组织型纤溶酶原激活剂和neuroserpin的神经保护作用
摘要
目的：tPA是中枢神经系统内重要的丝氨酸蛋白激酶,tPA与其抑制剂neuroserpin在神经元的生长、发育以及多种病理条件下发挥作用。海马和皮层区是对缺血性损害比较敏感的脑区,也有较高的tPA和neuroserpin活性。本研究的主要目的是阐明急性脑缺血时tPA和neuroserpin对神经元的作用。
方法：本研究观察体外模型中不同程度的氧糖剥夺对海马、皮层区神经元tPA活性和对野生型和tPA基因敲除小鼠神经元生存的影响。体内模型利用双侧颈总动脉阻塞或大脑中动脉阻塞模型造成全脑或局部脑缺血,观察不同程度的缺血对海马、皮层区内源性tPA和neuroserpin活性影响和对野生型和tPA基因敲除小鼠神经元生存的影响。同时,利用外源性tPA和neuroserpin作为一种预处理的方法,评价不同时间的预处理对神经元的保护作用和相关机制。
结果：明胶酶谱法显示,正常情况下海马CA1区缺乏tPA的蛋白水解活性,在亚致死性缺血发作时,皮层和海马CA1区tPA的表达快速增加。这种内源性tPA可以减少致死性缺血损害后海马神经元死亡,但对于皮层神经元则没有保护作用。tPA和纤溶酶原基因敲除小鼠海马CA1区因为缺乏tPA和纤溶酶的活性没有使神经元在随后的致死性缺血性损害中得到保护。在致死性缺血损害的同时,若给予500nM的外源性tPA可以使海马区神经元的存活从55.71±1.9%提高到73.6±6.4%,无活性tPA使神经元的存活提高到80.02±1.55%。α2-抗血纤溶酶、MK801和渥曼青霉素没有减弱tPA的保护作用,而且单独给予纤溶酶也没有早期预处理作用,RAP完全消除tPA的早期预处理作用。在致死性缺血损害发生前24小时,给予60nM的tPA即可以使神经元生存率从62±2.88%升至88.28±2.72%,单独给予纤溶酶可使神经元生存率提高到86.44±1.64%,而无活性tPA和纤溶酶原并没有神经保护作用。α2-抗血纤溶酶、抑肽酶和ε-氨基己酸、MK801和渥曼青霉素均减弱tPA的保护作用,RAP增加了tPA的延迟预处理作用。与早期预处理不同,tPA可以减弱卡英酸导致的兴奋性毒性。
免疫组化显示,正常情况下皮层和海马区存在少量neuroserpin的表达。亚致死性缺血发作诱发皮层和海马区neuroserpin的表达增加。给予外源性neuroserpin有比较显著的早期预处理作用,可以使野生型和tPA-/-小鼠海马神经元生存率分别增加到83.3±3.8%和92.0±1.6%；皮层神经元生存率分别增加到79.8±2.2%和82.3±2.4%。MK-801或neuroserpin可阻止纤溶酶导致的神经元死亡,生存率分别从74.2±1.7%上升至88.8±1.1%和94.0±1.3%。neuroserpin也可以减弱卡英酸导致的兴奋性毒性,使生存率升至98.3±2.3%。MCAO后给予外源性neuroserpin使野生型和tPA-/-小鼠脑梗死体积分别降低了48.3%和32.7%。
结论：预处理诱发的内源性tPA保护小鼠海马神经元,但对皮层神经元并没有保护作用。外源性tPA的早期预处理作用独立于纤溶酶原/纤溶酶系统,也不依赖于NMDA受体激活和Akt的磷酸化,而需与低密度脂蛋白受体家族相互作用激活细胞信号通路介导早期神经保护。tPA的延迟预处理作用需要他的蛋白水解活性,使纤溶酶原转化为纤溶酶,纤溶酶裂解NMDA受体的NR2A亚基使之激活,进而介导Akt磷酸化起到神经保护作用。预处理诱发的内源性neuroserpin保护小鼠海马和皮层神经元。neuroserpin的神经保护作用很大程度依赖于抑制了纤溶酶激活NMDA受体介导的兴奋性毒性细胞死亡,而不依赖其抑制tPA的能力。
Objective:TPA is an important serine protease in the central nervous system. It plays a critical role, along with its inhibitor neuroserpin, in neuronal survival under physiological and pathological conditions. Since cotical and hippocampal neurons are highly vulnerable to hypoxia-induced cell death, and the concentrations of tPA and neuroserpin in these regions of the brain are higher, we investigated the roles of tPA and neuroserpin in neuronal cell-survival after a hypoxic insult. The roles of exogenous as well as endogenous tPA and neuroserpin were examined.
Methods:We assessed the activity of tPA released from cortical or hippocampal neurons using Elisa. We also looked into tPA-confered neuronal survival in wild- type and tPA deficient mice from OGD induced cell death in vitro model using MTT assay. In vivo, the effects of endogenous tPA and neuroserpin in cortical or hippocampal neurons on neuronal cell death were assessed after the induction of ischemia using BCCAO and MCAO models, which result in the ischemia of the forebrain and focal brain respectively. Furthermore, the neuroprotective mechanisms and effects of tPA and neuroserpin were elucidated by treating with exsogenous tPA and neuroserpin at different time points as a method of preconditioning.
Results:Using an in situ zymography assay, we found that proteolytic activity of tPA is absent in the CA1 layer under normal oxygen concentrations. The activity of tPA in the cortical and CA1 layers increased immediately after exposure to hypoxia. The increased levels of endogenous tPA induced by brief hypoxia,resulted in the protection of hippocampal but not cortical neurons from subsequent lethal hypoxia in wild-type mice. In contrast, the protective effect of ischemic preconditioning was absent in tPA and plasminogen deficient mice. Our results indicate that treatment with 500 nM recombinant tPA simultaneously with OGD increases hippocampal neuronal survival from 55.71%±1.9% to 73.6%±6.4%, whereas inactive tPA increased hippocampal neuronal survival to 80.02±1.55%. Moreover, We found that not only didα2-antiplasmin, MK-801 or wortmannin not abrogate the protective effects of tPA, but also incubation with plasmin alone failed to induce neuronal survival. Furthermore,the LRP-extracellular domain binding protein, RAP, abrogated the protective effects of tPA in the early preconditioning model showing that tPA does not need proteolytic activity to confer this protection.In a delayed preconditioning model,however,we found that incubation with 60 nM of tPA or plasmin 24 hours before exposure to lethal OGD increased neuronal survival from 62±2.88% to 88.28%±2.72% and 86.44%±1.64%, respectively, but treatment with inactive tPA or plasminogen alone did not have a protective effect. The protective effect of tPA was inhibited by coincubation with a2-antiplasmin, aprotinin, EACA, MK-801 or wortmannin,showing that it is proteolysis dependent. Moreover in contrast to our observations with early preconditioning, we found that incubation with tPA 24 hours before the excitotoxic injury with kainic acid had a neuroprotective effect.
Immunofluorescence analysis showed that there is low expression of neuroserpin in the hippocampus and cortex under normoxia. The activity of neuroserpin in cortical and hippocampal CA1 layer increases immediately after exposure to hypoxic insult. In contrast to lethal ischemia, a sublethal ischemic injury induces a significant increase in the expression of neuroserpin in the hippocampus and cortex. Treatment with exogenous neuroserpin during OGD increases the survival of hippocampal neurons in wild-type and tPA deficient mice to 83.3±3.8% and 92.0±1.6% respectively and cortical neurons to 79.8±2.2% and 82.3±2.4%, respectively. Compared to untreated cells, plasmin decreases neuronal survival to 74.2±1.7%, and that this effect is significantly inhibited by co-incubation with either MK-801 (88.8±1.1%) or neuroserpin (94±1.3%). Incubation with kainic acid alone reduces neuronal survival to 78.2±1.8%, and that early/immediate preconditioning with neuroserpin increases cell survival to 98.3±2.3%. Despite a decrease in the volume of the ischemic lesion associated with genetic deficiency of tPA, treatment with neuroserpin caused a further reduction of 48.3% and 32.7% in the volume of the ischemic lesion in wild-type and tPA deficient mice.
Conclusions:Our data indicate that treatment of hippocampal neurons with tPA prior to lethal hypoxia confers neuro-protection. This protective effect is independent of plasminogen/plasmin and instead requires the engagement of a member of the LDL receptor family. Additionally, treatment with tPA also induces tolerance against a lethal insult applied 24 hours later. This delayed protective effect of tPA requires tPA's proteolytic activity and is mediated by plasmin via NMDAR-dependent Akt phosphorylation. Neuroserpin induces ischemic tolerance in wild-type and tPA deficient neurons and mice. Neuroprotective effect of neuroserpin is due, largely, to the inhibition of plasmin-mediated excitotoxin-induced cell death and is independent of neuroserpin's ability to inhibit tPA activity.
方法：本研究观察体外模型中不同程度的氧糖剥夺对海马、皮层区神经元tPA活性和对野生型和tPA基因敲除小鼠神经元生存的影响。体内模型利用双侧颈总动脉阻塞或大脑中动脉阻塞模型造成全脑或局部脑缺血,观察不同程度的缺血对海马、皮层区内源性tPA和neuroserpin活性影响和对野生型和tPA基因敲除小鼠神经元生存的影响。同时,利用外源性tPA和neuroserpin作为一种预处理的方法,评价不同时间的预处理对神经元的保护作用和相关机制。
结果：明胶酶谱法显示,正常情况下海马CA1区缺乏tPA的蛋白水解活性,在亚致死性缺血发作时,皮层和海马CA1区tPA的表达快速增加。这种内源性tPA可以减少致死性缺血损害后海马神经元死亡,但对于皮层神经元则没有保护作用。tPA和纤溶酶原基因敲除小鼠海马CA1区因为缺乏tPA和纤溶酶的活性没有使神经元在随后的致死性缺血性损害中得到保护。在致死性缺血损害的同时,若给予500nM的外源性tPA可以使海马区神经元的存活从55.71±1.9%提高到73.6±6.4%,无活性tPA使神经元的存活提高到80.02±1.55%。α2-抗血纤溶酶、MK801和渥曼青霉素没有减弱tPA的保护作用,而且单独给予纤溶酶也没有早期预处理作用,RAP完全消除tPA的早期预处理作用。在致死性缺血损害发生前24小时,给予60nM的tPA即可以使神经元生存率从62±2.88%升至88.28±2.72%,单独给予纤溶酶可使神经元生存率提高到86.44±1.64%,而无活性tPA和纤溶酶原并没有神经保护作用。α2-抗血纤溶酶、抑肽酶和ε-氨基己酸、MK801和渥曼青霉素均减弱tPA的保护作用,RAP增加了tPA的延迟预处理作用。与早期预处理不同,tPA可以减弱卡英酸导致的兴奋性毒性。
免疫组化显示,正常情况下皮层和海马区存在少量neuroserpin的表达。亚致死性缺血发作诱发皮层和海马区neuroserpin的表达增加。给予外源性neuroserpin有比较显著的早期预处理作用,可以使野生型和tPA-/-小鼠海马神经元生存率分别增加到83.3±3.8%和92.0±1.6%；皮层神经元生存率分别增加到79.8±2.2%和82.3±2.4%。MK-801或neuroserpin可阻止纤溶酶导致的神经元死亡,生存率分别从74.2±1.7%上升至88.8±1.1%和94.0±1.3%。neuroserpin也可以减弱卡英酸导致的兴奋性毒性,使生存率升至98.3±2.3%。MCAO后给予外源性neuroserpin使野生型和tPA-/-小鼠脑梗死体积分别降低了48.3%和32.7%。
结论：预处理诱发的内源性tPA保护小鼠海马神经元,但对皮层神经元并没有保护作用。外源性tPA的早期预处理作用独立于纤溶酶原/纤溶酶系统,也不依赖于NMDA受体激活和Akt的磷酸化,而需与低密度脂蛋白受体家族相互作用激活细胞信号通路介导早期神经保护。tPA的延迟预处理作用需要他的蛋白水解活性,使纤溶酶原转化为纤溶酶,纤溶酶裂解NMDA受体的NR2A亚基使之激活,进而介导Akt磷酸化起到神经保护作用。预处理诱发的内源性neuroserpin保护小鼠海马和皮层神经元。neuroserpin的神经保护作用很大程度依赖于抑制了纤溶酶激活NMDA受体介导的兴奋性毒性细胞死亡,而不依赖其抑制tPA的能力。
Objective:TPA is an important serine protease in the central nervous system. It plays a critical role, along with its inhibitor neuroserpin, in neuronal survival under physiological and pathological conditions. Since cotical and hippocampal neurons are highly vulnerable to hypoxia-induced cell death, and the concentrations of tPA and neuroserpin in these regions of the brain are higher, we investigated the roles of tPA and neuroserpin in neuronal cell-survival after a hypoxic insult. The roles of exogenous as well as endogenous tPA and neuroserpin were examined.
Methods:We assessed the activity of tPA released from cortical or hippocampal neurons using Elisa. We also looked into tPA-confered neuronal survival in wild- type and tPA deficient mice from OGD induced cell death in vitro model using MTT assay. In vivo, the effects of endogenous tPA and neuroserpin in cortical or hippocampal neurons on neuronal cell death were assessed after the induction of ischemia using BCCAO and MCAO models, which result in the ischemia of the forebrain and focal brain respectively. Furthermore, the neuroprotective mechanisms and effects of tPA and neuroserpin were elucidated by treating with exsogenous tPA and neuroserpin at different time points as a method of preconditioning.
Results:Using an in situ zymography assay, we found that proteolytic activity of tPA is absent in the CA1 layer under normal oxygen concentrations. The activity of tPA in the cortical and CA1 layers increased immediately after exposure to hypoxia. The increased levels of endogenous tPA induced by brief hypoxia,resulted in the protection of hippocampal but not cortical neurons from subsequent lethal hypoxia in wild-type mice. In contrast, the protective effect of ischemic preconditioning was absent in tPA and plasminogen deficient mice. Our results indicate that treatment with 500 nM recombinant tPA simultaneously with OGD increases hippocampal neuronal survival from 55.71%±1.9% to 73.6%±6.4%, whereas inactive tPA increased hippocampal neuronal survival to 80.02±1.55%. Moreover, We found that not only didα2-antiplasmin, MK-801 or wortmannin not abrogate the protective effects of tPA, but also incubation with plasmin alone failed to induce neuronal survival. Furthermore,the LRP-extracellular domain binding protein, RAP, abrogated the protective effects of tPA in the early preconditioning model showing that tPA does not need proteolytic activity to confer this protection.In a delayed preconditioning model,however,we found that incubation with 60 nM of tPA or plasmin 24 hours before exposure to lethal OGD increased neuronal survival from 62±2.88% to 88.28%±2.72% and 86.44%±1.64%, respectively, but treatment with inactive tPA or plasminogen alone did not have a protective effect. The protective effect of tPA was inhibited by coincubation with a2-antiplasmin, aprotinin, EACA, MK-801 or wortmannin,showing that it is proteolysis dependent. Moreover in contrast to our observations with early preconditioning, we found that incubation with tPA 24 hours before the excitotoxic injury with kainic acid had a neuroprotective effect.
Immunofluorescence analysis showed that there is low expression of neuroserpin in the hippocampus and cortex under normoxia. The activity of neuroserpin in cortical and hippocampal CA1 layer increases immediately after exposure to hypoxic insult. In contrast to lethal ischemia, a sublethal ischemic injury induces a significant increase in the expression of neuroserpin in the hippocampus and cortex. Treatment with exogenous neuroserpin during OGD increases the survival of hippocampal neurons in wild-type and tPA deficient mice to 83.3±3.8% and 92.0±1.6% respectively and cortical neurons to 79.8±2.2% and 82.3±2.4%, respectively. Compared to untreated cells, plasmin decreases neuronal survival to 74.2±1.7%, and that this effect is significantly inhibited by co-incubation with either MK-801 (88.8±1.1%) or neuroserpin (94±1.3%). Incubation with kainic acid alone reduces neuronal survival to 78.2±1.8%, and that early/immediate preconditioning with neuroserpin increases cell survival to 98.3±2.3%. Despite a decrease in the volume of the ischemic lesion associated with genetic deficiency of tPA, treatment with neuroserpin caused a further reduction of 48.3% and 32.7% in the volume of the ischemic lesion in wild-type and tPA deficient mice.
Conclusions:Our data indicate that treatment of hippocampal neurons with tPA prior to lethal hypoxia confers neuro-protection. This protective effect is independent of plasminogen/plasmin and instead requires the engagement of a member of the LDL receptor family. Additionally, treatment with tPA also induces tolerance against a lethal insult applied 24 hours later. This delayed protective effect of tPA requires tPA's proteolytic activity and is mediated by plasmin via NMDAR-dependent Akt phosphorylation. Neuroserpin induces ischemic tolerance in wild-type and tPA deficient neurons and mice. Neuroprotective effect of neuroserpin is due, largely, to the inhibition of plasmin-mediated excitotoxin-induced cell death and is independent of neuroserpin's ability to inhibit tPA activity.
引文
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