low levels in neurons.In addition,different forms of neural injury and different neuropathological conditions as inflammation result in the induction of the exptession of TSPO in the nervous system,mainly in microglia.The induction of TSPO expression in reactive microglia suggests that TSPO may be involved in the regulation of reactive microglia.Furthermore,TSPO ligands-PK 11195 and Ro5-4864 (PK 11195,an antagonists of PBR;Ro5-4864,an agonists of PBR) have been intensively investigated in regard to its anti-inflammatory action in peripheral system.However,the precise role of TSPO in reactive microglia is unknown.Moreover,in the last few years,there has been an increased interest in understanding which associations between TSPO expression and microglia activation are,whether TSPO ligands can inhibit microglia activation and reduce secretion of inflammatory cytokines or not,and what the exact mechanisms by which TSPO ligands confer protection are.Therefore,lastly,it is critically important to understand the function and how TSPO expression is regulated in the microglia function in order to indentify of TSPO as a potential target for development of new therapeutic strategies to decrease inflammation associated to some central nervous system degenerative diseases.
Objectives
1.To determine the associations between TSPO expression and microglia activation.
2.To explore the inhibitory effect of TSPO ligands on microglia activation.
3. To study the role of TSPO gene in inflammatory process induced by microglia.
4.To explore the exact mechanisms by which TSPO ligands confer inhibition effect on microglia activation.
Research Contents
1.Levels of proinflammatory cytokines in microglial cells after LPS treatment.
2.TSPO expression in the LPS-induced microglia activation.
3.Effects of TSPO ligands on levels of proinflammatory cytokines in microglial cells after LPS treatment.
4.Effects of TSPO gene silenced by TSPO siRNA on levels of proinflammatory cytokines in microglial cells after LPS treatment.
5.The inhibitory effect of TSPO ligands on levels of proinflammatory cytokines in microglial cells transfected with TSPO siRNA after LPS treatment.
6.Signaling pathways in effect on TSPO ligands on levels of proinflammatory cytokines in microglial cells after LPS treatment.
7.Effects of TSPO ligands on mRNA stability of proinflammatory cytokines in microglial cells after LPS treatment.
Methods
1.We treated BV-2 microglial cells cultures with LPS (l00 ng/ml) to induce microglia activation and tested the levels of proinflammatory cytokines (TNF-α、IL-1βand IL - 6) and the morphology of BV-2 cells in different time (30 min,1 h,2 h,4 h,6 h,12 h,24 h) of LPS treatment with ELISA and inverted phase contrast microscope.
2.We treated BV-2 microglial cells cultures with LPS (l00 ng/ml) to induce microglia activation and tested TSPO expression in different time (4 h,8 h,24 h,48 h) of LPS treatment with Real-time PCR.
3.We explored effects of TSPO ligands (PK 11195 and Ro5-4864) at different dose (10μM、50μM、100μM) on productions and mRNA expressions of proinflamma- tory cytokines in BV-2 cells after LPS treatment (l00 ng/ml) with ELISA and Real-time PCR.
4.We transfected TSPO siRNA into BV-2 cells and analysed the expression of TSPO in BV-2 cells after transfected with TSPO siRNA in order to determined effect of silenced TSPO gene in BV-2 cells after transfected with TSPO siRNA with Real-time PCR and Western blot.After that,we studied effects of silenced TSPO gene on productions and mRNA expressions of proinflammatory cytokines in BV-2 cells after LPS treatment (l00 ng/ml) with ELISA and Real-time PCR.
5.We studied effects of TSPO ligands (PK 11195 and Ro5-4864) at different dose (10μM、50μM、100μM) on productions and mRNA expressions of proinflamma- tory cytokines in BV-2 cells transfected with TSPO siRNA after LPS treatment (l00 ng/ml) with ELISA and Real-time PCR.
6.We explored effects of TSPO ligands (PK 11195 and Ro5-4864) at different dose (10μM、50μM、100μM) on MAPK pathway (Erk,JNK and p38) and IκB degra- dation in BV-2 cells after LPS treatment (l00 ng/ml) with Western blot.
7.We studied effects of TSPO ligands (PK 11195 and Ro5-4864) at the dose of 100μM for 24 h on a single VB-2 intracellular calcium concentration ([Ca2 +] i) by flow cytometry.
8.We treated BV-2 microglial cells cultures with LPS (l00 ng/ml) for 2 h to induce microglia activation.Following,LPS-induced reactive microglia were exposed for 1 h and 2 h to ACTD+PK 11195、ACTD+Ro5-48643 and ACTD+DMSO,respectively,for measurement of mRNA expressions of IL-1βand IL–6 with Real-time PCR,and analysis of mRNA degradation of IL-1βand IL–6.
Results
1.LPS induced BV-2 microglial cells activation,as follows:dynamic morphology changes in cell growth to Amoeba-like appearance,levels of proinflammatory cytokines increased,such as,TNF-α、IL-lβand IL -6. Levels of proinflamma- tory cytokines increased in time and dose-dependent way of LPS.
2.The TSPO expression was detected in resting BV-2 cells at low level,but increased in LPS-induced BV-2 cells in time-dependent way,increasing signifycantly in 24 h and 48 h after LPS treatment(P <0.01).
3.TSPO ligands (PK 11195 and Ro5-4864) showed anti-inflammatory properies. They inhibited reactive BV-2 cells after LPS treatment and reduced levels of IL-l βand IL -6, except for TNF-α.On IL-1β, Ro5-4864 showed the same inhibitory effects as PK 11195, and Ro5-4864 showed more strong inhibitor than PK 11195 on IL-6.So,Ro5-4864 showed more strong anti-inflammatory properies than PK 11195 on IL-6.
4. The expression and protein of TSPO were less in BV-2 cells after transfected with TSPO siRNA than in BV-2 cells after transfected with control siRNA.The difference between the two groups was significant (P <0.01).The results showed that TSPO siRNA can downregulate effectively the expression and protein of TSPO.However,the products of TNF-α、IL-lβand IL-6 did not decrease in BV-2 cells transfected with TSPO siRNA relative to those in BV-2 cells transfected with control siRNA after LPS treatment.In other words,down- regulation of TSPO had no effect on levels of proinflammatory cytokines,such as,TNF-α、IL-lβand IL-6 in BV-2 cells treated by LPS.The results showed that TSPO gene does not directly mediate inflammation,or play a second role in inflammatory process induced by reactive BV-2 cells.
5. TSPO ligands (PK 11195 and Ro5-4864) had reduced levels of IL-lβand IL-6 in BV-2 cells transfected with TSPO siRNA and control groups (BV-2 cells transfected with control siRNA) after LPS treatment. The difference between the two groups was not significant (P >0.01).TSPO gene did not mediate the inhibitory effect of TSPO ligands (PK 11195 and Ro5-4864) on levels of proinflammatory cytokines, such as, IL-lβand IL-6 in BV-2 cells treated by LPS. The result showed that TSPO gene does not directly regulate or play a role for transmitting information to the other subunits in the anti-inflammatory of TSPO ligands.
6. TSPO ligands (PK 11195 and Ro5-4864) had no affect on Iκ- B degradation and phosphorylation of Erk,JNK and p38 in BV-2 cells after LPS treatment. However,PK 11195 and Ro5-4864 had affect on [Ca2+]i in BV-2 cells. PK 11195 increased significantly [Ca2+]i from 1.95±0.16 to 3.37±0.14(MFI). The difference between PK 1195 treatment and control groups was significant (P <0.01);Ro5-4864 decreased significantly [Ca2+]i in BV-2 cells from 1.95±0.16 to 1.56±0.09(MFI).The difference between Ro5-4864 treatment and control groups was significant (P <0.01).
7. TSPO ligands (PK 11195 and Ro5-4864) accelerated degradation of IL-1βand IL- 6 mRNA.The reductions of IL-1βand IL -6 mRNA were 60.2 %、64.3 % and 69.4 %、74.1 % at 1 h and 2 h treatment of PK 11195,and they were 58.2 %、60.2 % and 66.9 %、70.0 % with Ro5-4864 treatment in LPS-induced BV-2cells. The half-life of mRNA of IL-1βand IL-6 in LPS-induced BV-2cells after PK 11195 or Ro5-4864 treatment were significantly shorter that that in control groups,from 2 h to 1 h.The findings showed PK 11195 and Ro5-4864 decreased mRNA stability of IL-1βand IL -6.
Conclusions
1.LPS can induce microglia activation to grow with Amoeba-like appearance,and synthesize and secrete proinflammatory cytokines,such as,TNF-α、IL-lβand IL -6 through MAPKs signal transduction pathways and NF-κB transcription factor.
2.In resting microglia,TSPO expression is low.But in activated microglia after LPS treatment , TSPO expression increases in time-dependent way , increasing significantly in 24 h and 48 h. Combined with the first study finding, the results show that increased TSPO expression is closely associated with micrglia activation,and may be related to the secretion of inflammatory cytokines.So,The induction of TSPO expression in reactive microglia suggests that TSPO may be involved in the regulation of reactive microglia.
3.TSPO ligands are of anti-inflammatory properies.They can inhibite reactive microglia after LPS treatment and reduce levels of proinflammatory cytokines. Nevertheless,TSPO sub-unit does not mediate the inhibitory effect of TSPO ligands on levels of proinflammatory cytokines,and only play a role for transmitting information to the other sub-units (VDAC and ANT).So,the other two sub-units (VDAC and ANT) in PBR complex may involve in anti- inflammatory properies of TSPO ligands. These findings suggest that the three sub-units (TSPO、VDAC and ANT) are interlinked and interacted to constitute a complex of PBR. Isoquinoline carboxamides (such as PK 11195) can be indivi- dually bind the isoquinoline binding site (TSPO).However,interactions among TSPO、VDAC and ANT are considered to play a role in the process that benzodiazepine-type drugs (such as Ro5-4864 ) bind specifically TSPO.So,Ro5- 4864 showed more strong inhibitor than PK 11195 on IL-6,and on IL-1β, Ro5-4864 showed the same inhibitory effects as PK 11195.In general,Ro5-4864 has showed more strong anti-inflammatory properies than PK 11195.These findings support the concept on renaming the PBR to TSPO,which reflect more accurately the cellular and physiological functions in which TSPO has important role.
4.TSPO ligands can inhibit reactive microglia after LPS treatment and reduce levels of proinflammatory cytokines (IL-1βand IL-6) through decreasing mRNA stability of proinflammatory cytokines and Ca2+-mediated signaling pathways,except through MAPKs signal transduction pathways and NF-κB transcription factor.
5. PK 11195 and Ro5-4864 play different roles in intercellular concentration of calcium([Ca2 +]i) in microglial cells.PK 11195 increased significantly [Ca2+]i ,and Ro5-4864 decreased significantly [Ca2+]i in microglial cells.Combined with their results in inflammation induced by microglia,it is inaccurate that PK 11195 is generally known as PBR antagonists and Ro5-4864 as PBR agonists.Further,it is relatively exact that PK 11195 is known as voltage-dependent anion channel (VDAC) antagonists and Ro5-4864 as VDAC agonists according to their properties.We will further study the work in the future.
小胶质细胞是脑中最重要的免疫效应细胞。小胶质细胞激活介导的脑内慢性炎症反应在许多种神经系统疾病的病理进程中扮演极其重要角色,这些神经系统疾病包括脑肿瘤、脑缺血、脑外伤、脑感染、神经系统变性疾病等等。在神经系统疾病过程中,小胶质细胞扮演的角色不仅仅是“反应性增生”--简单地对死亡细胞的残骸进行清除,而是直接参与了疾病病理过程的启动、进展和最后结局。激活的小胶质细胞会产生过量的对神经元有损害作用细胞因子,如一氧化氮(NO)、肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)和自由基等多种物质,引起各种不同程度的炎症反应和细胞凋亡构成的“病理级联”变化,最终导致神经元的损伤或死亡。基于上述发现,以抑制小胶质细胞的激活过程为靶点,延缓神经变性疾病的进程已经成为防治神经退行性疾病的一个重要策略,是近年来神经生物学和神经病学研究的热点。
外周型苯二氮卓受体转运蛋白[TSPO 18 kDa,即异喹啉结合点,曾称为外周型苯二氮卓受体(PBR)]在中枢神经系统中主要分布在小胶质细胞线粒体外膜,在神经元分布很少。最近研究表明,TSPO在静息小胶质细胞中的表达很低,而在激活的小胶质细胞中,TSPO呈现明显高表达,这说明了TSPO可能具有调节小胶质细胞功能状态的作用。同时,TSPO配体PK 11195和Ro5-4864(PK 11195称为PBR的拮抗剂,Ro5-4864称为PBR激动剂)良好的外周抗炎作用在近年备受关注,初步的研究表明TSPO配体也具有神经保护作用。但TSPO表达与小胶质细胞功能状态的关系目前尚未明确,TSPO表达与小胶质细胞炎症反应关系又是怎样?TSPO配体是否具有抑制中枢神经系统中小胶质细胞的激活作用和减少活化小胶质细胞释放炎症因子?如果有,通过何种机制?等等。这些问题在近年来备受关注,亟待阐明。
研究目的
1.研究TSPO表达与小胶质细胞炎症反应关系。
2.研究TSPO配体对小胶质细胞的激活抑制作用。
3.研究TSPO基因在小胶质细胞炎症反应中的作用。
4.研究TSPO配体抑制小胶质细胞活化的作用机制。
研究内容
1.LPS对小胶质细胞分泌炎症因子的影响。
2.TSPO在LPS诱导小胶质细胞活化中的表达。
3.TSPO配体对LPS诱导小胶质细胞分泌炎症因子的影响。
4.沉默TSPO基因对LPS诱导小胶质细胞分泌炎症因子的影响。
5.在TSPO基因沉默下TSPO配体对LPS诱导小胶质细胞分泌炎症因子的影响。
6.TSPO配体抑制LPS诱导小胶质细胞分泌炎症因子的信号传导通路的研究。
7.TSPO配体对LPS诱导小胶质细胞分泌炎症因子mRNA稳定性的影响。
研究方法
1.在BV-2小胶质细胞培养体系上,加入LPS(l00 ng/ml)分别于30 min,1 h,2 h,4 h,6 h,12 h,24 h后用倒置相差显微镜观察BV-2细胞的生长分布状况及形态学改变,用ELISA测定BV-2细胞释放TNF-α、IL-1β和IL-6三种细胞因子水平。
2.在BV-2细胞培养体系上,加入LPS(l00 ng/ml)分别于分别于4 h,8 h,24 h,48 h后用Real-time PCR检测TSPO在LPS诱导BV-2细胞中的表达。
3.在BV-2细胞培养体系上,加入LPS(l00 ng/ml)造成BV-2细胞活化状态的细胞模型,然后给予不同剂量(10μM、50μM、100μM)TSPO配体(PK 11195和Ro5-4864),用ELISA和Real-time PCR观察不同剂量TSPO配体(PK 11195和Ro5-4864)对LPS诱导BV-2细胞分泌炎症因子的影响。
4.用TSPO siRNA转染BV-2细胞,转染48 h后,用在Real-time PCR和Western blot检测TSPO基因沉默效果;在转染TSPO siRNA BV-2细胞培养培养体系上,加入LPS(l00 ng/ml)于4 h后用ELISA和Real-time PCR检测沉默TSPO基因对LPS诱导BV-2细胞分泌炎症因子(TNF-α、IL-1β和IL-6)的影响。
5.在转染TSPO siRNA BV-2细胞培养体系上,加入LPS(l00 ng/ml)造成转染TSPO siRNA BV-2细胞活化状态的细胞模型,然后给予不同剂量(10μM、50μM、100μM)TSPO配体(PK 11195和Ro5-4864),用ELISA和Real-time PCR观察不同剂量TSPO配体(PK 11195和Ro5-4864)对LPS诱导转染TSPO siRNA BV-2细胞分泌炎症因子的影响。
6.通过Western blot技术检测给予不同剂量(10μM、50μM、100μM)TSPO配体(PK 11195和Ro5-4864)处理经LPS诱导的BV-2细胞内的Erk、JNK及p38的磷酸化程度及IκB的降解程度,从而了解TSPO配体(PK 11195和Ro5-4864)对BV-2细胞内MAPK及NF-κB的激活情况。
7.用流式细胞仪检测在100μM TSPO配体(PK 11195和Ro5-4864)作用24 h时单个VB-2细胞的荧光强度(MFI),分析TSPO配体(PK 11195和Ro5-4864)对单个VB-2细胞内钙离子浓度([Ca2 +]i)的影响情况。
8.在BV-2细胞培养体系上,加入LPS(l00 ng/ml)处理BV-2细胞2 h后,分成3组分别加入ACTD+PK 11195、ACTD+Ro5-48643和ACTD+DMSO(ACTD剂量10μg/ml, PK 11195剂量100μM, Ro5-48643剂量100μM)再作用1 h、2 h后,用Real time-PCR技术检测IL-1β和IL-6 mRNA含量,分析IL-1β和IL-6 mRNA降解情况。
研究结果
1.LPS可诱导BV-2细胞活化,表现为:BV-2细胞形态随着LPS作用时间延长逐渐变成呈现典型的阿米巴样“活化状态小胶质细胞”外观;活化的BV-2细胞合成、释放TNF-α、IL-lβ和IL -6等炎症因子,并与LPS作用时间和剂量呈正相关。
2.TSPO在静息的BV-2细胞中有一定量表达,表达量不多,在LPS诱导BV-2细胞活化中表达增多,并随LPS干预时间延长而呈增多趋势,在LPS作用24 h时才有明显增多,48 h增多更显著(P<0.01)。
3.TSPO配体PK 11195和Ro5-4864有抗炎作用,它们能显著在抑制LPS诱导BV-2细胞分泌IL-1β和IL-6,并与剂量呈正相关,浓度越高,抑制效果越强。但对TNF-α没有抑制作用。对IL-1β,Ro5-4864抑制效果与PK 11195相当,但对IL-6,Ro5-4864抑制效能比PK 11195强,显示Ro5-4864比PK 11195具有更强抗炎作用。
4. BV-2细胞转染TSPO siRNA后TSPO mRNA表达和蛋白含量均比对照组低,两者差异有统计学意义(P <0.01),表明TSPO siRNA能有效沉默TSPO基因表达。沉默TSPO基因后LPS活化BV-2细胞分泌的TNF-α、IL-1β和IL-6并没有减少,表明沉默TSPO基因对LPS活化BV-2细胞分泌的TNF-α、IL-1β和IL-6无抑制作用,提示TSPO基因不直接介导BV-2细胞的炎症反应,或者在BV-2细胞的炎症反应不是处于主导作用。
5.转染TSPO siRNA BV-2细胞在LPS+ PK 11195和LPS+ Ro5-4864处理后IL-lβ和IL-6的分泌量呈现明显下降;转染control siRNA BV-2细胞在同样LPS+ PK 11195和LPS+ Ro5-4864处理后IL-lβ和IL-6的分泌量也呈现明显下降,但它们之间差异无统计学意义(P >0.05)。表明TSPO配体PK 11195和Ro5-4864抑制LPS诱导BV-2细胞分泌IL-1β、IL-6不受TSPO基因的影响,提示TSPO基因不直接调节TSPO配体的抗炎作用,或者在TSPO配体的抗炎作用处于次要作用。
6.PK 11195和Ro5-4864不影响LPS诱导BV-2细胞内Erk,JNK,p38蛋白磷酸化和IκB蛋白的降解,但能影响BV-2细胞内Ca2+浓度,PK 11195能显著地引起BV-2细胞内Ca2+浓度增加,细胞内Ca2+荧光值(MFI)由1.95±0.16升高到3.37±0.14,两者之间差异有统计学意义(P <0.01);Ro5-4864却作用相反,能显著地降低BV-2细胞内Ca2+浓度,细胞内Ca2+荧光值(MFI)由1.95±0.16降低到1.56±0.09,两者之间差异有统计学意义(P <0.01)。
7. TSPO配体PK 11195和Ro5-4864能加快LPS诱导BV-2细胞IL-1β和IL-6 mRNA降解速度,在PK 11195作用1 h、2 h后,LPS诱导BV-2细胞内IL-1β和IL-6 mRNA分别减少60.2 %、64.3 %和69.4 %、74.1 %;在Ro5-4864作用下,IL-1β和IL-6 mRNA分别减少58.2 %、60.2 %和66.9 %、70.0 %。IL-1β和IL-6 mRNA半衰期明显缩短,均由原来2 h缩短到1 h左右。表明PK 1195和Ro5-4864能降低IL-1β和IL-6 mRNA稳定性。
结论
1. LPS可诱导小胶质细胞的应激活化,活化的小胶质细胞形态呈现阿米巴样“活化状态小胶质细胞”外观,并合成、释放TNF-α、IL-lβ和IL -6等炎症因子。LPS是通过MAPKs信号转导通路和NF -κB转录因子转导来诱导小胶质细胞分泌炎症因子。
2.TSPO在小胶质细胞中确有表达,在静息的小胶质细胞中表达较低,在LPS诱导小胶质细胞活化中(在LPS作用24 h以后)呈现高表达,结合第一部分研究结果表明了TSPO表达与BV-2细胞的激活状态呈正相关。TSPO表达升高是小胶质细胞活化状态的后期反应事件,可反映小胶质细胞活化状态,可能参与调节小胶质细胞活化的功能。
3.TSPO配体PK 11195和Ro5-4864有抗炎作用,它们能抑制LPS诱导的小胶质细胞活性,减少LPS活化小胶质细胞分泌IL-1β和IL-6等炎症因子。TSPO配体PK 11195和Ro5-4864抑制LPS活化小胶质细胞分泌IL-1β、IL-6不通过TSPO基因(即不受TSPO基因的影响),说明了TSPO基因不直接介入TSPO配体的抗炎作用,或者在TSPO配体的抗炎作用处于次要作用,起着传递信息作用,把信息传递给PBR另两个亚单位(VDAC和ANT),进一步说明了PBR三个亚单位(TSPO,VDAC和ANT)是相互联系、相互作用形成一个复合体。异喹啉(PK 11195)可单独结合到异喹啉结合点(TSPO)上,但与TSPO特异结合的苯二氮卓类药物(Ro5-4864)则需要这3个亚单位之间的相互作用。因此,Ro5-4864抑制LPS诱导BV-2细胞分泌IL-6的效能比PK 11195强,而在抑制IL-1β上两者效果相当,显示Ro5-4864比PK 11195具有更强抗炎作用。这些研究结果表明了反映了把原先称为PBR的DBI亚单位改称TSPO 18 kDa [translocator protein 18 kDa (转运蛋白18 kDa)]更能确切反应TSPO生理、药物功能,有利于进一步阐明PBR的结构和功能。
4.TSPO配体PK 11195和Ro5-4864不是通过MAPKs信号转导通路和NF -κB转录因子转导来抑制LPS活化小胶质细胞分泌IL-1β、IL-6,而可能通过通过调节小胶质细胞内钙离子浓度,影响钙离子的信号转导通路来抑制炎症因子分泌。另外,PK 11195和Ro5-4864影响IL-1β和IL-6 mRNA的稳定性,加快IL-1β和IL-6 mRNA降解,缩短IL-1β和IL-6 mRNA半衰期,从而减少IL-1β和IL-6蛋白的含量。
5.在影响小胶质细胞细胞内Ca2+浓度方面,PK 11195和Ro5-4864的作用是相反的。PK 11195能显著地增加小胶质细胞细胞内Ca2+浓度,Ro5-4864却能显著地降低小胶质细胞细胞内Ca2+浓度,结合上述TSPO在小胶质细胞炎症反应中作用,认为把PK 11195和Ro5-4864统称为PBR拮抗剂和激动剂是不确切的,可能称为电压依赖性阴离子通道(VDAC)的拮抗剂和激动剂比较确切地反应它们的属性,这方面工作有待进一步研究。
Background and Significance
Chronic inflammatory process in the brain, triggered by microglia,may play a significant role in the pathologies of several neurological disorders,including brain tumors,cerebral ischemia,brain trauma,brain infections,neurodegenerative disorders.Microglia,the primary resident immune surveillance cell in the brain,lie in the core of these pathogensis.In addition to their phagocytic role--clearing died cell debris,activated miroglia can synthesize and secrete potential neurotoxins that may cause neuronal damage or aggravate underlying pathology.These neurotoxins include nitric oxide (NO),tumor necrosis factor-α(TNF-α),interleukin-lβ(IL-lβ),inter- leukin-6 (IL-6) and free radicals etc.Therefore,in recent years,it is a emerging conception that inhibition of microglial activation may be a novel therapeutic target to slow down the progress of these diseases.
Translocator protein (TSPO,18 kDa),an 18 kDa protein,was initially identified as a peripheral binding site for diazepam and previously known as the peripheral-type benzodiazepine receptor (PBR). TSPO is primarily localized at outer mitochondrial membranes.In the normal brain,overall TSPO expression is low,and TSPO is mainly found in glia and at very low levels in neurons.In addition,different forms of neural injury and different neuropathological conditions as inflammation result in the induction of the exptession of TSPO in the nervous system,mainly in microglia.The induction of TSPO expression in reactive microglia suggests that TSPO may be involved in the regulation of reactive microglia.Furthermore,TSPO ligands-PK 11195 and Ro5-4864 (PK 11195,an antagonists of PBR;Ro5-4864,an agonists of PBR) have been intensively investigated in regard to its anti-inflammatory action in peripheral system.However,the precise role of TSPO in reactive microglia is unknown.Moreover,in the last few years,there has been an increased interest in understanding which associations between TSPO expression and microglia activation are,whether TSPO ligands can inhibit microglia activation and reduce secretion of inflammatory cytokines or not,and what the exact mechanisms by which TSPO ligands confer protection are.Therefore,lastly,it is critically important to understand the function and how TSPO expression is regulated in the microglia function in order to indentify of TSPO as a potential target for development of new therapeutic strategies to decrease inflammation associated to some central nervous system degenerative diseases.
Objectives
1.To determine the associations between TSPO expression and microglia activation.
2.To explore the inhibitory effect of TSPO ligands on microglia activation.
3. To study the role of TSPO gene in inflammatory process induced by microglia.
4.To explore the exact mechanisms by which TSPO ligands confer inhibition effect on microglia activation.
Research Contents
1.Levels of proinflammatory cytokines in microglial cells after LPS treatment.
2.TSPO expression in the LPS-induced microglia activation.
3.Effects of TSPO ligands on levels of proinflammatory cytokines in microglial cells after LPS treatment.
4.Effects of TSPO gene silenced by TSPO siRNA on levels of proinflammatory cytokines in microglial cells after LPS treatment.
5.The inhibitory effect of TSPO ligands on levels of proinflammatory cytokines in microglial cells transfected with TSPO siRNA after LPS treatment.
6.Signaling pathways in effect on TSPO ligands on levels of proinflammatory cytokines in microglial cells after LPS treatment.
7.Effects of TSPO ligands on mRNA stability of proinflammatory cytokines in microglial cells after LPS treatment.
Methods
1.We treated BV-2 microglial cells cultures with LPS (l00 ng/ml) to induce microglia activation and tested the levels of proinflammatory cytokines (TNF-α、IL-1βand IL - 6) and the morphology of BV-2 cells in different time (30 min,1 h,2 h,4 h,6 h,12 h,24 h) of LPS treatment with ELISA and inverted phase contrast microscope.
2.We treated BV-2 microglial cells cultures with LPS (l00 ng/ml) to induce microglia activation and tested TSPO expression in different time (4 h,8 h,24 h,48 h) of LPS treatment with Real-time PCR.
3.We explored effects of TSPO ligands (PK 11195 and Ro5-4864) at different dose (10μM、50μM、100μM) on productions and mRNA expressions of proinflamma- tory cytokines in BV-2 cells after LPS treatment (l00 ng/ml) with ELISA and Real-time PCR.
4.We transfected TSPO siRNA into BV-2 cells and analysed the expression of TSPO in BV-2 cells after transfected with TSPO siRNA in order to determined effect of silenced TSPO gene in BV-2 cells after transfected with TSPO siRNA with Real-time PCR and Western blot.After that,we studied effects of silenced TSPO gene on productions and mRNA expressions of proinflammatory cytokines in BV-2 cells after LPS treatment (l00 ng/ml) with ELISA and Real-time PCR.
5.We studied effects of TSPO ligands (PK 11195 and Ro5-4864) at different dose (10μM、50μM、100μM) on productions and mRNA expressions of proinflamma- tory cytokines in BV-2 cells transfected with TSPO siRNA after LPS treatment (l00 ng/ml) with ELISA and Real-time PCR.
6.We explored effects of TSPO ligands (PK 11195 and Ro5-4864) at different dose (10μM、50μM、100μM) on MAPK pathway (Erk,JNK and p38) and IκB degra- dation in BV-2 cells after LPS treatment (l00 ng/ml) with Western blot.
7.We studied effects of TSPO ligands (PK 11195 and Ro5-4864) at the dose of 100μM for 24 h on a single VB-2 intracellular calcium concentration ([Ca2 +] i) by flow cytometry.
8.We treated BV-2 microglial cells cultures with LPS (l00 ng/ml) for 2 h to induce microglia activation.Following,LPS-induced reactive microglia were exposed for 1 h and 2 h to ACTD+PK 11195、ACTD+Ro5-48643 and ACTD+DMSO,respectively,for measurement of mRNA expressions of IL-1βand IL–6 with Real-time PCR,and analysis of mRNA degradation of IL-1βand IL–6.
Results
1.LPS induced BV-2 microglial cells activation,as follows:dynamic morphology changes in cell growth to Amoeba-like appearance,levels of proinflammatory cytokines increased,such as,TNF-α、IL-lβand IL -6. Levels of proinflamma- tory cytokines increased in time and dose-dependent way of LPS.
2.The TSPO expression was detected in resting BV-2 cells at low level,but increased in LPS-induced BV-2 cells in time-dependent way,increasing signifycantly in 24 h and 48 h after LPS treatment(P <0.01).
3.TSPO ligands (PK 11195 and Ro5-4864) showed anti-inflammatory properies. They inhibited reactive BV-2 cells after LPS treatment and reduced levels of IL-l βand IL -6, except for TNF-α.On IL-1β, Ro5-4864 showed the same inhibitory effects as PK 11195, and Ro5-4864 showed more strong inhibitor than PK 11195 on IL-6.So,Ro5-4864 showed more strong anti-inflammatory properies than PK 11195 on IL-6.
4. The expression and protein of TSPO were less in BV-2 cells after transfected with TSPO siRNA than in BV-2 cells after transfected with control siRNA.The difference between the two groups was significant (P <0.01).The results showed that TSPO siRNA can downregulate effectively the expression and protein of TSPO.However,the products of TNF-α、IL-lβand IL-6 did not decrease in BV-2 cells transfected with TSPO siRNA relative to those in BV-2 cells transfected with control siRNA after LPS treatment.In other words,down- regulation of TSPO had no effect on levels of proinflammatory cytokines,such as,TNF-α、IL-lβand IL-6 in BV-2 cells treated by LPS.The results showed that TSPO gene does not directly mediate inflammation,or play a second role in inflammatory process induced by reactive BV-2 cells.
5. TSPO ligands (PK 11195 and Ro5-4864) had reduced levels of IL-lβand IL-6 in BV-2 cells transfected with TSPO siRNA and control groups (BV-2 cells transfected with control siRNA) after LPS treatment. The difference between the two groups was not significant (P >0.01).TSPO gene did not mediate the inhibitory effect of TSPO ligands (PK 11195 and Ro5-4864) on levels of proinflammatory cytokines, such as, IL-lβand IL-6 in BV-2 cells treated by LPS. The result showed that TSPO gene does not directly regulate or play a role for transmitting information to the other subunits in the anti-inflammatory of TSPO ligands.
6. TSPO ligands (PK 11195 and Ro5-4864) had no affect on Iκ- B degradation and phosphorylation of Erk,JNK and p38 in BV-2 cells after LPS treatment. However,PK 11195 and Ro5-4864 had affect on [Ca2+]i in BV-2 cells. PK 11195 increased significantly [Ca2+]i from 1.95±0.16 to 3.37±0.14(MFI). The difference between PK 1195 treatment and control groups was significant (P <0.01);Ro5-4864 decreased significantly [Ca2+]i in BV-2 cells from 1.95±0.16 to 1.56±0.09(MFI).The difference between Ro5-4864 treatment and control groups was significant (P <0.01).
7. TSPO ligands (PK 11195 and Ro5-4864) accelerated degradation of IL-1βand IL- 6 mRNA.The reductions of IL-1βand IL -6 mRNA were 60.2 %、64.3 % and 69.4 %、74.1 % at 1 h and 2 h treatment of PK 11195,and they were 58.2 %、60.2 % and 66.9 %、70.0 % with Ro5-4864 treatment in LPS-induced BV-2cells. The half-life of mRNA of IL-1βand IL-6 in LPS-induced BV-2cells after PK 11195 or Ro5-4864 treatment were significantly shorter that that in control groups,from 2 h to 1 h.The findings showed PK 11195 and Ro5-4864 decreased mRNA stability of IL-1βand IL -6.
Conclusions
1.LPS can induce microglia activation to grow with Amoeba-like appearance,and synthesize and secrete proinflammatory cytokines,such as,TNF-α、IL-lβand IL -6 through MAPKs signal transduction pathways and NF-κB transcription factor.
2.In resting microglia,TSPO expression is low.But in activated microglia after LPS treatment , TSPO expression increases in time-dependent way , increasing significantly in 24 h and 48 h. Combined with the first study finding, the results show that increased TSPO expression is closely associated with micrglia activation,and may be related to the secretion of inflammatory cytokines.So,The induction of TSPO expression in reactive microglia suggests that TSPO may be involved in the regulation of reactive microglia.
3.TSPO ligands are of anti-inflammatory properies.They can inhibite reactive microglia after LPS treatment and reduce levels of proinflammatory cytokines. Nevertheless,TSPO sub-unit does not mediate the inhibitory effect of TSPO ligands on levels of proinflammatory cytokines,and only play a role for transmitting information to the other sub-units (VDAC and ANT).So,the other two sub-units (VDAC and ANT) in PBR complex may involve in anti- inflammatory properies of TSPO ligands. These findings suggest that the three sub-units (TSPO、VDAC and ANT) are interlinked and interacted to constitute a complex of PBR. Isoquinoline carboxamides (such as PK 11195) can be indivi- dually bind the isoquinoline binding site (TSPO).However,interactions among TSPO、VDAC and ANT are considered to play a role in the process that benzodiazepine-type drugs (such as Ro5-4864 ) bind specifically TSPO.So,Ro5- 4864 showed more strong inhibitor than PK 11195 on IL-6,and on IL-1β, Ro5-4864 showed the same inhibitory effects as PK 11195.In general,Ro5-4864 has showed more strong anti-inflammatory properies than PK 11195.These findings support the concept on renaming the PBR to TSPO,which reflect more accurately the cellular and physiological functions in which TSPO has important role.
4.TSPO ligands can inhibit reactive microglia after LPS treatment and reduce levels of proinflammatory cytokines (IL-1βand IL-6) through decreasing mRNA stability of proinflammatory cytokines and Ca2+-mediated signaling pathways,except through MAPKs signal transduction pathways and NF-κB transcription factor.
5. PK 11195 and Ro5-4864 play different roles in intercellular concentration of calcium([Ca2 +]i) in microglial cells.PK 11195 increased significantly [Ca2+]i ,and Ro5-4864 decreased significantly [Ca2+]i in microglial cells.Combined with their results in inflammation induced by microglia,it is inaccurate that PK 11195 is generally known as PBR antagonists and Ro5-4864 as PBR agonists.Further,it is relatively exact that PK 11195 is known as voltage-dependent anion channel (VDAC) antagonists and Ro5-4864 as VDAC agonists according to their properties.We will further study the work in the future.
引文
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