缺血再灌注脑损伤后蛇床子素的作用及机制研究
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摘要
缺血性脑血管病是中枢神经系统的常见病和多发病;位列十大致死疾病前三、是首位致残因素,其发生率、病死率及致残率正在逐年上升。因此,脑缺血再灌注的分子机制和治疗方法的研究是国内外学者的研究热点。蛇床子素(osthole,OST)是香豆素类化合物的主要成分,来源于草本植物蛇床子,自然资源十分丰富。近年来大量实验表明,OST具有抗炎、抗凝血、扩张血管、抑制血栓形成、改善学习记忆、调血脂和潜在的神经保护作用。本研究应用大鼠的脑缺血再灌注模型,观察OST对缺血性脑损伤的保护作用,初步探讨OST保护作用可能的分子机制以及与内皮型一氧化氮合成酶(endothelial nitric oxide synthase, eNOS)相关通路之间的关系。旨在明确OST对缺血性脑损伤的神经保护作用及其可能的作用机制,为临床应用OST治疗缺血性脑损伤提供理论基础。
实验一、缺血性脑损伤后OST预处理的保护作用
目的:观察缺血性脑损伤后OST的保护作用。方法:步骤一:建立大鼠大脑中动脉阻塞(middle cerebral artery occlusion,MCAO)脑缺血再灌注模型。步骤二:实验用Sprague–Dawle(SD)大鼠45只随机分为假手术组(Sham组)、单纯缺血再灌注损伤组(MCAO组)和不同剂量OST预处理组(OST10+MCAO组、OST20+MCAO组、OST40+MCAO组);Sham组动物仅接受手术,没有动脉夹闭的过程;MCAO前30min,对OST预处理组动物分别腹腔注射OST 10mg/kg、20mg/kg、40mg/kg。再灌注24h后,采取双盲的形式对各实验组动物分别进行神经功能缺陷评分(neurological deficit score,NDS)。而后,每组随机选取3只动物用于伊红染色法( hematoxylin-eosin staining, HE染色)观察缺血脑组织形态学变化;3只用于2%红四氮唑(TTC)染色观察缺血脑组织的面积;3只用于干湿重法观察缺血脑组织的水肿程度。结果:在缺血再灌注24h后,OST预处理组大鼠的神经功能缺陷评分、缺血脑组织面积和脑水肿程度明显低于单纯缺血的MCAO组。组织形态学结果也是OST预处理组损伤明显减轻(P< 0.01)。其剂量在40 mg/kg时表现出神经保护作用最明显。结论:在大鼠的MCAO脑缺血再灌注损伤模型中,OST有明显的神经保护作用,在40 mg/kg时最明显。
实验二、缺血性脑损伤后OST预处理保护作用的机制
目的:观察OST治疗缺血性脑损伤时,丙二醛(malondialdehyde,MDA)、谷胱甘肽(glutathione,GSH)、髓过氧化物酶(myeloperoxidase,MPO)、白细胞介素(interleukin,IL)-1β和IL-8的改变与作用。方法:实验用SD大鼠36只随机分为假手术组(Sham组)、单纯缺血再灌注损伤组(MCAO组)和OST预处理组(40mg/kg)。再灌注24h后,每组随机选取3只动物用于检测MDA;3只用于检测GSH;3只用于检测MPO的活性;3只用于检测IL-1β和IL-8。结果:在缺血再灌注24h后,OST预处理不但增加了GSH的含量,而且降低了MDA、IL-1β和IL-8的水平以及MPO的活性(P < 0.01)。结论:缺血再灌注脑损伤后OST的保护作用与其抗炎抗氧化活性密切相关。
实验三、缺血性脑损伤后OST预处理保护作用的分子机制
目的:探讨缺血性脑损伤后OST保护作用时分子机制。方法:将SD大鼠随机分为假手术组(Sham组)、空载体组(vehicle组)、单纯OST预处理组(osthole组)、OST与一氧化氮合酶非选择性阻断剂左旋硝基精氨酸甲酯(NG-nitro-L-arginine methyl ester,L-NAME)共同给药组(osthole+L-NAME组)、OST与特异性PI3K阻断剂LY-294002共同给药组(osthole+LY294002组)、OST与PPARγ选择性阻断剂GW9662共同给药组(osthole+GW9662组)。再灌注24h后,通过TUNEL染色和Caspase3活性的检测验证OST的抗凋亡作用;用试剂盒检测缺血脑组织一氧化氮(nitric oxide,NO)以及硝基硌氨酸的含量;Western Blot检测三种一氧化氮合酶、TNF-α、arginase I、p-Akt、Akt、p-eNOS的蛋白表达;通过TTC染色和NDS分析各种阻断剂对OST作用的影响。结果:再灌注24h后,OST明显减少了缺血周围神经元的凋亡,降低了Caspase3的活性;增加了缺血区NO的含量但没有增加硝基硌氨酸的含量;减低了iNOS的表达增加了eNOS的表达,未改变nNOS的表达;L-NAME可完全阻断OST的保护作用;OST增加表达的eNOS可被GW9662通过增加TNF-α/arginase I的表达抑制;OST增加的eNOS磷酸化可被LY294002通过减少Akt的磷酸化来抑制。结论:OST可能是通过增加eNOS的表达,从而增加NO介导的抗凋亡作用达到神经保护作用。
Ischemic cerebrovascular disease of the central nervous system is common and frequent diseases,is one of the three killer diseases,is the first disability factors, and its incidence, mortality and disability are increasing year by year. Therefore, the molecular mechanisms and treatment of cerebral ischemia-reperfusion are research focus for domestic and foreign scholars. Osthole (OST) is the main component of coumarin compounds,derived from the herb Cnidium,and is rich in natural resources. In recent years,a large number of experiments show that OST has anti-inflammatory,anti-clotting,dilates blood vessels,inhibits thrombosis,improves learning and memory,and has potential neuroprotective effect. In this study,we will discusse the neuroprotective effect of OST and its possible molecular mechanisms,as well as the relationship of the effect and endothelial nitric oxide synthase (eNOS) relevant pathway in rats by cerebral ischemia-reperfusion model. The aim of this study is to clarify the neuroprotective effect of OST and its possible mechanism on ischemic brain injury, which will provide a theoretical basis for OST to be used in the clinical treatment of ischemic brain injury.
Part I Neuroprotective effects of OST in ischemic brain injury
Objective: To identify neuroprotective effects of OST in ischemic brain injury. Methods:Step One:Create a rat middle cerebral artery occlusion (MCAO) model of cerebral ischemia. Step Two: Male Sprague–Dawley rats were randomly divided into five groups: Sham group, MCAO group, pretreatment groups which were treated with osthole 10, 20 or 40 mg/kg (IP) 30 min before MCAO respectively. Twenty four hours after reperfusion, rats in all groups were evaluated neurological deficit score (NDS) by taking the form of double-blind. Then, three rats in each group were randomly selected for hematoxylin-eosin(HE) staining to observe morphological changes in ischemic brain tissue, three rats were randomly selected for 2% of the 2,3,5-triphenyltetrazolium chloride (TTC) staining to evaluate ischemic area of brain tissue, three rats were selected for the dry and wet weight to observe edema. Result:Pretreatment with OST significantly decreased the volume of infarction, NDS and edema compared with rats in the MCAO group at 24 h after MCAO. The histopathological changes of OST groups are also better than that of MCAO group (P < 0.01). Furthermore, the dose of 40 mg/kg of OST was more protective than the dose of 20 mg/kg and 10 mg/kg on the cerebral injury after MCAO. Conclusion:Pretreatment with OST can prevent neurons from the ischemia injury in rats with MCAO. The dose of 40 mg/kg of OST was more protective than the other dose on the cerebral injury after MCAO.
Part II The potential mechanisms of nuroprotective effects of OST in ischemic brain injury
Objective:To observe some indices of anti-inflammatory and antioxidant when pretreatment with OST prevents neurons from the ischemia injury in rats with MCAO. Methods:Male Sprague–Dawley rats were randomly divided into three groups: Sham group, MCAO group and pretreatment with OST groups. Twenty four hours after reperfusion, the rats in each of the groups were subdivided into four subgroups consisting of 3 animals. The first subgroup was used for detecting MDA; the second subgroup was used for detecting GSH; the third subgroup was used for detecting MPO; and the fourth subgroup was used for detecting IL-1βand IL-8 by ELISA. Results:Pretreatment with OST significantly increased in GSH, and decreased MDA, MPO, IL-1βand IL-8 compared with rats in the MCAO group at 24 h after MCAO. Conclusion:The antioxidative action and anti-inflammatory property of OST may contribute to a beneficial effect against stroke.
PartⅢThe molecule mechanisms of nuroprotective effects of OST in ischemic brain injury
Objective:To investigate the neuroprotective effect of OST on acute ischemic stroke induced by MCAO in rats and the underlying mechanism.Methods: Adult male Sprague-Dawley rats weighing 250 to 280g were subjected to 2h MCAO and pretreated with vehicle (20% Tween-80), osthole alone, or osthole plus NG-nitro-L-arginine methyl ester (L-NAME, a nonselective NOS inhibitor), LY-294002 (a specific PI3K inhibitor) or GW9662 (a selective PPARγantagonist) at 30min before the transient occlusion. Neurological deficit scores (NDS) and infarct volumes of brain were assessed at 24h and 72h after MCAO. Neuronal apoptosis, NO concentration and activated caspase-3, iNOS, nNOS, eNOS, phosphorylated eNOS (p-eNOS), Akt, phosphorylated Akt (p-Akt), Tumor necrosis factor-α(TNF-α) and arginase I proteins expression were also determined at 24h after MCAO. Results:Pre-administration of osthole on rats with MCAO-induced acute ischemic stroke resulted in a significant decrease both in NDS and infarction volume and in the levels of neuronal apoptosis, activated caspase-3 and iNOS proteins expression at 24h after MCAO. In contrary, NO concentration and eNOS protein expression were increased. The neuroprotective effect of osthole was completely blocked by NOS inhibitor L-NAME. Furthermore, osthole-induced eNOS protein expression and phosphorylation was blocked by GW9662 and LY-294002 respectively. And the phosphorylation of eNOS had a greater effect on osthole neuroprotection than the expression of eNOS. Conclusion:Our results provided direct evidence that osthole attenuates cerebral ischemic neuroinjury via eNOS-dependent and NO-mediated anti-apoptotic action in which both eNOS protein up-regulation and phosphorylation are involved, with the latter being the primary pathway.
实验一、缺血性脑损伤后OST预处理的保护作用
目的:观察缺血性脑损伤后OST的保护作用。方法:步骤一:建立大鼠大脑中动脉阻塞(middle cerebral artery occlusion,MCAO)脑缺血再灌注模型。步骤二:实验用Sprague–Dawle(SD)大鼠45只随机分为假手术组(Sham组)、单纯缺血再灌注损伤组(MCAO组)和不同剂量OST预处理组(OST10+MCAO组、OST20+MCAO组、OST40+MCAO组);Sham组动物仅接受手术,没有动脉夹闭的过程;MCAO前30min,对OST预处理组动物分别腹腔注射OST 10mg/kg、20mg/kg、40mg/kg。再灌注24h后,采取双盲的形式对各实验组动物分别进行神经功能缺陷评分(neurological deficit score,NDS)。而后,每组随机选取3只动物用于伊红染色法( hematoxylin-eosin staining, HE染色)观察缺血脑组织形态学变化;3只用于2%红四氮唑(TTC)染色观察缺血脑组织的面积;3只用于干湿重法观察缺血脑组织的水肿程度。结果:在缺血再灌注24h后,OST预处理组大鼠的神经功能缺陷评分、缺血脑组织面积和脑水肿程度明显低于单纯缺血的MCAO组。组织形态学结果也是OST预处理组损伤明显减轻(P< 0.01)。其剂量在40 mg/kg时表现出神经保护作用最明显。结论:在大鼠的MCAO脑缺血再灌注损伤模型中,OST有明显的神经保护作用,在40 mg/kg时最明显。
实验二、缺血性脑损伤后OST预处理保护作用的机制
目的:观察OST治疗缺血性脑损伤时,丙二醛(malondialdehyde,MDA)、谷胱甘肽(glutathione,GSH)、髓过氧化物酶(myeloperoxidase,MPO)、白细胞介素(interleukin,IL)-1β和IL-8的改变与作用。方法:实验用SD大鼠36只随机分为假手术组(Sham组)、单纯缺血再灌注损伤组(MCAO组)和OST预处理组(40mg/kg)。再灌注24h后,每组随机选取3只动物用于检测MDA;3只用于检测GSH;3只用于检测MPO的活性;3只用于检测IL-1β和IL-8。结果:在缺血再灌注24h后,OST预处理不但增加了GSH的含量,而且降低了MDA、IL-1β和IL-8的水平以及MPO的活性(P < 0.01)。结论:缺血再灌注脑损伤后OST的保护作用与其抗炎抗氧化活性密切相关。
实验三、缺血性脑损伤后OST预处理保护作用的分子机制
目的:探讨缺血性脑损伤后OST保护作用时分子机制。方法:将SD大鼠随机分为假手术组(Sham组)、空载体组(vehicle组)、单纯OST预处理组(osthole组)、OST与一氧化氮合酶非选择性阻断剂左旋硝基精氨酸甲酯(NG-nitro-L-arginine methyl ester,L-NAME)共同给药组(osthole+L-NAME组)、OST与特异性PI3K阻断剂LY-294002共同给药组(osthole+LY294002组)、OST与PPARγ选择性阻断剂GW9662共同给药组(osthole+GW9662组)。再灌注24h后,通过TUNEL染色和Caspase3活性的检测验证OST的抗凋亡作用;用试剂盒检测缺血脑组织一氧化氮(nitric oxide,NO)以及硝基硌氨酸的含量;Western Blot检测三种一氧化氮合酶、TNF-α、arginase I、p-Akt、Akt、p-eNOS的蛋白表达;通过TTC染色和NDS分析各种阻断剂对OST作用的影响。结果:再灌注24h后,OST明显减少了缺血周围神经元的凋亡,降低了Caspase3的活性;增加了缺血区NO的含量但没有增加硝基硌氨酸的含量;减低了iNOS的表达增加了eNOS的表达,未改变nNOS的表达;L-NAME可完全阻断OST的保护作用;OST增加表达的eNOS可被GW9662通过增加TNF-α/arginase I的表达抑制;OST增加的eNOS磷酸化可被LY294002通过减少Akt的磷酸化来抑制。结论:OST可能是通过增加eNOS的表达,从而增加NO介导的抗凋亡作用达到神经保护作用。
Ischemic cerebrovascular disease of the central nervous system is common and frequent diseases,is one of the three killer diseases,is the first disability factors, and its incidence, mortality and disability are increasing year by year. Therefore, the molecular mechanisms and treatment of cerebral ischemia-reperfusion are research focus for domestic and foreign scholars. Osthole (OST) is the main component of coumarin compounds,derived from the herb Cnidium,and is rich in natural resources. In recent years,a large number of experiments show that OST has anti-inflammatory,anti-clotting,dilates blood vessels,inhibits thrombosis,improves learning and memory,and has potential neuroprotective effect. In this study,we will discusse the neuroprotective effect of OST and its possible molecular mechanisms,as well as the relationship of the effect and endothelial nitric oxide synthase (eNOS) relevant pathway in rats by cerebral ischemia-reperfusion model. The aim of this study is to clarify the neuroprotective effect of OST and its possible mechanism on ischemic brain injury, which will provide a theoretical basis for OST to be used in the clinical treatment of ischemic brain injury.
Part I Neuroprotective effects of OST in ischemic brain injury
Objective: To identify neuroprotective effects of OST in ischemic brain injury. Methods:Step One:Create a rat middle cerebral artery occlusion (MCAO) model of cerebral ischemia. Step Two: Male Sprague–Dawley rats were randomly divided into five groups: Sham group, MCAO group, pretreatment groups which were treated with osthole 10, 20 or 40 mg/kg (IP) 30 min before MCAO respectively. Twenty four hours after reperfusion, rats in all groups were evaluated neurological deficit score (NDS) by taking the form of double-blind. Then, three rats in each group were randomly selected for hematoxylin-eosin(HE) staining to observe morphological changes in ischemic brain tissue, three rats were randomly selected for 2% of the 2,3,5-triphenyltetrazolium chloride (TTC) staining to evaluate ischemic area of brain tissue, three rats were selected for the dry and wet weight to observe edema. Result:Pretreatment with OST significantly decreased the volume of infarction, NDS and edema compared with rats in the MCAO group at 24 h after MCAO. The histopathological changes of OST groups are also better than that of MCAO group (P < 0.01). Furthermore, the dose of 40 mg/kg of OST was more protective than the dose of 20 mg/kg and 10 mg/kg on the cerebral injury after MCAO. Conclusion:Pretreatment with OST can prevent neurons from the ischemia injury in rats with MCAO. The dose of 40 mg/kg of OST was more protective than the other dose on the cerebral injury after MCAO.
Part II The potential mechanisms of nuroprotective effects of OST in ischemic brain injury
Objective:To observe some indices of anti-inflammatory and antioxidant when pretreatment with OST prevents neurons from the ischemia injury in rats with MCAO. Methods:Male Sprague–Dawley rats were randomly divided into three groups: Sham group, MCAO group and pretreatment with OST groups. Twenty four hours after reperfusion, the rats in each of the groups were subdivided into four subgroups consisting of 3 animals. The first subgroup was used for detecting MDA; the second subgroup was used for detecting GSH; the third subgroup was used for detecting MPO; and the fourth subgroup was used for detecting IL-1βand IL-8 by ELISA. Results:Pretreatment with OST significantly increased in GSH, and decreased MDA, MPO, IL-1βand IL-8 compared with rats in the MCAO group at 24 h after MCAO. Conclusion:The antioxidative action and anti-inflammatory property of OST may contribute to a beneficial effect against stroke.
PartⅢThe molecule mechanisms of nuroprotective effects of OST in ischemic brain injury
Objective:To investigate the neuroprotective effect of OST on acute ischemic stroke induced by MCAO in rats and the underlying mechanism.Methods: Adult male Sprague-Dawley rats weighing 250 to 280g were subjected to 2h MCAO and pretreated with vehicle (20% Tween-80), osthole alone, or osthole plus NG-nitro-L-arginine methyl ester (L-NAME, a nonselective NOS inhibitor), LY-294002 (a specific PI3K inhibitor) or GW9662 (a selective PPARγantagonist) at 30min before the transient occlusion. Neurological deficit scores (NDS) and infarct volumes of brain were assessed at 24h and 72h after MCAO. Neuronal apoptosis, NO concentration and activated caspase-3, iNOS, nNOS, eNOS, phosphorylated eNOS (p-eNOS), Akt, phosphorylated Akt (p-Akt), Tumor necrosis factor-α(TNF-α) and arginase I proteins expression were also determined at 24h after MCAO. Results:Pre-administration of osthole on rats with MCAO-induced acute ischemic stroke resulted in a significant decrease both in NDS and infarction volume and in the levels of neuronal apoptosis, activated caspase-3 and iNOS proteins expression at 24h after MCAO. In contrary, NO concentration and eNOS protein expression were increased. The neuroprotective effect of osthole was completely blocked by NOS inhibitor L-NAME. Furthermore, osthole-induced eNOS protein expression and phosphorylation was blocked by GW9662 and LY-294002 respectively. And the phosphorylation of eNOS had a greater effect on osthole neuroprotection than the expression of eNOS. Conclusion:Our results provided direct evidence that osthole attenuates cerebral ischemic neuroinjury via eNOS-dependent and NO-mediated anti-apoptotic action in which both eNOS protein up-regulation and phosphorylation are involved, with the latter being the primary pathway.
引文
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