他莫昔芬在大鼠蛛网膜下腔出血后早期脑损伤中的神经保护作用及机制研究
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摘要
目的：应用蛛网膜下腔出血（SAH）后早期脑损伤（EBI）模型，探讨他莫昔芬（Tamoxifen TMX）对大鼠蛛网膜下腔出血后早期脑损伤是否具有神经保护作用。
方法：48只健康成年雄性SD大鼠随机分为对照组（n=12），SAH组（n=12），安慰剂组（n=12）和他莫昔芬治疗组（n=12）。应用视交叉前池一次注血法制成SAH后EBI模型，在蛛网膜下腔出血后2h、24h及36h分别腹腔注射他莫昔芬，48小时后处死大鼠，取颞底皮层脑组织做标本，测定脑水肿变化及血脑屏障变化，探讨他莫昔芬对大鼠SAH后EBI是否具有神经保护作用。
结果：与对照组相比，SAH组大鼠脑组织含水量明显增加，48h时水肿百分数达到82.51%，血脑屏障破坏明显，48h时测定皮层脑组织伊文氏蓝（EB）含量达到21.5ng/mg；与SAH组相比，他莫昔芬治疗后大鼠脑水肿指数降低，48h时水肿百分数80.55%，血脑屏障功能改善，48h时测定皮层脑组织EB含量13.2ng/mg；安慰剂组与SAH组相比改善不明显。
结论：1．通过构建大鼠SAH模型，能够观察到大鼠SAH后48h脑组织含水量增加明显，血脑屏障破坏明显，说明SAH后存在EBI。2．应用他莫昔芬治疗后，能有效降低SAH后脑水肿、改善血脑屏障，提示他莫昔芬对大鼠SAH后EBI具有神经保护作用。
目的：研究SAH后大脑皮层TLR4（Toll样受体4）/NF-κ B（核因子κB）信号通路及其下游炎症因子及细胞活素的表达变化及他莫昔芬对TLR4/NF-κ B信号通路的干预作用，探讨他莫昔芬对SAH后EBI神经保护作用机制。
方法：60只健康成年雄性SD大鼠随机分为：对照组(n=15), SAH组(n=15),SAH+安慰剂组(n=15)和SAH+他莫昔芬治疗组(n=15)。采用立体定向注射技术，构建视交叉前池一次注血SAH模型，对照组开骨窗但不注入动脉血，他莫昔芬治疗组给予他莫昔芬腹腔注射治疗，每次注射剂量5mg/kg，在SAH后2h、24h、36h分别腹腔注射。安慰剂组注射等容量溶剂，溶剂为1%乙醇。48小时后处死大鼠，取颞底皮层脑组织做标本，采用Western blot法测定TLR4、NF-κB及ICAM-1表达情况；免疫组化法检测TLR4、NF-κB及ICAM-1表达，EMSA测定NF-κB的DNA活性。通过ELISA方法分析大鼠脑皮层中细胞活素因子IL-1β, TNF-α和IL-6表达情况比较。
结果：Western blot结果显示对照组TLR4、NF-κB及ICAM-1蛋白水平较弱；与对照组相比，SAH组TLR4、NF-κB及ICAM-1蛋白水平明显增高(P <0.01)；SAH组与安慰剂组对比无明显差异(P>0.05)；他莫昔芬治疗组中TLR4、NF-κB及ICAM-1蛋白水平明显低于SAH组与安慰剂组(P <0.01)。免疫组化（TLR4、NF-κB及ICAM-1蛋白免疫反应性主要在神经元细胞，细胞核棕色黄染代表阳性）结果显示对照组TLR4、NF-κB及ICAM-1阳性率较低；与对照组相比，SAH组TLR4、NF-κB及ICAM-1阳性率明显增高(P <0.01)；SAH组与安慰剂组对比无明显差异(P>0.05)；他莫昔芬治疗组中TLR4、NF-κB及ICAM-1阳性率低于SAH组及安慰剂组(P <0.01)。EMSA结果显示对照组NF-κB的结合活性较弱；与对照组相比，SAH组NF-κB的结合活性明显增高(P <0.01)；SAH组与安慰剂组对比无明显差异(P>0.05)；他莫昔芬治疗组中NF-κB的结合活性明显低于SAH组与安慰剂组（P<0.01）。ELISA结果显示对照组中IL-1β,TNF-α和IL-6表达水平较低；与对照组相比，SAH组IL-1β, TNF-α和IL-6表达水平明显增高(P <0.01)；SAH组与安慰剂组对比无明显差异(P>0.05)；他莫昔芬治疗组中IL-1β, TNF-α和IL-6表达水平明显低于SAH组与安慰剂组(P <0.01)。
结论：SAH后早期能激活TLR4/NF-κB信号通路，激活其下游的细胞活素/趋化因子诱导炎症反应，可能是引起SAH后EBI的重要机制，他莫昔芬可能通过抑制此传导通路，减轻免疫炎症，从而对SAH后EBI起到神经保护作用。
Objective: To investigate neuroprotection of Tamoxifen on early brain injury in malerats after subarachnoid hemorrahage, such as brain edema, and blood-brain barrier (BBB)impairment.
Methods: forty-eight health male Sprague-dawley(SD) rats were assigned randomlyinto following groups: Control group（n=12）, SAH group（n=12）, SAH+vehicle group（n=12）, SAH+Tamoxifen group（n=12）.All SAH animals were subjected to injectionof0.3ml fresh arterial, non-heparinized blood into suprachiasmatic cistern in20seconds.Male rats were given5mg/kg injections of tamoxifen at post-SAH hours2h,24h and36h.Brain samples adjacent to the clotted blood were extracted at48h after SAH. Controlanimals underwent exactly the same procedure as described above with the exception thatno blood was injected intracisternally. Cerebral edema and blood-brain barrier permeabilitywere detected at48h after experimental SAH.
Results: Significant increase (P <0.01) in water content was detected in the brainsamples at48h after SAH when compared with rats in control group. The mean value ofbrain water content in the cortex was decreased by tamoxifen administration (P <0.01) ascompared with SAH+vehicle group. The pattern of EB extravasation in SAH or SAH+vehicle group demonstrated a significant increase (P <0.01) in BBB permeability of EBrelative to rats of control group. Administration of tamoxifen significantly inhibited EBextravasation(P <0.01) after SAH.
Conclusions:1. As compared with control group, clinical behavior functionimpairment caused by SAH was evident in SAH subjects. SAH group significantlyattenuate blood-brain barrier (BBB), increase brain edema compared to control group.2.Post-SAH tamoxifen treatment significantly ameliorated the EBI, such as the clinicalbehavior scale, brain edema, and blood-brain barrier (BBB) impairment. It suggests thatTamoxifen could attenuate EBI in this rat SAH model.
Objective: The aim of the current study was to investigate whether tamoxifenadministration modulate TLR4/NF-κB signaling pathway in the brain at the early braininjury (EBI) of SAH.
Methods: Sixty male Sprague Dawley rats weighing from300to350g wererandomly divided into control group（n=15）, SAH group（n=15）, SAH+vehicle group（n=15） and SAH+tamoxifen group（n=15）.All SAH animals were subjected toinjection of0.3ml fresh arterial, non-heparinized blood into suprachiasmatic cistern in20seconds. Male rats were given5mg/kg injections of tamoxifen at post-SAH hours2h24hand36h. Rats of SAH+vehicle group received equal volumes of vehicle (1%ethanol) atcorresponding time points. Brain samples（adjacent to the clotted blood） were extracted at48h after SAH. Control animals underwent exactly the same procedure as described abovewith the exception that no blood was injected intracisternally.We measured the expressionsof TLR4, NF-κB, intercellular adhesion molecule-1(ICAM-1) by Western Blot；andTLR4、NF-κB and ICAM-1expressions by Immunohistochemistry.NF-κB DNA bindingactivity were quantified by EMSA.
Results: Western Blot Analysis for detecting TLR4, NF-κB and ICAM-1expressionsafter SAH. These proteins were expressed at a low level in the rat brains of control group. The levels of TLR4, NF-κB and ICAM-1were significantly increased in the cortex inSAH group and SAH+vehicle group as compared with that of control group (P <0.01). Theprotein expressions had no significant difference between SAH group and SAH+vehiclegroup (P>0.05). After tamoxifen injections, the decreased expression of TLR4, NF-κBand ICAM-1was markedly further induced in animals of SAH+tamoxifen group (P<0.01).Immunohistochemical study showed that positive TLR4, NF-κB and ICAM-1were mainlylocated at the neurons, with little expression at glial cells. The immunoreactivity of TLR4,NF-κB and ICAM-1was weak in the cortex samples in control group with only a fewTLR4, NF-κB and ICAM-1positive cells in the brain. More TLR4, NF-κB and ICAM-1positively immunostained neurons appeared in SAH group and SAH+vehicle group. InSAH+tamoxifen group, the number of TLR4, NF-κB and ICAM-1positive cells was lessthan SAH group and SAH+vehicle group. TLR4,NF-κB and ICAM-1immunoreactivities of parenchymal cells in the cortex were progressively induced bytamoxifen therapy at48h after blood injection(P <0.01). EMSA autoradiography of NF-κBDNA binding activity in the brain was shown that Low NF-κB binding activity (weakEMSA autoradiography) was found in the control group. Compared with the control group,NF-κB binding activity significantly increased (P <0.01) in SAH group and SAH+vehiclegroup. There was no statistically significant difference between SAH group and SAH+vehicle group (P>0.05). In SAH+tamoxifen group, NF-κB binding activity wassignificantly down-regulated (P <0.01)after tamoxifen injections.
Conclusions: SAH could induce an activation of TLR4/NF-κB signaling pathway thatmight play a central role in the inflammatory response that leads to secondary insults afterSAH. The therapeutic benefit of post-SAH tamoxifen administration might be due to itssalutary effect on modulating TLR4/NF-κB signaling pathway.
方法：48只健康成年雄性SD大鼠随机分为对照组（n=12），SAH组（n=12），安慰剂组（n=12）和他莫昔芬治疗组（n=12）。应用视交叉前池一次注血法制成SAH后EBI模型，在蛛网膜下腔出血后2h、24h及36h分别腹腔注射他莫昔芬，48小时后处死大鼠，取颞底皮层脑组织做标本，测定脑水肿变化及血脑屏障变化，探讨他莫昔芬对大鼠SAH后EBI是否具有神经保护作用。
结果：与对照组相比，SAH组大鼠脑组织含水量明显增加，48h时水肿百分数达到82.51%，血脑屏障破坏明显，48h时测定皮层脑组织伊文氏蓝（EB）含量达到21.5ng/mg；与SAH组相比，他莫昔芬治疗后大鼠脑水肿指数降低，48h时水肿百分数80.55%，血脑屏障功能改善，48h时测定皮层脑组织EB含量13.2ng/mg；安慰剂组与SAH组相比改善不明显。
结论：1．通过构建大鼠SAH模型，能够观察到大鼠SAH后48h脑组织含水量增加明显，血脑屏障破坏明显，说明SAH后存在EBI。2．应用他莫昔芬治疗后，能有效降低SAH后脑水肿、改善血脑屏障，提示他莫昔芬对大鼠SAH后EBI具有神经保护作用。
目的：研究SAH后大脑皮层TLR4（Toll样受体4）/NF-κ B（核因子κB）信号通路及其下游炎症因子及细胞活素的表达变化及他莫昔芬对TLR4/NF-κ B信号通路的干预作用，探讨他莫昔芬对SAH后EBI神经保护作用机制。
方法：60只健康成年雄性SD大鼠随机分为：对照组(n=15), SAH组(n=15),SAH+安慰剂组(n=15)和SAH+他莫昔芬治疗组(n=15)。采用立体定向注射技术，构建视交叉前池一次注血SAH模型，对照组开骨窗但不注入动脉血，他莫昔芬治疗组给予他莫昔芬腹腔注射治疗，每次注射剂量5mg/kg，在SAH后2h、24h、36h分别腹腔注射。安慰剂组注射等容量溶剂，溶剂为1%乙醇。48小时后处死大鼠，取颞底皮层脑组织做标本，采用Western blot法测定TLR4、NF-κB及ICAM-1表达情况；免疫组化法检测TLR4、NF-κB及ICAM-1表达，EMSA测定NF-κB的DNA活性。通过ELISA方法分析大鼠脑皮层中细胞活素因子IL-1β, TNF-α和IL-6表达情况比较。
结果：Western blot结果显示对照组TLR4、NF-κB及ICAM-1蛋白水平较弱；与对照组相比，SAH组TLR4、NF-κB及ICAM-1蛋白水平明显增高(P <0.01)；SAH组与安慰剂组对比无明显差异(P>0.05)；他莫昔芬治疗组中TLR4、NF-κB及ICAM-1蛋白水平明显低于SAH组与安慰剂组(P <0.01)。免疫组化（TLR4、NF-κB及ICAM-1蛋白免疫反应性主要在神经元细胞，细胞核棕色黄染代表阳性）结果显示对照组TLR4、NF-κB及ICAM-1阳性率较低；与对照组相比，SAH组TLR4、NF-κB及ICAM-1阳性率明显增高(P <0.01)；SAH组与安慰剂组对比无明显差异(P>0.05)；他莫昔芬治疗组中TLR4、NF-κB及ICAM-1阳性率低于SAH组及安慰剂组(P <0.01)。EMSA结果显示对照组NF-κB的结合活性较弱；与对照组相比，SAH组NF-κB的结合活性明显增高(P <0.01)；SAH组与安慰剂组对比无明显差异(P>0.05)；他莫昔芬治疗组中NF-κB的结合活性明显低于SAH组与安慰剂组（P<0.01）。ELISA结果显示对照组中IL-1β,TNF-α和IL-6表达水平较低；与对照组相比，SAH组IL-1β, TNF-α和IL-6表达水平明显增高(P <0.01)；SAH组与安慰剂组对比无明显差异(P>0.05)；他莫昔芬治疗组中IL-1β, TNF-α和IL-6表达水平明显低于SAH组与安慰剂组(P <0.01)。
结论：SAH后早期能激活TLR4/NF-κB信号通路，激活其下游的细胞活素/趋化因子诱导炎症反应，可能是引起SAH后EBI的重要机制，他莫昔芬可能通过抑制此传导通路，减轻免疫炎症，从而对SAH后EBI起到神经保护作用。
Objective: To investigate neuroprotection of Tamoxifen on early brain injury in malerats after subarachnoid hemorrahage, such as brain edema, and blood-brain barrier (BBB)impairment.
Methods: forty-eight health male Sprague-dawley(SD) rats were assigned randomlyinto following groups: Control group（n=12）, SAH group（n=12）, SAH+vehicle group（n=12）, SAH+Tamoxifen group（n=12）.All SAH animals were subjected to injectionof0.3ml fresh arterial, non-heparinized blood into suprachiasmatic cistern in20seconds.Male rats were given5mg/kg injections of tamoxifen at post-SAH hours2h,24h and36h.Brain samples adjacent to the clotted blood were extracted at48h after SAH. Controlanimals underwent exactly the same procedure as described above with the exception thatno blood was injected intracisternally. Cerebral edema and blood-brain barrier permeabilitywere detected at48h after experimental SAH.
Results: Significant increase (P <0.01) in water content was detected in the brainsamples at48h after SAH when compared with rats in control group. The mean value ofbrain water content in the cortex was decreased by tamoxifen administration (P <0.01) ascompared with SAH+vehicle group. The pattern of EB extravasation in SAH or SAH+vehicle group demonstrated a significant increase (P <0.01) in BBB permeability of EBrelative to rats of control group. Administration of tamoxifen significantly inhibited EBextravasation(P <0.01) after SAH.
Conclusions:1. As compared with control group, clinical behavior functionimpairment caused by SAH was evident in SAH subjects. SAH group significantlyattenuate blood-brain barrier (BBB), increase brain edema compared to control group.2.Post-SAH tamoxifen treatment significantly ameliorated the EBI, such as the clinicalbehavior scale, brain edema, and blood-brain barrier (BBB) impairment. It suggests thatTamoxifen could attenuate EBI in this rat SAH model.
Objective: The aim of the current study was to investigate whether tamoxifenadministration modulate TLR4/NF-κB signaling pathway in the brain at the early braininjury (EBI) of SAH.
Methods: Sixty male Sprague Dawley rats weighing from300to350g wererandomly divided into control group（n=15）, SAH group（n=15）, SAH+vehicle group（n=15） and SAH+tamoxifen group（n=15）.All SAH animals were subjected toinjection of0.3ml fresh arterial, non-heparinized blood into suprachiasmatic cistern in20seconds. Male rats were given5mg/kg injections of tamoxifen at post-SAH hours2h24hand36h. Rats of SAH+vehicle group received equal volumes of vehicle (1%ethanol) atcorresponding time points. Brain samples（adjacent to the clotted blood） were extracted at48h after SAH. Control animals underwent exactly the same procedure as described abovewith the exception that no blood was injected intracisternally.We measured the expressionsof TLR4, NF-κB, intercellular adhesion molecule-1(ICAM-1) by Western Blot；andTLR4、NF-κB and ICAM-1expressions by Immunohistochemistry.NF-κB DNA bindingactivity were quantified by EMSA.
Results: Western Blot Analysis for detecting TLR4, NF-κB and ICAM-1expressionsafter SAH. These proteins were expressed at a low level in the rat brains of control group. The levels of TLR4, NF-κB and ICAM-1were significantly increased in the cortex inSAH group and SAH+vehicle group as compared with that of control group (P <0.01). Theprotein expressions had no significant difference between SAH group and SAH+vehiclegroup (P>0.05). After tamoxifen injections, the decreased expression of TLR4, NF-κBand ICAM-1was markedly further induced in animals of SAH+tamoxifen group (P<0.01).Immunohistochemical study showed that positive TLR4, NF-κB and ICAM-1were mainlylocated at the neurons, with little expression at glial cells. The immunoreactivity of TLR4,NF-κB and ICAM-1was weak in the cortex samples in control group with only a fewTLR4, NF-κB and ICAM-1positive cells in the brain. More TLR4, NF-κB and ICAM-1positively immunostained neurons appeared in SAH group and SAH+vehicle group. InSAH+tamoxifen group, the number of TLR4, NF-κB and ICAM-1positive cells was lessthan SAH group and SAH+vehicle group. TLR4,NF-κB and ICAM-1immunoreactivities of parenchymal cells in the cortex were progressively induced bytamoxifen therapy at48h after blood injection(P <0.01). EMSA autoradiography of NF-κBDNA binding activity in the brain was shown that Low NF-κB binding activity (weakEMSA autoradiography) was found in the control group. Compared with the control group,NF-κB binding activity significantly increased (P <0.01) in SAH group and SAH+vehiclegroup. There was no statistically significant difference between SAH group and SAH+vehicle group (P>0.05). In SAH+tamoxifen group, NF-κB binding activity wassignificantly down-regulated (P <0.01)after tamoxifen injections.
Conclusions: SAH could induce an activation of TLR4/NF-κB signaling pathway thatmight play a central role in the inflammatory response that leads to secondary insults afterSAH. The therapeutic benefit of post-SAH tamoxifen administration might be due to itssalutary effect on modulating TLR4/NF-κB signaling pathway.
引文
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