甲磺酸法舒地尔Rho激酶抑制剂对缺血性脑损伤的保护作用及机制研究
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摘要
目的观察甲磺酸法舒地尔(fasudil mesylate，FM)对犬脑血管痉挛的舒张作用，并探讨其对缺血性脑损伤的保护作用及机制研究。方法1．经十二指肠给予麦角胺咖啡因片建立犬脑血管痉挛模型，观察给予FM后两小时内脑血流量、脑血管阻力、股动脉血流量、股动脉血管阻力、心率、收缩压、舒张压及平均动脉压的变化；用离体血管环实验方法观察FM对血管舒缩功能的影响；2．大鼠局灶性脑缺血采用大脑中动脉栓塞(middle cerebral artery occlusion，MCAO)2 h再灌注24 h模型，模型成功后观察神经行为学评分，检测脑梗死体积，脑组织形态学变化，及诱导型一氧化氮合酶(inducednitric oxide synthetase，iNOS)和内皮型一氧化氮合酶(endothelium nitric oxide synthetase，eNOS)的表达；3．采用急性离体脑片培养氧糖剥夺(oxygen-glucose deprivation，OGD)／再氧合(Reoxygenation，REO)模型，观察FM对脑片组织细胞活力的影响，并检测脑片组织中iNOS及过氧化物歧化酶(superoxide dismutase，SOD)的活性；4．利用过氧化氢(hydrogen peroxide，H_2O_2)造氧化应激模型，观察FM对PCl2细胞活力的影响。通过Hoechst染色，丫啶橙(Acridine orange，AO)／溴化乙啶(Ethidium bromide，EB)荧光双染观察细胞凋亡，2，7-二氯氢化荧光素(2’，7’-dichlorodihydrofluorescindiacetate，DHCF-DA)荧光染色观察细胞内过氧化物的生成，硝基四氮唑蓝(nitrobluetetrazolium，NBT)定量检测细胞内过氧化物水平；并通过qPCR及Western blot的方法检测凋亡相关基因Bax／bcl-2的表达。结果(1)FM(0．35、1．2、3．5 mg·kg~(-1))给药后可依剂量地降低脑血管阻力，增加脑血流量，作用持续2h；最大流量增加值与模型对照组比较可达27％；而其对股动脉血流量、股动脉血管阻力、心率、收缩压、舒张压及平均动脉压的影响较轻微；在离体血管环实验中，FM对甲氧胺(methoxamine，Met)及氯化钾(postassium，KCl)所致的血管收缩均有明显的舒张作用，其舒张作用在有内皮组与去内皮组之间无统计学差异；FM能使Met量效曲线非平行右移，E_(max)降低。(2)FM可改善大鼠大脑中动脉栓塞引起的神经行为学障碍，减少脑梗死体积，显著减少皮层神经元丢失，同时检测到皮层脑组织中eNOS蛋白表达明显增加，iNOS蛋白表达降低。(3)FM可显著改善大鼠皮层及海马脑片OGD／REO损伤后的脑片组织活性，同时抑制脑片组织中炎症相关蛋白iNOS的活性并增加SOD的活性。(4)FM可显著抑制H_2O_2所致PCl2细胞活力下降并抑制细胞凋亡，同时降低细胞内过氧化物的水平，并在mRNA及蛋白水平均降低Bax／bcl-2的比率。结论(1)FM静脉输注给药对犬痉挛脑血管有扩张作用，可明显降低脑血管阻力，增加脑血流量；与其对外周血管的作用比较，FM对脑血管作用选择性强，起效剂量低，起效亦较快；FM的舒血管作用与血管内皮细胞无明显关联，此作用为非内皮依赖性舒张作用。(2)在整体动物和离体脑片水平均观察到FM对脑缺血损伤有明显的保护作用，此作用可能与eNOS／iNOS有关；而进一步在细胞水平发现FM对脑损伤的保护作用可能与其直接抑制细胞损伤和细胞凋亡有关，而降低细胞内过氧化物的水平及抑制线粒体Bcl-2家族成员介导的细胞凋亡可能参与了此作用。
Aim To investigate the neuroprotective effect of fasudil mesylate (FM) and the underlyingmechanisms.Methods 1.The relaxation effect of FM was studied using cerebralvasospasm (CVS) in vivo and isolated aortic rings in vitro.2.FM was investigated for itsneuroprotective potential in rats with ischemia following middle cerebral artery occlusion(MCAO) and reperfusion.Rats were randomly assigned to sham,vehicle or FM groups.Infarct volume,neurological deficit score,morphology and molecular biological markerswere assessed.FM (10 mg·kg~(-1)) or NS was administered at 48h,24h and 2h before MCAO.Immunohistochemistry and western blot were used for detection of inducible nitric oxidesynthase (iNOS) and endothelium nitric oxide synthase (eNOS).3.The model of oxygenand glucose deprivation (OGD) insult in rat cortical and hippocampal brain slices was usedto investigate the neuroprotective effect of FM in vitro.FM (10,100μM) wereco-incubated with the slices for 30 min prior to and during OGD insult respectively.Brainslices viability was evaluated by using the 2,3,5-triphenyl tetrazolium chloride (TTC)method;The fluorescence of propidium iodide (PI) staining was used for quantification ofcellular survival,and lactate dehydrogenase (LDH) activity in incubation medium wasassessed to evaluate the degree of injury.Brain slices were collected at the end of theexperiment and stored at -70℃for analysis of iNOS and superoxide dismutase (SOD).4.The effect of FM on hydrogen peroxide (H_2O_2)induced neurotoxicity in PC12 cells wasinvestigated.PC12 cells were damaged by 300μM H_2O_2 for 12 h.Thiazoyl bluetetrazolium bromide (MTT) method and LDH release were detected to determine cellactivity.Hoechst 33258 staining and Acridine orange (AO)/Ethidium bromide (EB)double-staining were used to observe morphology changes of the cells. 2',7'-dichlorodihydrofluorescin diacetate (DHCF-DA) staining and nitroblue tetrazolium(NBT) method were used for quantification of intracellular ROS in PC12 cells.The qPCRand western blot method were used to test the mRNA and protein expression of Bax andbcl-2.ResultsⅠ(1) FM (0.35、1.2、3.5 mg·kg~(-1)) decreased cerebrovascular resistance(CVR) and increased cerebral blood flow (CBF) dose-dependently,and the relaxationeffects of FM on cerebral vessels were much stronger than on peripheral vessels.(2) FMshowed dose-dependent relaxation of isolated aortic rings contracted by pretreatment withMethoxamine (Met) or KCL.The relaxation IC_(50) of FM to the rabbit and rat aortic ringscontracted by KCL are 37.15μtM and 0.74μM respectively,and the relaxation IC_(50) of FMand Prasozin (Pra) to the rabbit aortic rings contracted by Met are 27.54μM and 0.01μMrespectively.In addition,the relaxation action of FM had no obvious difference inendothelium-intact and endothelium-removal groups.(3) The Met dose-effect relationshipcurve was significantly shifted to the right by 0.3μM and 3μM of FM,and E_(max) wasdecreased.ⅡGross anatomy showed that cerebral infarct size was significantly smaller inthe FM-treated than in the non FM-treated ischemic rats.In the brain regions vulnerableto ischemia of ischemic rats,FM was also found to significantly restore the enzyme proteinexpression level of endothelial nitric oxide synthase (eNOS),which was decreased inischemia.However,it remarkably reduced the protein synthesis of inducible nitric oxidesynthase (iNOS) that was induced by ischemia and reperfusion.ⅢIn rat brain slices treatedwith OGD/REO injury,FM increased the neuronal cell viability by 40 % for cortex and by61% for hippocampus respectively.Finally,in the presence of OGD and FM,superoxidedismutase (SOD) activity was increased by 50 % for cortex and by 58 % for hippocampus,compared to OGD only group.ⅣPretreatment with FM prior to H_2O_2 exposuresignificantly elevated cell viability,reduced H_2O_2-induced cell apoptosis,and decreasedintracellular accumulation of reactive oxygen species (ROS).Furthermore,FM alsoreversed the upregulation of Bax/Bcl-2 ratio,the downstream cascade following ROS.
Conclusions These results suggest that:1) The relaxation effects of FM on cerebral vessels were much stronger than on peripheral vessels in vivo,and the action was in anendothelium-independent manner;2) FM not only provided neuroprotective effects onneurological deficit and cerebral infarct size after MCAO/Reperfusion,but also amelioratedcell apoptosis induced by oxidative stress insult on PC12 cells directly.The mechanismsmay be involved in the increasing CBF,ameliorating vascular endothelium function,alleviation of intracellular ROS and reactive nitrogen species (RNS) generation,anddepressing of Bcl-2 family-related apoptotic signaling pathway.
Aim To investigate the neuroprotective effect of fasudil mesylate (FM) and the underlyingmechanisms.Methods 1.The relaxation effect of FM was studied using cerebralvasospasm (CVS) in vivo and isolated aortic rings in vitro.2.FM was investigated for itsneuroprotective potential in rats with ischemia following middle cerebral artery occlusion(MCAO) and reperfusion.Rats were randomly assigned to sham,vehicle or FM groups.Infarct volume,neurological deficit score,morphology and molecular biological markerswere assessed.FM (10 mg·kg~(-1)) or NS was administered at 48h,24h and 2h before MCAO.Immunohistochemistry and western blot were used for detection of inducible nitric oxidesynthase (iNOS) and endothelium nitric oxide synthase (eNOS).3.The model of oxygenand glucose deprivation (OGD) insult in rat cortical and hippocampal brain slices was usedto investigate the neuroprotective effect of FM in vitro.FM (10,100μM) wereco-incubated with the slices for 30 min prior to and during OGD insult respectively.Brainslices viability was evaluated by using the 2,3,5-triphenyl tetrazolium chloride (TTC)method;The fluorescence of propidium iodide (PI) staining was used for quantification ofcellular survival,and lactate dehydrogenase (LDH) activity in incubation medium wasassessed to evaluate the degree of injury.Brain slices were collected at the end of theexperiment and stored at -70℃for analysis of iNOS and superoxide dismutase (SOD).4.The effect of FM on hydrogen peroxide (H_2O_2)induced neurotoxicity in PC12 cells wasinvestigated.PC12 cells were damaged by 300μM H_2O_2 for 12 h.Thiazoyl bluetetrazolium bromide (MTT) method and LDH release were detected to determine cellactivity.Hoechst 33258 staining and Acridine orange (AO)/Ethidium bromide (EB)double-staining were used to observe morphology changes of the cells. 2',7'-dichlorodihydrofluorescin diacetate (DHCF-DA) staining and nitroblue tetrazolium(NBT) method were used for quantification of intracellular ROS in PC12 cells.The qPCRand western blot method were used to test the mRNA and protein expression of Bax andbcl-2.ResultsⅠ(1) FM (0.35、1.2、3.5 mg·kg~(-1)) decreased cerebrovascular resistance(CVR) and increased cerebral blood flow (CBF) dose-dependently,and the relaxationeffects of FM on cerebral vessels were much stronger than on peripheral vessels.(2) FMshowed dose-dependent relaxation of isolated aortic rings contracted by pretreatment withMethoxamine (Met) or KCL.The relaxation IC_(50) of FM to the rabbit and rat aortic ringscontracted by KCL are 37.15μtM and 0.74μM respectively,and the relaxation IC_(50) of FMand Prasozin (Pra) to the rabbit aortic rings contracted by Met are 27.54μM and 0.01μMrespectively.In addition,the relaxation action of FM had no obvious difference inendothelium-intact and endothelium-removal groups.(3) The Met dose-effect relationshipcurve was significantly shifted to the right by 0.3μM and 3μM of FM,and E_(max) wasdecreased.ⅡGross anatomy showed that cerebral infarct size was significantly smaller inthe FM-treated than in the non FM-treated ischemic rats.In the brain regions vulnerableto ischemia of ischemic rats,FM was also found to significantly restore the enzyme proteinexpression level of endothelial nitric oxide synthase (eNOS),which was decreased inischemia.However,it remarkably reduced the protein synthesis of inducible nitric oxidesynthase (iNOS) that was induced by ischemia and reperfusion.ⅢIn rat brain slices treatedwith OGD/REO injury,FM increased the neuronal cell viability by 40 % for cortex and by61% for hippocampus respectively.Finally,in the presence of OGD and FM,superoxidedismutase (SOD) activity was increased by 50 % for cortex and by 58 % for hippocampus,compared to OGD only group.ⅣPretreatment with FM prior to H_2O_2 exposuresignificantly elevated cell viability,reduced H_2O_2-induced cell apoptosis,and decreasedintracellular accumulation of reactive oxygen species (ROS).Furthermore,FM alsoreversed the upregulation of Bax/Bcl-2 ratio,the downstream cascade following ROS.
Conclusions These results suggest that:1) The relaxation effects of FM on cerebral vessels were much stronger than on peripheral vessels in vivo,and the action was in anendothelium-independent manner;2) FM not only provided neuroprotective effects onneurological deficit and cerebral infarct size after MCAO/Reperfusion,but also amelioratedcell apoptosis induced by oxidative stress insult on PC12 cells directly.The mechanismsmay be involved in the increasing CBF,ameliorating vascular endothelium function,alleviation of intracellular ROS and reactive nitrogen species (RNS) generation,anddepressing of Bcl-2 family-related apoptotic signaling pathway.
引文
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