摘要
中枢神经系统电生理学特性变化决定了人类意识状态，而基础是离子通道和神经递质受体系统的功能状态。异氟烷发挥全麻作用机制是使神经细胞超极化，已有研究证实异氟烷在不同神经细胞可诱导产生毒性，但异氟烷预处理神经细胞却可产生保护作用，其机制目前不清。Ca~(2+)作为一个广泛意义上的信号分子在神经细胞活动中起重要作用，钙离子稳态失衡而导致钙超载是神经细胞损伤的最后通路。内质网作为细胞内钙储备的主要场所，Ca~(2+)与内质网凋亡途径有着不可分割的关系，1，4，5-三磷酸肌醇受体(IP_3R)是位于细胞内质网上的Ca~(2+)释放的主要调节因子。因此我们假设内质网膜IP_3R通道在异氟烷的神经毒性和神经保护作用中起重要作用。因此本课题首先研究不同浓度和作用时间的异氟烷对新生大鼠皮层神经细胞的影响，通过观察细胞生长形态和检测细胞活性，并检测[Ca~(2+)]_i的变化，明确异氟烷对新生大鼠皮层神经细胞产生神经毒性的浓度与时间；其次，通过加入IP_3R拮抗剂，观察异氟烷神经毒性作用的变化和细胞[Ca~(2+)]_i的变化，探讨其作用机制可能是通过内质网IP_3R钙通道引起神经细胞凋亡损伤，并于七氟烷进行对比研究；之后，研究了Ca~(2+)在异氟烷诱导IP_3R易感性增强的PS-1突变型PC12细胞凋亡中的机制，进一步证实异氟烷是通过内质网IP_3R钙通道引起神经细胞凋亡损伤；最后，异氟烷预处理新生大鼠皮层神经细胞，进一步观察[Ca~(2+)]_i变化，同时应用IP_3R体拮抗剂，证实Ca~(2+)-IP_3R通道是否在异氟烷预处理保护作用中起到重要作用。结果证实：异氟烷对新生大鼠皮层神经细胞随着浓度和作用时间不同而影响不同，1MAC异氟烷12h可能通过Ca~(2+)-神经细胞凋亡过程引起新生大鼠皮层神经细胞损害，神经细胞内[Ca~(2+)]_i快速增加主要通过内质网上IP_3R介导，而相同浓度和时间的七氟烷不产生细胞毒性，且七氟烷对神经细胞[Ca~(2+)]_i影响不显著，提示相同剂量异氟烷对神经细胞的毒性大于七氟烷。异氟烷预处理原代培养新生大鼠皮层神经细胞，可通过抑制细胞膜Ca~(2+)内流和诱导内质网IP_3R通道Ca~(2+)的泄漏，降低谷氨酸诱发的[Ca~(2+)]_i升高，减少细胞凋亡。提示异氟烷预处理对神经细胞具有一定的保护效应。
第一部分不同浓度和时间异氟烷对新生大鼠皮层神经细胞存活率及钙离子浓度的影响
目的观察不同浓度和时间异氟醚对原代培养大鼠皮层神经细胞的存活率，以及与细胞内钙离子稳态失衡的关系，探讨异氟烷的神经细胞毒性及机制。方法取新生24 h内的Wistar大鼠，通过分离、纯化、原代接种培养皮层神经细胞12d后，分别采用相当0．5、1、2MAC浓度的异氟醚对大鼠皮层神经细胞处理1、2、4、8、12、24h后，噻唑兰(MTT)及乳酸脱氢酶(LDH)法检测细胞的存活率。应用激光共聚焦显微镜动态观察异氟醚处理后，活细胞内Ca~(2+)浓度([Ca~(2+)]_i)的变化。结果0．5MAC异氟烷24h，LDH与对照组百分比显著降低，而MTT与对照组比百分比显著升高(P<0．01)，细胞外液有钙条件下[Ca~(2+)]_i升高(P<0．01)，1MAC浓度异氟烷12、24h和2MAC8、12、24h，LDH与对照组百分比显著升高，而MTT与对照组比百分比显著降低(P<0．001)，降低了细胞存活率，并使[Ca~(2+)]_i大量快速升高(P<0．001)。结论0．5MAC异氟烷24h内不引起原代培养大鼠皮层神经细胞毒性，而提高了其细胞存活率，这可能与细胞内钙离子快速负反馈有关；1MAC异氟烷12h后，2MAC异氟烷8h后，可引起原代培养大鼠皮层神经细胞毒性，且呈浓度和时间依赖性，这可能与细胞内钙离子稳态失衡引起神经细胞钙超载有关。
第二部分异氟烷和七氟烷诱导原代培养大鼠皮层神经细胞损伤中钙离子浓度的变化的比较研究
目的观察异氟烷和七氟烷对原代培养大鼠皮层神经细胞的损伤，以及与细胞内质网应激导致钙离子稳态失衡的关系，探讨异氟烷的神经细胞损伤机制。方法取新生24 h内的Wistar大鼠皮层神经细胞，原代培养12d后，分别采用相当1MAC浓度的异氟烷或七氟烷对大鼠皮层神经细胞处理12h，噻唑兰(MTT)及乳酸脱氢酶(LDH)法检测细胞的存活率。应用激光共聚焦显微镜动态观察加入异氟烷或七氟烷处理后，活细胞内Ca~2浓度([Ca~(2+)]_i)的变化，同时检测肌醇三磷酸受体(IP3)的拮抗剂光溜海绵素(Xestospongin C)对异氟烷诱导细胞毒性和[Ca~(2+)]_i变化的影响。结果1MAC浓度的异氟烷12h对原代培养大鼠皮层神经细胞产生毒性，LDH与对照组百分比显著升高，而MTT与对照组比百分比显著降低(P<0．01)，降低了细胞存活率，并使[Ca~(2+)]_i大量快速升高，[Ca~(2+)]_i峰值与基础值的百分比和对照组比较显著增加(P<0．01)，XC显著抑制异氟烷细胞毒性，LDH和MTT与对照组百分比无显著变化，[Ca~(2+)]_i峰值与基础值的百分比和异氟烷组比较显著降低(P<0．01)。相同浓度的七氟烷不引起新生大鼠皮层神经细胞类似的细胞毒性和[Ca~(2+)]_i峰值的升高。结论异氟烷通过内质网应激激活IP_3R引起[Ca~(2+)]_i升高，从而可能导致神经细胞损伤；相同浓度的七氟烷不引起类似的细胞毒性和[Ca~(2+)]_i峰值的升高。提示相同浓度的异氟烷神经毒性大于七氟烷。
第三部分异氟烷诱发PS-1突变型PC12细胞凋亡对钙离子浓度的影响机制
目的研究异氟烷对野生型和PS-1突变型小鼠PC12细胞凋亡以及其对细胞内钙离子稳态失衡的影响，探讨其作用机制。方法分别用1MAC异氟烷对野生型和PS-1突变型基因转染的小鼠PC12细胞处理12h后，用乳酸脱氢酶(LDH)法检测细胞的存活率，碘化丙啶(PI)检测法测定细胞凋亡的数量及免疫印迹(Western-blot)技术，检测细胞凋亡相关蛋白：Bcl-2和Bax蛋白的变化。观察1MAC异氟烷对PS-1突变PC12细胞中[Ca~(2+)]_i的影响。同时检测IP3R的抑制剂XC对异氟烷诱导PC12细胞凋亡和[Ca~(2+)]_i的影响。结果1MAC浓度的异氟烷12h诱导PS-1突变PC12细胞存活率下降，LDH与对照组百分比显著升高，PI染色与对照比明显增高(P<0．01)，凋亡细胞数量增多，凋亡蛋白Bcl-2表达减少和Bax表达增多(P<0．01)，并使[Ca~(2+)]_i大量快速升高，[Ca~(2+)]_i峰值与基础值的百分比和对照组比较显著增加(P<0．01)；同时XC显著抑制异氟烷诱导的细胞凋亡和凋亡蛋白变化，并显著抑制[Ca~(2+)]_i大量升高。而相同浓度的异氟烷不引起野生型(WT)PC12细胞凋亡和[Ca~(2+)]_i峰值的升高。结论异氟烷通过IP_3R途径，使Ca~(2+)从储存的内质网中快速释放，促使[Ca~(2+)]_i的快速增高，从而导致PS-1突变型PC12细胞凋亡增加。这可能是异氟烷神经毒性的可能机制。
第四部分异氟烷预处理对谷氨酸诱导大鼠皮层神经细胞凋亡的影响和钙离子浓度的变化
目的研究异氟烷预处理对谷氨酸诱导大鼠皮层神经细胞凋亡的影响，以及对细胞内钙离子稳态失衡的影响，探讨其神经细胞保护作用机制。方法新生24 h内的Wistar大鼠皮层神经细胞，原代培养12d后，采用1MAC异氟烷2h预处理新生大鼠皮层神经细胞后，进行低浓度谷氨酸细胞凋亡的诱导，用MTT法检测细胞的存活率，用碘化丙啶(PI)检测法测定细胞凋亡的数量，并观察异氟烷预处理后，对谷氨酸产生的[Ca~(2+)]_i的快速大量升高的影响。同时采用IP3R的抑制剂XC，观察其对异氟烷预处理谷氨酸诱导细胞凋亡的影响和[Ca~(2+)]_i的变化。结果1MAC异氟烷2h预处理显著提高谷氨酸处理后神经细胞的存活率，MTT与对照组百分比无显著改变，PI染色与对照比无显著改变(P>0．05)，[Ca~(2+)]_i峰值与基础值的百分比和对照组比较显著降低(P<0．01)，并抑制[Ca~(2+)]_i大量快速升高；同时加入XC的异氟烷预处理降低单纯异氟烷预处理对谷氨酸诱导神经细胞凋亡的改善，且在细胞外液无钙条件下，并不能改变[Ca~(2+)]_i峰值的升高。结论异氟烷预处理原代培养新生大鼠皮层神经细胞，可通过抑制细胞膜Ca~(2+)内流和内质网IP_3R通道降低谷氨酸诱发的[Ca~(2+)]_i升高，减少细胞凋亡。提示1MAC异氟烷预处理对神经细胞具有一定的保护作用。
PartⅠEffect of different concentration isoflurane exposure for different time on viability and intracellular calcium in rat primarycortical neurons
Objective This study examined and compared the viability effects of different concentration isoflurane exposure for different time on rat primary cortical neurons and their relationship with disruption of intracellular calcium homeostasis. Methods Primary rat cortical neurons were treated constantly with the equivalent of 0.5, 1 or 2 minimal alveolar concentration (MAC) of isoflurane exposure for 1,2,4,8,12,24 hours respectively. MTT reduction and LDH release assays were performed to evaluate cell viability. Changes of calcium concentration in cytosolic space ([Ca~(2+)]i) were imaged using real-time confocal microscopy after exposing rat primary cortical neurons to different concentration isoflurane. Results Isoflurane at 0.5 MAC exposure for 24 hours increased cell viability in primary rat cortical neurons, which was associated with a elevation of peak [Ca~(2+)]_i. Isoflurane at 1 MAC exposure for 12 or 24 hours and 2MAC exposure for 8,12, or 24 hours induced cytotoxicity in primary rat cortical neurons, which was also associated with a high and fast elevation of peak [Ca~(2+)]_i. Conclusion Isoflurahe at 0.5MAC exposure within 24 hours did not induce neurotoxicity and elevations of [Ca~(2+)]_i in primary cortical neurons of rat.This effects mybe induced by Ca~(2+) negative feedback . Isoflurane at 1MAC exposure for longer than 12 hours and 2MAC exposure for longer than 8 hours induced neurotoxicity and decreased cell viability in primary cortical neurons of rat. This cytotoxic effects of isoflurane mybe induced by calcium overload in primary cortical neurons of rat.
PartⅡIsoflurane and sevoflurane induce cytotoxicity and change intracellular calcium concentration in rat primary cortical neurons
Objective This study examined and compared the cytotoxic effects of isoflurane and sevoflurane on rat primary cortical neurons and their relationship with disruption of intracellular calcium homeostasis .Methods Primary rat cortical neurons were treated with the equivalent of 1 minimal alveolar concentration (MAC) of isoflurane and sevoflurane for 12 hours. MTT reduction and LDH release assays were performed to evaluate cell viability. Changes of calcium concentration in the cytosolic space, [Ca~(2+)]_i, were determined after exposing primary rat cortical neurons to isoflurane and sevoflurane. We also determined the effects of IP_3 receptor antagonist xestospongin C on isoflurane-induced cytotoxicity and calcium release from the ER in primary rat cortical neurons. Results Isoflurane at 1 MAC for 12 hours induced cytotoxicity in primary rat cortical neurons, which was also associated with a high and fast elevation of peak [Ca~(2+)]_i. Xestospongin C significantly ameliorated isoflurane cytotoxicity in primary cortical neurons, as well as inhibited the calcium release from the ER in primary cortical neurons. Sevoflurane, at equivalent exposure to isoflurane, did not induce similar cytotoxicity or elevation of peak [Ca~(2+)]_i in primary rat cortical neurons. Conclusion These results suggested that isoflurane induced elevation in [Ca~(2+)]i, partially via elevated activity of IP3 receptors, which rendered cells vulnerable to isoflurane neurotoxicity. Sevoflurane, at an equivalent exposure to isoflurane, did not induce similar elevations of [Ca~(2+)]_i or neurotoxicity in primary cortical neurons of rat.
PartⅢEffect of isoflurane on apoptosis and intracellular calcium in Rat Pheochromocytoma Cells (PC12)
Objective This study examined and compared the apoptosis effects of isoflurane on different types of rat pheochromocytoma neurosecretory cells (PC12) and their relationship with disruption of intracellular calcium homeostasis. Methods PC12 cells transfected with wild type (WT) or the Alzheimer's muted PS1 (L286V) were treated with equivalent of 1 MAC of isoflurane for 12 hr. LDH release assays were performed to evaluate cell viability. Changes of calcium concentration in cytosolic space ([Ca~(2+)]_i) were imaged using real-time confocal microscopy after exposing different types of cells to isoflurane.We also determined the effects of IP3 receptor antagonist xestospongin C on isoflurane-induced apoptosis and calcium release from the ER in L286V PC12 cells. Results Isoflurane at 1 MAC for 12 hr induced apoptosis in L286V but not WT PC12 cells, which was also associated with greater and faster elevation of peak [Ca~(2+)]_i in L286V than in the WT PC12 cells. Xestospongin C significantly ameliorated isoflurane cytotoxicity in both L286V cells , as well as inhibited the calcium release from the ER in L286V cells. Conclusion These results suggest that the Alzheimer's PS1 mutation augments the isoflurane-induced elevation in [Ca~(2+)]i partially via elevated activity of IP3 receptors, which renders cells vulnerable to isoflurane neurotoxicity.
PartⅣEffects of isoflurane on Glutamate Induced apoptosii and Intracellular Calcium Change in rat primary cortical neurons
Objective To study the effects of isoflurane on glutamate induced apoptosis and intracellular calcium change in rat primary cortical neurons and its probable mechanism. Methods Rat primary cortical neurons were primarily cultured by using neonatal rat brains Primary rat cortical neurons were preconditioning with the equivalent of 1 MAC of isoflurane for 2 hours.Then low concentration glutamate induced neurons apoptosis . MTT reduction and LDH release assays were performed to evaluate cell viability. Using microfluorescent technique to detect the calcium signal and the effect of glutamate and sevoflurane on hippocampal neurons. We also determined the effects of IP3 receptor antagonist xestospongin C on isoflurane preconditioning in rat primary cortical neurons. Results Glutamate could increase apoptosis neurons and the intracellular free Ca concentration([Ca~(2+)]_i) obviously. 1.0 MAC isoflurane preconditioning decreased apoptosis neurons and inhibited the increase [Ca~(2+)]i induced by glutamate. Xestospongin C significantly ameliorated isoflurane neuroprotection in Rat primary cortical neurons, as well as inhibited the calcium release from the ER. Conclusion It is suggested that isoflurane preconditioning inhibites apoptosis and calcium overload induced by glutamate in rat primary cortical neurons.
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