百事乐胶囊对慢性应激抑郁大鼠海马神经重塑的影响
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摘要
目的：研究百事乐胶囊对慢性应激抑郁大鼠行为学、海马细胞形态结构和细胞增殖的影响,检测百事乐胶囊对海马Cx32.Cx43和SYP表达的影响,探讨百事乐胶囊对抑郁大鼠海马神经重塑的作用机制,为百事乐胶囊治疗抑郁症临床用药提供实验依据。
方法：从72只SD大鼠中随机选取18只作为正常组对照组,其他动物在给予21d不可预知的刺激后,随机分为模型组、氟西汀组(盐酸氟西汀组)、中药组(百事乐胶囊组),每组18只,雌雄各半。然后灌胃给药21d,其中模型组大鼠灌胃蒸馏水,氟西汀组灌胃盐酸氟西汀药液(1.8mg·kg-1·d-1),百事乐组灌胃百事乐胶囊药液(按生药量为1.33g·kg-1·d-1).每组随机选6只大鼠腹腔注射BrdU(100mg·kg-1·d-1)进行增殖细胞标记。在造模前、造模后和给药后3个时间点称量大鼠体质量,测定动物的水平活动、垂直活动和糖水消耗情况。每组取6个脑组织进行石蜡切片,采用HE染色法观察大鼠海马细胞形态变化,采用尼氏染色法观察大鼠海马神经功能变化,采用免疫组化染色法检测Cx32、Cx43和SYP的表达情况。取6个脑组织冷冻切片后进行BrdU免疫组织化学法染色,以观察海马增殖细胞。取6个脑组织分离海马,提取蛋白质,采用WB法检测Cx32、Cx43和SYP的表达情况。
结果：(1)慢性应激抑郁大鼠模型建立后,其体质量增加、水平活动和垂直活动次数、糖水偏好度均明显降低；与模型组比较,百事乐组大鼠体质量明显增加(P<0.05),水平活动(P<0.01)和垂直活动(P<0.05)增强,糖水偏好度显著提高(P<0.01)。
(2)HE染色结果显示,模型组大鼠海马CA1区和CA3区神经元出现异常变化,细胞体积缩小,核不规则,细胞排列散乱,有较多出现变性,核固缩深染,胞外空隙明显；百事乐组神经元形态结构与正常组近似,细胞结构完整,排列整齐,核大而圆,核仁清晰,仅少量细胞核变性。
(3)尼氏染色结果显示,模型组大鼠海马CA1区、CA3区和DG区部分神经元细胞轮廓模糊,尼氏小体数量变少,颜色变浅,胞间间隙变大；百事乐组神经元细胞排列均匀,轮廓清晰,尼氏小体丰富,胞质色深而均匀,与正常组接近。
(4)BrdU免疫组化显示,各组大鼠海马CA1、CA3和DG区均有一定数量的增殖细胞,DG区增殖细胞数要明显高于其他两个区域。与模型组相比,百事乐组大鼠海马CA1、CA3和DG区增殖细胞明显增加,有统计学差异(P<0.05)。百事乐组大鼠海马CA1、CA3和DG区增殖细胞数均高于氟西汀组。
(5)IHC和WB检测结果表明,模型组海马缝隙连接蛋白Cx32和Cx43的表达与正常组比较明显减少(P<0.01或P<0.05),海马突触素SYP的平均光密度及与p-actin的光密度比值比与正常组相比明显下降；与模型组相比,百事乐组大鼠海马Cx32、Cx43和SYP的表达明显增加,具有统计学意义(P<0.01或P<0.05)。
结论：(1)百事乐胶囊能促进慢性应激抑郁大鼠的体质量增加,提高大鼠的自发活动能力、对新奇环境的探索能力以及对幸福事件的反应性。
(2)百事乐胶囊具有神经保护作用,能减轻慢性应激引起大鼠海马神经元的萎缩和凋亡,并有海马神经功能恢复的作用。
(3)百事乐胶囊具有促慢性应激抑郁大鼠海马神经再生作用,其作用机制可能与激活海马DG区NPCs有关。
(4)Cx32、Cx43和SYP的表达上调可能是百事乐胶囊促进慢性应激抑郁大鼠海马神经可塑改变的重要机制。
(5)百事乐胶囊增强慢性应激抑郁大鼠海马缝隙连接蛋白Cx43表达可能是其促神经再生机制之一。
Objectives:The study was conducted to explore the effects of Baishile capsule on ethology, the morphology and cell proliferation of hippocampus, as well as Cx32, Cx43and SYP expressions of hippocampus in Chronic stress depression rats, and to explore the mechanisms of Baishile capsule remodeling hippocampus nerve of the chronic stress depression rats, which providing experimental evidences for Baishile capsule in the treatment of clinical depression drug.
Methods:Seventy-two SD rats were assigned randomly into four groups (18rats/group, half male and half female), normal control group, model group, fluoxetine group (fluoxetine hydrochloride group), and Baishile group (Baishile capsule group). Rats of model group, fluoxetine group and Baishile group were oral administrated with distilled water, fluoxetine hydrochloride soup (1.8mg·kg-1·d-1) and Baishile capsule soup (contented with1.33g·kg-1·d-1), respectively, for21days. Six rats were selected randomly from each group to intraperitoneal inject BrdU (100mg·kg-1·d-1) for proliferation cell markers. All rats were weight, horizontal and vertical activities and sugar consumptions were tested before and after molding, and after oral administration. Six cerebral tissues were selected randomly to make paraffin sections from each group, and then morphology changes of hippocampal cell and functional changes of hippocampal nerve were observed using HE staining and Nissl staining, respectively, Cx32, Cx43and SYP expressions were tested using immunohistochemical staning. And6cerebral tissues were selected to make frozen sections for hippocampal cell proliferation determination via BrdU immunohistochemistry staining. Hippocampus were separated from6cerebral tissues and protein were extracted for Cx32, Cx43and SYP protein expressions analyses using Western blot.
Results:
(1)Compared with the normal group, the body weight, the scores of rearing and crossing and sweet water consumption of rats in model group were all decreased (P<0.01or P<0.05). The body weights of rats in Baishile group were increased (P<0.05), the horizontal (P<0.01) and vertical (P<0.05) activities remarkably improved and sweet water consumption were obviously increased (P<0.01) than that of the model group.
(2) From the results of HE staining, the abnormal changes of the neurons in hippocampal CA1and CA3areas of the model group rats were observed, which exhibiting shrinking cell, irregular nuclei, scattered cell arrangement and more neuron turned degeneration, karyopyknosis and deeper color, lager intercellular gap. However, in the Baishile group, neuron morphology structure of is close to that of the normal group with integrity cell structure, neatly arranged, big and round nuclei, clear nucleolus and only a little of nuclei degeneration.
(3) The results of Nissl staining showed that some neuronal cell outlines of hippocampal CA1, CA3and DG areas in the model group rats were blur, fewer Nissl bodies, lighter color, larger intercellular while neronal cells arranged in uniform, outlines were clear, the number of Nissl bodies were rich, the cytoplastic was well-distributed and has deep color in Baishile group, which is closed to normal group.
(4) The results of BrdU immunohistochemistry showed that there were a certain numbers of proliferating cells in hippocampal CA1, CA3and DG region of all groups and the numbers of DG district proliferating cells were significantly larger than that of other two regions. The numbers of proliferating cells in hippocampal CA1, CA3and DG region of the Baishile group increased (P<0.05) significantly compared with the model group and fluoxetine group.
(5) The results of IHC and WB showed that gap junction proteins Cx32and Cx43expression levels as well as the average optical of synaptophysin SYP density and the ratio of its optical density to β-actin in the hippocampus of model group rats were significantly lower (P<0.01or P<0.05) than that of normal group; Cx32, Cx43and SYP protein expression levels in the hippocampal of Baishile group rats were significantly increased (P<0.01or P<0.05) compared with that of model group.
Conclusions:
(1) Baishile capsule can increase body weight, spontaneous the activity and the ability to explore the novel environment, as well as the reaction of the happy event of the chronic stress depression rats.
(2) Baishile capsules have neuroprotective effects, which reducing chronic stress-induced atrophy and apoptosis of rat hippocampal neurons and recovering hippocampal nerve function.
(3) Baishile Capsules promote hippocampal nerve regeneration of chronic stress induced depression rat, and its mechanism may be related to the activation of NPCs in the hippocampal DG region.
(4) The up-regulations of Cx32, Cx43and SYP expressions may be an important mechanism of Baishile Capsules improving plastic change of hippocampal neurons in the chronic stress depression rats.
(5) Baishile capsule enhanced hippocampus of Cx43expression may be partly resulting to promoting nerve regeneration.
方法：从72只SD大鼠中随机选取18只作为正常组对照组,其他动物在给予21d不可预知的刺激后,随机分为模型组、氟西汀组(盐酸氟西汀组)、中药组(百事乐胶囊组),每组18只,雌雄各半。然后灌胃给药21d,其中模型组大鼠灌胃蒸馏水,氟西汀组灌胃盐酸氟西汀药液(1.8mg·kg-1·d-1),百事乐组灌胃百事乐胶囊药液(按生药量为1.33g·kg-1·d-1).每组随机选6只大鼠腹腔注射BrdU(100mg·kg-1·d-1)进行增殖细胞标记。在造模前、造模后和给药后3个时间点称量大鼠体质量,测定动物的水平活动、垂直活动和糖水消耗情况。每组取6个脑组织进行石蜡切片,采用HE染色法观察大鼠海马细胞形态变化,采用尼氏染色法观察大鼠海马神经功能变化,采用免疫组化染色法检测Cx32、Cx43和SYP的表达情况。取6个脑组织冷冻切片后进行BrdU免疫组织化学法染色,以观察海马增殖细胞。取6个脑组织分离海马,提取蛋白质,采用WB法检测Cx32、Cx43和SYP的表达情况。
结果：(1)慢性应激抑郁大鼠模型建立后,其体质量增加、水平活动和垂直活动次数、糖水偏好度均明显降低；与模型组比较,百事乐组大鼠体质量明显增加(P<0.05),水平活动(P<0.01)和垂直活动(P<0.05)增强,糖水偏好度显著提高(P<0.01)。
(2)HE染色结果显示,模型组大鼠海马CA1区和CA3区神经元出现异常变化,细胞体积缩小,核不规则,细胞排列散乱,有较多出现变性,核固缩深染,胞外空隙明显；百事乐组神经元形态结构与正常组近似,细胞结构完整,排列整齐,核大而圆,核仁清晰,仅少量细胞核变性。
(3)尼氏染色结果显示,模型组大鼠海马CA1区、CA3区和DG区部分神经元细胞轮廓模糊,尼氏小体数量变少,颜色变浅,胞间间隙变大；百事乐组神经元细胞排列均匀,轮廓清晰,尼氏小体丰富,胞质色深而均匀,与正常组接近。
(4)BrdU免疫组化显示,各组大鼠海马CA1、CA3和DG区均有一定数量的增殖细胞,DG区增殖细胞数要明显高于其他两个区域。与模型组相比,百事乐组大鼠海马CA1、CA3和DG区增殖细胞明显增加,有统计学差异(P<0.05)。百事乐组大鼠海马CA1、CA3和DG区增殖细胞数均高于氟西汀组。
(5)IHC和WB检测结果表明,模型组海马缝隙连接蛋白Cx32和Cx43的表达与正常组比较明显减少(P<0.01或P<0.05),海马突触素SYP的平均光密度及与p-actin的光密度比值比与正常组相比明显下降；与模型组相比,百事乐组大鼠海马Cx32、Cx43和SYP的表达明显增加,具有统计学意义(P<0.01或P<0.05)。
结论：(1)百事乐胶囊能促进慢性应激抑郁大鼠的体质量增加,提高大鼠的自发活动能力、对新奇环境的探索能力以及对幸福事件的反应性。
(2)百事乐胶囊具有神经保护作用,能减轻慢性应激引起大鼠海马神经元的萎缩和凋亡,并有海马神经功能恢复的作用。
(3)百事乐胶囊具有促慢性应激抑郁大鼠海马神经再生作用,其作用机制可能与激活海马DG区NPCs有关。
(4)Cx32、Cx43和SYP的表达上调可能是百事乐胶囊促进慢性应激抑郁大鼠海马神经可塑改变的重要机制。
(5)百事乐胶囊增强慢性应激抑郁大鼠海马缝隙连接蛋白Cx43表达可能是其促神经再生机制之一。
Objectives:The study was conducted to explore the effects of Baishile capsule on ethology, the morphology and cell proliferation of hippocampus, as well as Cx32, Cx43and SYP expressions of hippocampus in Chronic stress depression rats, and to explore the mechanisms of Baishile capsule remodeling hippocampus nerve of the chronic stress depression rats, which providing experimental evidences for Baishile capsule in the treatment of clinical depression drug.
Methods:Seventy-two SD rats were assigned randomly into four groups (18rats/group, half male and half female), normal control group, model group, fluoxetine group (fluoxetine hydrochloride group), and Baishile group (Baishile capsule group). Rats of model group, fluoxetine group and Baishile group were oral administrated with distilled water, fluoxetine hydrochloride soup (1.8mg·kg-1·d-1) and Baishile capsule soup (contented with1.33g·kg-1·d-1), respectively, for21days. Six rats were selected randomly from each group to intraperitoneal inject BrdU (100mg·kg-1·d-1) for proliferation cell markers. All rats were weight, horizontal and vertical activities and sugar consumptions were tested before and after molding, and after oral administration. Six cerebral tissues were selected randomly to make paraffin sections from each group, and then morphology changes of hippocampal cell and functional changes of hippocampal nerve were observed using HE staining and Nissl staining, respectively, Cx32, Cx43and SYP expressions were tested using immunohistochemical staning. And6cerebral tissues were selected to make frozen sections for hippocampal cell proliferation determination via BrdU immunohistochemistry staining. Hippocampus were separated from6cerebral tissues and protein were extracted for Cx32, Cx43and SYP protein expressions analyses using Western blot.
Results:
(1)Compared with the normal group, the body weight, the scores of rearing and crossing and sweet water consumption of rats in model group were all decreased (P<0.01or P<0.05). The body weights of rats in Baishile group were increased (P<0.05), the horizontal (P<0.01) and vertical (P<0.05) activities remarkably improved and sweet water consumption were obviously increased (P<0.01) than that of the model group.
(2) From the results of HE staining, the abnormal changes of the neurons in hippocampal CA1and CA3areas of the model group rats were observed, which exhibiting shrinking cell, irregular nuclei, scattered cell arrangement and more neuron turned degeneration, karyopyknosis and deeper color, lager intercellular gap. However, in the Baishile group, neuron morphology structure of is close to that of the normal group with integrity cell structure, neatly arranged, big and round nuclei, clear nucleolus and only a little of nuclei degeneration.
(3) The results of Nissl staining showed that some neuronal cell outlines of hippocampal CA1, CA3and DG areas in the model group rats were blur, fewer Nissl bodies, lighter color, larger intercellular while neronal cells arranged in uniform, outlines were clear, the number of Nissl bodies were rich, the cytoplastic was well-distributed and has deep color in Baishile group, which is closed to normal group.
(4) The results of BrdU immunohistochemistry showed that there were a certain numbers of proliferating cells in hippocampal CA1, CA3and DG region of all groups and the numbers of DG district proliferating cells were significantly larger than that of other two regions. The numbers of proliferating cells in hippocampal CA1, CA3and DG region of the Baishile group increased (P<0.05) significantly compared with the model group and fluoxetine group.
(5) The results of IHC and WB showed that gap junction proteins Cx32and Cx43expression levels as well as the average optical of synaptophysin SYP density and the ratio of its optical density to β-actin in the hippocampus of model group rats were significantly lower (P<0.01or P<0.05) than that of normal group; Cx32, Cx43and SYP protein expression levels in the hippocampal of Baishile group rats were significantly increased (P<0.01or P<0.05) compared with that of model group.
Conclusions:
(1) Baishile capsule can increase body weight, spontaneous the activity and the ability to explore the novel environment, as well as the reaction of the happy event of the chronic stress depression rats.
(2) Baishile capsules have neuroprotective effects, which reducing chronic stress-induced atrophy and apoptosis of rat hippocampal neurons and recovering hippocampal nerve function.
(3) Baishile Capsules promote hippocampal nerve regeneration of chronic stress induced depression rat, and its mechanism may be related to the activation of NPCs in the hippocampal DG region.
(4) The up-regulations of Cx32, Cx43and SYP expressions may be an important mechanism of Baishile Capsules improving plastic change of hippocampal neurons in the chronic stress depression rats.
(5) Baishile capsule enhanced hippocampus of Cx43expression may be partly resulting to promoting nerve regeneration.
引文
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