钙调蛋白抑制剂三氟拉嗪抗脑缺血作用与机制研究
摘要
脑缺血是危害人类健康的主要疾病之一，它导致脑功能及脑结构发生不可逆的变化，也是临床上常见的预后较差的一种疾病。如何防治脑缺血损伤引起了基础与临床研究的广泛重视。针对脑缺血损伤的某些环节，寻找切实有效的脑卒中防治药物已成为当今医学领域的重大课题。本文利用离体缺氧模型，研究了钙调蛋白抑制剂三氟拉嗪的抗缺血机制与作用。
本文应用原代培养海马细胞的缺氧缺糖剥夺模型，通过使用激光扫描共聚焦显微技术和荧光标记技术，对缺氧过程中神经细胞的NO和钙离子变化进行了实时动态的检测。结果表明缺氧过程中，细胞内NO的合成和钙离子浓度有显著升高，NO和钙离子荧光的升高值分别为62％和174％；这种升高在去除细胞外液的钙离子后受到明显抑制，表明缺氧时胞内钙离子的增加主要来源于胞外的钙离子。
在培养海马细胞的缺氧缺糖剥夺模型中，钙调蛋白抑制剂三氟拉嗪(trifluoperazine，TFP)对缺氧导致的钙离子升高有明显的抑制作用，10μM和50μMTFP能够使缺氧诱导的细胞内Ca~(2+)的荧光升高降低56.4％和72.6％；TFP还能剂量依赖性抑制缺氧诱导的NO合成，50μMTFP能够明显抑制缺氧时细胞内NO合成的增加(P＜0.01)。由于通过NMDA受体内流的Ca~(2+)被认为在脑损伤中起重要作用，我们研究TFP对Glu诱发的Ca~(2+)升高的影响。结果表明TFP能够显著地抑制谷氨酸诱导的胞内Ca~(2+)的升高。这一结果也显示TFP可能通过作用NMDA受体来抑制缺氧时的钙离子升高。
采用海马脑片离体缺氧模型，我们观察了缺氧导致的兴奋性神经递质天冬氨酸(Asp)、谷氨酸(Glu)与抑制性神经递质牛磺酸(Tau)、Y-氨基丁酸(GABA)的含量变化以及TFP对这些氨基酸变化的影响。实验表明：缺氧能促进海马组织各氨基酸的释放，而TFP可以显著降低由缺氧引起的兴奋性氨基酸的释放。
为了探讨TFP在缺氧损伤中对神经细胞的保护作用，我们采用神经电生理技术，从电生理角度研究了TFP在海马组织缺氧灌流中的保护作用。结果发现TFP可以降低缺氧损伤电位(HIP)的出现率，提高复氧后脑片群峰电位(PS)的恢复率和恢复程度；我们还应用WST—1法，研究了TFP对培养海马神经细
廊江大学尊士学哎讼文
胞缺氧缺糖后活性的影响，发现用TFP作用后，细胞液的OD值比缺氧缺糖组有
显著升高（P＜0．05）。以上结果表明 TFP在缺氧损伤中对神经细胞有明显的保护
作用。
本论文研究了钙调蛋白抑制剂的抗缺血机制与作用，结果表明TFP对缺血
过程中兴奋性氨基酸释放、细胞内Ca卜升高和NO合成有明显的抑制作用：TFP
可能通过这些途径减轻缺氧对神经细胞的损伤，起到保护神经细胞的作用。本研
究为脑缺血的病理研究与临床治疗提供了新的思路，为抗脑缺血药物的开发提供
了新的筛选平台。
Ischemic stroke is a leading cause of death and serious, long-term disability in adults. Until recently, modem medicine has had very little power over this disease, but the world of stroke medicine is changing and new and better therapies are being developed every day. Researchers are studying the mechanisms of this disease and ways to prevent this injury to the brain. Scientists hope to develop surgical techniques and neuroprotective agents to prevent this damage and restore important functions to the stroke patients. This paper studied the neuroprotective effects and mechanisms of Calmodulin antagonist using animal ischemia model in vitro.
In this study, the effect of oxygen-glucose deprivation (OGD) on the intracelluar Ca2* and production of NO was investigated in cultured hippocampal neurons. The generation of NO and changes in intracellular Ca2* were evaluated using confocal laser scanning microscopy with diaminofluorescein diacetate (DAF-2 DA), an NO probe, and Fluo-3, a Ca2+ probe respectively. Results showed that OGD induced an increase in NO production and intracellular Ca2+ concentration ([Ca2+]j). when the extracellular calcium was removed, the increase in intercellular Ca2* during OGD was significantly lower, which suggested that ischemic increase in Ca2+ was mainly due to influx through plasma membrane Ca2+ channels. Calmodulin (CaM) antagonist trifluoperazine (TFP) could significantly reduced the OGD-induced elevation of [Ca2+]j .The increase in NO production was also attenuated by TFP dose-dependently. For calcium influx into cells through NMDA receptor was probably played an important pathogenetic role in ischemia, we studied the effect of TFP to Glu-induced The result showed that TFP reduced the increase of [Ca2+]j induced by Glu, which also indicated that TFP may inhibit Ca2+ influx during OGD by blocking NMDA receptor.
We studied the effect of TFP on the changes of level of amino acids (Asp, Glu, Tau, GABA) in the culture medium of brain slices during OGD. It was found that OGD increase the release of amino acids and TFP can significantly inhibit the increase of the excitatory amino acids (EAA).
3
The protective effects of TFP against hypoxic brain injury were studied by the extracellular recording technique in rat hippocampal slices. The results showed that treated with TFP, the appearance of hypoxic injury potential (HIP) was lower and the recovery amplitude of PS after reoxygenation was significantly higher than that of OGD group. We also investigated the effects of TFP to survival activities of cultured neuron injured by OGD using WST-1 assay. It was found that optical density (OD) of TFP group is higher than that of OGD group. Therefore, the above results showed that TFP had protective effects against brain hypoxic injury.
The protective effects and mechanisms of TFP in ischemia were studied in this thesis. The results indicated TFP have anti-ischemia effects through inhibiting EAA release, Ca2"1" overload and production of NO. Our experiments and results would be helpful for further studies in pathological mechanisms and clinic therapies to this disease.
本文应用原代培养海马细胞的缺氧缺糖剥夺模型，通过使用激光扫描共聚焦显微技术和荧光标记技术，对缺氧过程中神经细胞的NO和钙离子变化进行了实时动态的检测。结果表明缺氧过程中，细胞内NO的合成和钙离子浓度有显著升高，NO和钙离子荧光的升高值分别为62％和174％；这种升高在去除细胞外液的钙离子后受到明显抑制，表明缺氧时胞内钙离子的增加主要来源于胞外的钙离子。
在培养海马细胞的缺氧缺糖剥夺模型中，钙调蛋白抑制剂三氟拉嗪(trifluoperazine，TFP)对缺氧导致的钙离子升高有明显的抑制作用，10μM和50μMTFP能够使缺氧诱导的细胞内Ca~(2+)的荧光升高降低56.4％和72.6％；TFP还能剂量依赖性抑制缺氧诱导的NO合成，50μMTFP能够明显抑制缺氧时细胞内NO合成的增加(P＜0.01)。由于通过NMDA受体内流的Ca~(2+)被认为在脑损伤中起重要作用，我们研究TFP对Glu诱发的Ca~(2+)升高的影响。结果表明TFP能够显著地抑制谷氨酸诱导的胞内Ca~(2+)的升高。这一结果也显示TFP可能通过作用NMDA受体来抑制缺氧时的钙离子升高。
采用海马脑片离体缺氧模型，我们观察了缺氧导致的兴奋性神经递质天冬氨酸(Asp)、谷氨酸(Glu)与抑制性神经递质牛磺酸(Tau)、Y-氨基丁酸(GABA)的含量变化以及TFP对这些氨基酸变化的影响。实验表明：缺氧能促进海马组织各氨基酸的释放，而TFP可以显著降低由缺氧引起的兴奋性氨基酸的释放。
为了探讨TFP在缺氧损伤中对神经细胞的保护作用，我们采用神经电生理技术，从电生理角度研究了TFP在海马组织缺氧灌流中的保护作用。结果发现TFP可以降低缺氧损伤电位(HIP)的出现率，提高复氧后脑片群峰电位(PS)的恢复率和恢复程度；我们还应用WST—1法，研究了TFP对培养海马神经细
廊江大学尊士学哎讼文
胞缺氧缺糖后活性的影响，发现用TFP作用后，细胞液的OD值比缺氧缺糖组有
显著升高（P＜0．05）。以上结果表明 TFP在缺氧损伤中对神经细胞有明显的保护
作用。
本论文研究了钙调蛋白抑制剂的抗缺血机制与作用，结果表明TFP对缺血
过程中兴奋性氨基酸释放、细胞内Ca卜升高和NO合成有明显的抑制作用：TFP
可能通过这些途径减轻缺氧对神经细胞的损伤，起到保护神经细胞的作用。本研
究为脑缺血的病理研究与临床治疗提供了新的思路，为抗脑缺血药物的开发提供
了新的筛选平台。
Ischemic stroke is a leading cause of death and serious, long-term disability in adults. Until recently, modem medicine has had very little power over this disease, but the world of stroke medicine is changing and new and better therapies are being developed every day. Researchers are studying the mechanisms of this disease and ways to prevent this injury to the brain. Scientists hope to develop surgical techniques and neuroprotective agents to prevent this damage and restore important functions to the stroke patients. This paper studied the neuroprotective effects and mechanisms of Calmodulin antagonist using animal ischemia model in vitro.
In this study, the effect of oxygen-glucose deprivation (OGD) on the intracelluar Ca2* and production of NO was investigated in cultured hippocampal neurons. The generation of NO and changes in intracellular Ca2* were evaluated using confocal laser scanning microscopy with diaminofluorescein diacetate (DAF-2 DA), an NO probe, and Fluo-3, a Ca2+ probe respectively. Results showed that OGD induced an increase in NO production and intracellular Ca2+ concentration ([Ca2+]j). when the extracellular calcium was removed, the increase in intercellular Ca2* during OGD was significantly lower, which suggested that ischemic increase in Ca2+ was mainly due to influx through plasma membrane Ca2+ channels. Calmodulin (CaM) antagonist trifluoperazine (TFP) could significantly reduced the OGD-induced elevation of [Ca2+]j .The increase in NO production was also attenuated by TFP dose-dependently. For calcium influx into cells through NMDA receptor was probably played an important pathogenetic role in ischemia, we studied the effect of TFP to Glu-induced The result showed that TFP reduced the increase of [Ca2+]j induced by Glu, which also indicated that TFP may inhibit Ca2+ influx during OGD by blocking NMDA receptor.
We studied the effect of TFP on the changes of level of amino acids (Asp, Glu, Tau, GABA) in the culture medium of brain slices during OGD. It was found that OGD increase the release of amino acids and TFP can significantly inhibit the increase of the excitatory amino acids (EAA).
3
The protective effects of TFP against hypoxic brain injury were studied by the extracellular recording technique in rat hippocampal slices. The results showed that treated with TFP, the appearance of hypoxic injury potential (HIP) was lower and the recovery amplitude of PS after reoxygenation was significantly higher than that of OGD group. We also investigated the effects of TFP to survival activities of cultured neuron injured by OGD using WST-1 assay. It was found that optical density (OD) of TFP group is higher than that of OGD group. Therefore, the above results showed that TFP had protective effects against brain hypoxic injury.
The protective effects and mechanisms of TFP in ischemia were studied in this thesis. The results indicated TFP have anti-ischemia effects through inhibiting EAA release, Ca2"1" overload and production of NO. Our experiments and results would be helpful for further studies in pathological mechanisms and clinic therapies to this disease.
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