半胱氨酰白三烯对脑的致损伤作用及其机制研究
发布时间：2018-08-04 15:44
【摘要】： 目前认为，各种脑损伤(脑缺血、脑外伤)的继发性损伤，或称二次脑损伤因素，是造成脑损害发生、发展的重要原因。这些因素涉及：脑缺血、能量代谢障碍、钙离子超载、氧自由基堆积、兴奋性氨基酸的神经毒作用、炎性因子刺激等。其中，炎症是脑损伤病理生理过程中的一个重要组成环节，半胱氨酰白三烯(cysteinyl leukotrienes, CysLTs，包括LTC_4、LTD_4和LTE_4)是一类重要的炎症介质，是花生四烯酸5-脂氧合酶(5-lipoxygenase, 5-LOX)的代谢产物。CysLTs通过激活半胱氨酰白三烯受体(包括CysLT_1和CysLT_2受体)，参与多种炎症病理过程，介导平滑肌痉挛、微血管渗漏等反应。近年证明，除了在哮喘、过敏性鼻炎等炎症疾病发病过程中起重要作用外，CysLTs也参与脑卒中、脑外伤、脑肿瘤、癫痫等中枢神经系统疾病的病理生理过程。脑缺血后CysLTs释放增加，5-LOX抑制剂能减少CysLTs产生，保护脑缺血性损伤，本实验室也发现，CysLT_1受体拮抗剂普鲁司特和孟鲁司特对实验性脑缺血损伤有保护作用，普鲁司特对NMDA引起的皮层损伤及小鼠脑冷冻伤也有保护作用。这些发现均提示CysLTs参与脑损伤病理过程，然而，CysLTs对神经元是否有直接致损伤作用?这种作用通过哪种受体亚型介导?这些问题仍有待阐明。 脑损伤是高度复杂的病理过程，而脑水肿是各种脑损伤的共同病理环节。脑水肿一般包括血管性脑水肿和细胞性脑水肿。血管性脑水肿(vasogenic brainedema)是由于血脑屏障通透性增高，，导致血浆蛋白渗漏到细胞间隙，造成细胞间隙胶体渗透压增高而导致脑组织肿胀；细胞性脑水肿(cytotoxic brain edema)是由于细胞能量代谢障碍，导致离子泵(如Na~+-K~+-ATP酶等)转运功能失调，离子蓄积在细胞内而导致细胞肿胀。脑水肿形成的根本原因，在于水分子跨细胞膜转运功能障碍，这种障碍涉及水通道蛋白(aquaporins,AQPs)。 AQPs是一组介导水分子跨膜转运的细胞膜蛋白，AQP4是脑内最主要的AQPs亚型。已经发现，包括脑外伤、脑缺血、脑肿瘤等多种脑损伤病理中，伴随脑内AQP4表达上调，而且与脑水肿发生密切相关，对AQP4基因敲除动物的研究结果提示，AQP4对血管性脑水肿和细胞性脑水肿的形成均有影响。在我们的前期工作中，以药理学方法证实CysLTs／CysLT受体参与缺血性脑损伤，其机制与血脑屏障(BBB)破坏、脑水肿发生相关，但是，在脑水肿形成过程中CysLTs与脑内AQP4间是否存在联系，以及与AQP4表达调节有关的CysLT受体亚型等问题，有待于进一步阐明。 为深入探讨CysLTs对脑的直接致损伤作用，本研究建立CysLTs小鼠皮层注射模型，考察CysLTs对血脑屏障功能、脑水肿的影响，以及CysLTs引起的神经元变性、死亡和脑梗死等作用；同时，观察CysLT_1受体拮抗剂普鲁司特对CysLTs致脑损伤作用的影响。我们还建立了大鼠原代星形胶质细胞LTD_4损伤模型，考察LTD_4对AQP4表达的调节作用；同时，以普鲁司特和CysLT_1／CysLT_2受体非选择性拮抗剂BAYu9773干预，以了解与该作用有关的CysLT受体亚型。 第—部分 外源性半胱氨酰白三烯对小鼠脑皮层的致损伤作用 脑损伤引起脑内CysLTs释放增加，CysLT受体诱导表达；5-LOX抑制剂能减少CysLTs产生，减轻脑缺血性损伤；CysLT_1受体拮抗剂普鲁司特和孟鲁司特，也可减轻实验性脑缺血损伤。这些结果均表明，CysLTs参与脑损伤过程。为进一步探讨CysLTs对脑的直接致损伤作用及其特征，了解与CysLTs致脑损伤作用有关的受体亚型，我们研究了CysLTs(LTC_4、LTD_4)小鼠皮层注射致脑损伤的量效关系和时效关系，同时观察了CysLTs引起的BBB功能损害、脑水肿形成、神经元变性、死亡，以及对皮层AQP4表达的影响。结果显示，小鼠皮层注射LTC_4、LTD_4(＞1ng/0.5μl PBS)均可造成皮层损伤；LTD_4(1ng/0.5μl PBS)造成的皮层损伤，发生于注射后6小时，伴随皮层内源性IgG渗出增加，脑水肿形成，同时出现Fluoro-Jade B染色阳性细胞(变性神经元)数量增加，存活神经元计数减少，以及皮层AQP4表达上调。CysLT_1受体拮抗剂普鲁司特，能减小LTD_4引起的皮层梗死面积，抑制皮层内源性IgG渗出及神经元变性、死亡；但是，不影响LTD_4引起的脑水肿和皮层AQP4表达上调。结果表明，CysLTs对小鼠皮层具有致损伤作用，其机制与BBB破坏、脑水肿发生相关；CysLTs通过CysLT_1受体介导BBB开放，引起血管性脑水肿，导致脑损伤；CysLTs还可能通过上调AQP4表达引起细胞性脑水肿，而该作用并非由CysLT_1受体介导。 第二部分 白三烯D_4对大鼠原代星形胶质细胞水通道蛋白4的调节作用 脑内水平衡与水通道蛋白(aquaporins，AQPs)有关。其中，AQP4是脑内最重要的AQP亚型，AQP4主要分布在脑内星形胶质细胞及其突起，也表达在室管膜细胞以及脑血管内皮细胞，是调节脑内水平衡的一种主要机制。脑损伤(脑缺血、脑外伤、脑肿瘤和脑水中毒)可以引起AQP4表达改变，与脑水肿形成密切相关。AQP4基因缺失可以减轻局灶性脑缺血、脑水中毒及细菌性脑膜炎引起的细胞性水肿，但可促进脑肿瘤、脑脓肿，皮层冷冻伤和脑积水引起的血管性水肿形成；提示AQP4对脑血管性水肿具有抑制作用，但促进细胞性水肿形成。在第一部分研究中，我们发现LTD_4引起的脑水肿伴随皮层AQP4表达增加，CysLT_1受体拮抗剂普鲁司特不影响该作用。为了验证CysLTs对AQP4表达的调节作用，阐明与该作用有关的CysLT受体亚型，我们建立了大鼠原代星形胶质细胞LTD_4损伤模型。结果发现，LTD_4(10~(-9)-10~(-7)mol／L)使体外培养的大鼠原代星形胶质细胞AQP4表达上调，同时伴随细胞形态改变，作用具有浓度依赖性。研究还发现，大鼠原代星形胶质细胞仅有微量CysLT_2受体mRNA表达，而CysLT_1受体mRNA表达相对较高，LTD_4(10~(-9)-10~(-7)mol／L)对星形胶质细胞CysLT_1受体mRNA表达无显著影响，但可浓度依赖性上调CysLT_2受体mRNA表达。选择性CysLT_1受体拮抗剂普鲁司特、孟鲁司特，对LTD_4(10~(-9)-10~(-7)mol／L)引起的AQP4表达上调无显著影响；CysLT_1／CysLT_2受体非选择性拮抗剂BAYu9773，显著抑制LTD_4(10~(-9)-10~(-7)mol／L)引起的AQP4表达上调。这些结果提示，LTD_4可上调AQP4表达，并诱导表达星形胶质细胞CysLT_2受体；提示炎症过程中释放的CysLTs可通过CysLT_2受体促进细胞性脑水肿形成，这可能是CysLTs致脑损伤作用的另一机制。 总结 1、外源性CysLTs(LTC_4、LTD_4)对小鼠脑皮层具有时间和剂量依赖的致损伤作用，其机制与血脑屏障破坏相关。CysLT_1受体拮抗剂普鲁司特对CysLTs引起的血脑屏障破坏和皮层损伤具有保护作用，表明CysLTs通过CysLT_1受体诱导血管性脑水肿，导致脑损伤。 2、外源性LTD_4引起小鼠脑皮层AQP4表达上调和脑水肿；普鲁司特对LTD_4引起的AQP4表达上调和脑水肿无抑制作用。 3、外源性LTD_4浓度依赖性上调大鼠原代星形胶质细胞AQP4表达；CysLT_1受体拮抗剂普鲁司特、孟鲁司特对LTD_4引起的AQP4表达上调无明显作用，但CysLT受体非选择性拮抗剂BAYu9773可阻断这种上调；LTD_4还可浓度依赖性上调CysLT_2受体mRNA表达。表明LTD_4可通过激动CysLT_2受体调节AQP4表达，引起细胞性脑水肿。
[Abstract]:It is believed that the secondary injury of brain injury (cerebral ischemia, brain injury), or two times of brain injury, is an important cause of the development of brain damage. These factors include cerebral ischemia, energy metabolism disorder, calcium overload, oxygen free radical accumulation, stimulating amino acid neurotoxicity, inflammatory factor stimulation and so on. Disease is an important component of the pathophysiological process of brain injury. Cysteinyl leukotrienes (CysLTs, including LTC_4, LTD_4 and LTE_4) is an important class of inflammatory mediators, and is a metabolite of the 5- lipoxygenase (5-lipoxygenase, 5-LOX) of peanut four, which activates the cysteinyl leukotriene receptor (including Cy) by activating the receptor of the cysteinyl leukotrienes (5-lipoxygenase, 5-LOX). SLT_1 and CysLT_2 receptor), involved in a variety of inflammatory pathological processes, mediating smooth muscle spasm, microvascular leakage and other reactions. In recent years, in addition to the important role of asthma, allergic rhinitis and other inflammatory diseases, CysLTs also participates in the pathophysiological process of cerebral apoplexy, brain trauma, brain swelling, epilepsy and other central nervous system diseases. CysLTs release increases after ischemia, and 5-LOX inhibitors can reduce CysLTs production and protect ischemic brain damage. This laboratory also found that the CysLT_1 receptor antagonist pruscit and montelukast have protective effects on experimental cerebral ischemia injury. Prusxate also protects the cortex injury caused by NMDA and the frozen brain injury in mice. It is suggested that CysLTs is involved in the pathological process of brain injury. However, does CysLTs have direct damage to neurons? Which receptor subtypes are mediated by this effect? These problems remain to be elucidated.
Brain edema is a highly complex pathological process, and brain edema is a common pathological link of various brain injuries. Cerebral edema usually includes vascular cerebral edema and cellular brain edema. Vascular cerebral edema (vasogenic brainedema) is due to the increase of blood brain barrier permeability, causing plasma egg white leakage to intercellular space and intercellular colloid infiltration. The increase of pressure leads to the swelling of the brain tissue; cellular brain edema (cytotoxic brain edema) is due to the disorder of cell energy metabolism, which leads to the imbalance of the transport function of the ion pump (such as Na~+-K~+-ATP enzyme). The accumulation of ions in the cell causes the swelling of the cells. The root cause of the formation of brain edema lies in the transcellular membrane transport dysfunction of water molecules. The barrier involves aquaporins (AQPs).
AQPs is a group of cell membrane proteins that mediate transmembrane transport of water molecules. AQP4 is the most important AQPs subtype in the brain. It has been found that the expression of AQP4 in brain injury, cerebral ischemia and brain tumor is associated with the up regulation of the expression of AQP4 in the brain, and it is closely related to brain edema. The results of the study of AQP4 gene knockout animals suggest that AQP4 is on the blood vessels. In our previous work, the mechanism of CysLTs / CysLT receptor involved in ischemic brain injury was related to the destruction of the blood brain barrier (BBB) and the occurrence of brain edema in our previous work. However, there was a relationship between CysLTs and AQP4 in the formation of brain edema, and with AQP4. The expression of CysLT receptor subtypes needs further clarification.
In order to investigate the direct damage of CysLTs to the brain, this study established an injection model of CysLTs mice to investigate the effect of CysLTs on the function of blood brain barrier and brain edema, as well as the effects of CysLTs induced degeneration, death and cerebral infarction. At the same time, the effect of CysLT_1 receptor antagonist prusst on CysLTs induced brain damage was observed. We also established the LTD_4 damage model of rat primary astrocytes to investigate the role of LTD_4 in the regulation of AQP4 expression; at the same time, the CysLT receptor subtype related to this effect was detected by the intervention of Prussian and CysLT_1 / CysLT_2 receptor non selective antagonist BAYu9773.
Part - Part
Effects of exogenous cysteinyl leukotriene on cerebral cortex in mice
Brain injury causes increased CysLTs release in the brain, induced expression of CysLT receptor, 5-LOX inhibitor can reduce CysLTs production and reduce cerebral ischemic damage; CysLT_1 receptor antagonist pruscit and montelukast can also reduce experimental cerebral ischemia injury. These results suggest that CysLTs and brain damage process. To further explore CysLTs to the brain Direct injury and its characteristics, and understanding of the receptor subtypes associated with brain damage induced by CysLTs, we studied the dose effect relationship and aging relationship of cerebral injury induced by cortical injection of CysLTs (LTC_4, LTD_4) mice, and observed the BBB function damage caused by CysLTs, the formation of brain edema, neuron degeneration, death, and the expression of AQP4 in the cortex of the cortex. The results showed that the cortical injection of LTC_4, LTD_4 (> 1ng/0.5 Mu L PBS) in mice could cause cortical damage, and the cortical injury caused by LTD_4 (1ng/0.5 Mu L PBS) occurred at 6 hours after the injection, accompanied by the increase of endogenous IgG exudation in the cortex, the formation of brain edema, and the increase in the number of Fluoro-Jade B staining positive cells (denatured neurons). The decrease of the cell count and the up-regulation of.CysLT_1 receptor antagonist prushia, the expression of AQP4, can reduce the area of cortical infarct caused by LTD_4, inhibit the endogenous IgG exudation and degeneration of the cortex, and die. However, it does not affect the brain edema caused by LTD_4 and the expression of AQP4 in the cortex. The results show that CysLTs has a damage to the cortex of the mouse. The mechanism is related to BBB destruction and brain edema; CysLTs is open to BBB through CysLT_1 receptor, causing vascular cerebral edema and causing brain damage; CysLTs may also induce cellular brain edema by up regulation of AQP4 expression, and this effect is not mediated by CysLT_1 receptor.
The second part
Regulatory effect of leukotriene D_4 on aquaporin 4 in rat primary astrocytes
Brain water balance is related to aquaporins (AQPs). Among them, AQP4 is the most important AQP subtype in the brain. AQP4 is mainly distributed in astrocytes and their protrusions in the brain. It is also expressed in ependymal cells and cerebral vascular endothelial cells. It is a major mechanism for regulating the balance of water in the brain. Brain injury (cerebral ischemia, brain injury, brain tumor and brain tumor) Cerebral water intoxication can cause changes in AQP4 expression..AQP4 gene deletion closely related to brain edema can reduce focal cerebral ischemia, cerebral water intoxication and bacterial meningitis caused by cellular edema, but can promote cerebral tumor, brain abscess, cerebral cortex freeze injury and hydrocephalus formation caused by cerebral hydrocephalus, prompting AQP4 to cerebral vascular water Swelling has a inhibitory effect, but promotes the formation of cellular edema. In the first part of the study, we found that LTD_4 induced brain edema was associated with an increase in the expression of AQP4 in the cortex, and the CysLT_1 receptor antagonist, prusthe did not affect this effect. In order to verify the regulatory role of CysLTs on AQP4 expression, we set up the CysLT receptor subtype related to this role. The results showed that LTD_4 (10~ (-9) -10~ (-7) mol / L) increased the AQP4 expression of the primary astrocytes in vitro, and accompanied the cell morphologic changes in the rat. It was found that the primary astrocytes of the rats had a concentration dependent effect. It was also found that the primary astrocytes of the rat were only the mRNA expression of the CysLT_2 receptor in the primary astrocytes. The expression of CysLT_1 receptor mRNA is relatively high, and LTD_4 (10~ (-9) -10~ (-7) mol / L) has no significant effect on mRNA expression of CysLT_1 receptor in astrocytes, but the concentration dependent up regulation of CysLT_2 receptor expression. The CysLT_1 / CysLT_2 receptor non selective antagonist, BAYu9773, significantly inhibits the up regulation of LTD_4 (10~ (-9) -10~ (-7) mol / L). These results suggest that LTD_4 can up-regulate the expression and induce the expression of astrocyte receptor. The formation of brain edema may be another mechanism of CysLTs induced brain injury.
summary
1, exogenous CysLTs (LTC_4, LTD_4) has a time and dose dependent damage to the cerebral cortex of mice. The mechanism is protected by the.CysLT_1 receptor antagonist prusk, a.CysLT_1 receptor antagonist, on the damage of blood brain barrier and cortical damage caused by CysLTs, which indicates that CysLTs can induce vascular cerebral edema through the CysLT_1 receptor. Brain damage.
2. Exogenous LTD_4 induced up-regulation of AQP4 expression in the cerebral cortex and cerebral edema in mice; Propristine did not inhibit up-regulation of AQP4 expression and brain edema induced by LTD_4.
3, exogenous LTD_4 concentration dependent up up the expression of AQP4 in rat primary astrocytes; CysLT_1 receptor antagonist pruscid and montelukast did not increase the up regulation of AQP4 expression induced by LTD_4, but CysLT receptor non selective antagonist BAYu9773 could block the up regulation, and LTD_4 also can increase the expression of CysLT_2 receptor mRNA in a concentration dependent manner. It is suggested that LTD_4 can regulate the expression of AQP4 by stimulating CysLT_2 receptor and induce cellular brain edema.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R363
本文编号：2164349
[Abstract]:It is believed that the secondary injury of brain injury (cerebral ischemia, brain injury), or two times of brain injury, is an important cause of the development of brain damage. These factors include cerebral ischemia, energy metabolism disorder, calcium overload, oxygen free radical accumulation, stimulating amino acid neurotoxicity, inflammatory factor stimulation and so on. Disease is an important component of the pathophysiological process of brain injury. Cysteinyl leukotrienes (CysLTs, including LTC_4, LTD_4 and LTE_4) is an important class of inflammatory mediators, and is a metabolite of the 5- lipoxygenase (5-lipoxygenase, 5-LOX) of peanut four, which activates the cysteinyl leukotriene receptor (including Cy) by activating the receptor of the cysteinyl leukotrienes (5-lipoxygenase, 5-LOX). SLT_1 and CysLT_2 receptor), involved in a variety of inflammatory pathological processes, mediating smooth muscle spasm, microvascular leakage and other reactions. In recent years, in addition to the important role of asthma, allergic rhinitis and other inflammatory diseases, CysLTs also participates in the pathophysiological process of cerebral apoplexy, brain trauma, brain swelling, epilepsy and other central nervous system diseases. CysLTs release increases after ischemia, and 5-LOX inhibitors can reduce CysLTs production and protect ischemic brain damage. This laboratory also found that the CysLT_1 receptor antagonist pruscit and montelukast have protective effects on experimental cerebral ischemia injury. Prusxate also protects the cortex injury caused by NMDA and the frozen brain injury in mice. It is suggested that CysLTs is involved in the pathological process of brain injury. However, does CysLTs have direct damage to neurons? Which receptor subtypes are mediated by this effect? These problems remain to be elucidated.
Brain edema is a highly complex pathological process, and brain edema is a common pathological link of various brain injuries. Cerebral edema usually includes vascular cerebral edema and cellular brain edema. Vascular cerebral edema (vasogenic brainedema) is due to the increase of blood brain barrier permeability, causing plasma egg white leakage to intercellular space and intercellular colloid infiltration. The increase of pressure leads to the swelling of the brain tissue; cellular brain edema (cytotoxic brain edema) is due to the disorder of cell energy metabolism, which leads to the imbalance of the transport function of the ion pump (such as Na~+-K~+-ATP enzyme). The accumulation of ions in the cell causes the swelling of the cells. The root cause of the formation of brain edema lies in the transcellular membrane transport dysfunction of water molecules. The barrier involves aquaporins (AQPs).
AQPs is a group of cell membrane proteins that mediate transmembrane transport of water molecules. AQP4 is the most important AQPs subtype in the brain. It has been found that the expression of AQP4 in brain injury, cerebral ischemia and brain tumor is associated with the up regulation of the expression of AQP4 in the brain, and it is closely related to brain edema. The results of the study of AQP4 gene knockout animals suggest that AQP4 is on the blood vessels. In our previous work, the mechanism of CysLTs / CysLT receptor involved in ischemic brain injury was related to the destruction of the blood brain barrier (BBB) and the occurrence of brain edema in our previous work. However, there was a relationship between CysLTs and AQP4 in the formation of brain edema, and with AQP4. The expression of CysLT receptor subtypes needs further clarification.
In order to investigate the direct damage of CysLTs to the brain, this study established an injection model of CysLTs mice to investigate the effect of CysLTs on the function of blood brain barrier and brain edema, as well as the effects of CysLTs induced degeneration, death and cerebral infarction. At the same time, the effect of CysLT_1 receptor antagonist prusst on CysLTs induced brain damage was observed. We also established the LTD_4 damage model of rat primary astrocytes to investigate the role of LTD_4 in the regulation of AQP4 expression; at the same time, the CysLT receptor subtype related to this effect was detected by the intervention of Prussian and CysLT_1 / CysLT_2 receptor non selective antagonist BAYu9773.
Part - Part
Effects of exogenous cysteinyl leukotriene on cerebral cortex in mice
Brain injury causes increased CysLTs release in the brain, induced expression of CysLT receptor, 5-LOX inhibitor can reduce CysLTs production and reduce cerebral ischemic damage; CysLT_1 receptor antagonist pruscit and montelukast can also reduce experimental cerebral ischemia injury. These results suggest that CysLTs and brain damage process. To further explore CysLTs to the brain Direct injury and its characteristics, and understanding of the receptor subtypes associated with brain damage induced by CysLTs, we studied the dose effect relationship and aging relationship of cerebral injury induced by cortical injection of CysLTs (LTC_4, LTD_4) mice, and observed the BBB function damage caused by CysLTs, the formation of brain edema, neuron degeneration, death, and the expression of AQP4 in the cortex of the cortex. The results showed that the cortical injection of LTC_4, LTD_4 (> 1ng/0.5 Mu L PBS) in mice could cause cortical damage, and the cortical injury caused by LTD_4 (1ng/0.5 Mu L PBS) occurred at 6 hours after the injection, accompanied by the increase of endogenous IgG exudation in the cortex, the formation of brain edema, and the increase in the number of Fluoro-Jade B staining positive cells (denatured neurons). The decrease of the cell count and the up-regulation of.CysLT_1 receptor antagonist prushia, the expression of AQP4, can reduce the area of cortical infarct caused by LTD_4, inhibit the endogenous IgG exudation and degeneration of the cortex, and die. However, it does not affect the brain edema caused by LTD_4 and the expression of AQP4 in the cortex. The results show that CysLTs has a damage to the cortex of the mouse. The mechanism is related to BBB destruction and brain edema; CysLTs is open to BBB through CysLT_1 receptor, causing vascular cerebral edema and causing brain damage; CysLTs may also induce cellular brain edema by up regulation of AQP4 expression, and this effect is not mediated by CysLT_1 receptor.
The second part
Regulatory effect of leukotriene D_4 on aquaporin 4 in rat primary astrocytes
Brain water balance is related to aquaporins (AQPs). Among them, AQP4 is the most important AQP subtype in the brain. AQP4 is mainly distributed in astrocytes and their protrusions in the brain. It is also expressed in ependymal cells and cerebral vascular endothelial cells. It is a major mechanism for regulating the balance of water in the brain. Brain injury (cerebral ischemia, brain injury, brain tumor and brain tumor) Cerebral water intoxication can cause changes in AQP4 expression..AQP4 gene deletion closely related to brain edema can reduce focal cerebral ischemia, cerebral water intoxication and bacterial meningitis caused by cellular edema, but can promote cerebral tumor, brain abscess, cerebral cortex freeze injury and hydrocephalus formation caused by cerebral hydrocephalus, prompting AQP4 to cerebral vascular water Swelling has a inhibitory effect, but promotes the formation of cellular edema. In the first part of the study, we found that LTD_4 induced brain edema was associated with an increase in the expression of AQP4 in the cortex, and the CysLT_1 receptor antagonist, prusthe did not affect this effect. In order to verify the regulatory role of CysLTs on AQP4 expression, we set up the CysLT receptor subtype related to this role. The results showed that LTD_4 (10~ (-9) -10~ (-7) mol / L) increased the AQP4 expression of the primary astrocytes in vitro, and accompanied the cell morphologic changes in the rat. It was found that the primary astrocytes of the rats had a concentration dependent effect. It was also found that the primary astrocytes of the rat were only the mRNA expression of the CysLT_2 receptor in the primary astrocytes. The expression of CysLT_1 receptor mRNA is relatively high, and LTD_4 (10~ (-9) -10~ (-7) mol / L) has no significant effect on mRNA expression of CysLT_1 receptor in astrocytes, but the concentration dependent up regulation of CysLT_2 receptor expression. The CysLT_1 / CysLT_2 receptor non selective antagonist, BAYu9773, significantly inhibits the up regulation of LTD_4 (10~ (-9) -10~ (-7) mol / L). These results suggest that LTD_4 can up-regulate the expression and induce the expression of astrocyte receptor. The formation of brain edema may be another mechanism of CysLTs induced brain injury.
summary
1, exogenous CysLTs (LTC_4, LTD_4) has a time and dose dependent damage to the cerebral cortex of mice. The mechanism is protected by the.CysLT_1 receptor antagonist prusk, a.CysLT_1 receptor antagonist, on the damage of blood brain barrier and cortical damage caused by CysLTs, which indicates that CysLTs can induce vascular cerebral edema through the CysLT_1 receptor. Brain damage.
2. Exogenous LTD_4 induced up-regulation of AQP4 expression in the cerebral cortex and cerebral edema in mice; Propristine did not inhibit up-regulation of AQP4 expression and brain edema induced by LTD_4.
3, exogenous LTD_4 concentration dependent up up the expression of AQP4 in rat primary astrocytes; CysLT_1 receptor antagonist pruscid and montelukast did not increase the up regulation of AQP4 expression induced by LTD_4, but CysLT receptor non selective antagonist BAYu9773 could block the up regulation, and LTD_4 also can increase the expression of CysLT_2 receptor mRNA in a concentration dependent manner. It is suggested that LTD_4 can regulate the expression of AQP4 by stimulating CysLT_2 receptor and induce cellular brain edema.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2006
【分类号】：R363
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