温胆汤对精神分裂症模型鼠NRG1-ErbB4信号通路及海马组织超微结构的影响
|
摘要
目的:研究温胆汤对精神分裂症模型鼠NRG1-ErbB4信号通路及其海马组织超微结构的影响。方法:将60只实验大鼠随机分为正常组(A)、模型组(B)、氯氮平组(C)、温胆汤40 mg·kg~(-1)组(D)、温胆汤20 mg·kg~(-1)组(E)和温胆汤10 mg·kg~(-1)组(F)。D、E、F组予温胆汤灌胃,每次给药20 mL·kg~(-1)(相当于D、E、F组生药量40、20、10 g·kg~(-1)),C组予氯氮平原药20 mg·kg~(-1)灌胃,A、B予等量生理盐水灌胃,1次/d,共21 d。除A组外,其余5组大鼠在最后一次给药2 h后于左侧腹腔一次性注射MK-801(0.6 mg·kg~(-1))诱发精神分裂症大鼠模型,A组给予等量生理盐水腹腔注射。造模后观察并记录各组大鼠不同时间的刻板行为改变,处死大鼠并取其海马组织待测。采用H600透射电镜观察各组大鼠海马组织神经元细胞和神经胶质细胞的超微结构,Western Bloting测定各组大鼠海马组织中NRG1、ErbB4的蛋白和磷酸化表达。结果:各组大鼠造模60 min后,与B组比较,除F组外,其余各组大鼠刻板行为均有极显著性差异(P<0.01)。与B组比较,D、E组大鼠海马组织神经元细胞和神经胶质细胞凋亡明显减少;NRG1、ErbB4蛋白表达显著下降、磷酸化表达明显升高(P<0.01)。结论:温胆汤可能通过调节精神分裂症模型鼠NRG1、ErbB4的蛋白和磷酸化表达,进而调控NRG1-ErbB4信号通路的功能,改善海马组织的超微结构,达到防治精神分裂症的目的。
Objective: To study the effect of Wendan Decoction on the NRG1-ErbB4 signaling pathway and the ultrastructure of hippocampus in schizophrenic model rats. Methods: Sixty experimental rats were randomly divided into normal group(A), model group(B), clozapine group(C), Wendan Decoction 40 mg/kg group(D), Wendan Decoction 20 mg·kg~(-1 )group(E) and Wendan Decoction 10 mg/kg group(F). Group D, E and F were given Wendan Decoction by gavage. Each dose was given 20 mL·kg~(-1)(equivalent to D, E, F in group 40, 20, 10 g·kg~(-1)). The C group was given the clozapine original medicine for the stomach, A and B were given the same amount of normal saline, once a day. In addition to the A group, the other 5 groups were injected MK-801(0.6 mg·kg~(-1)) in the left abdominal cavity after the last dose of 2 h in the left abdominal cavity to induce the rat model of schizophrenia, and the A group was given the same amount of saline injection. After modeling, stereotyped behavior changes were observed and recorded in different groups of rats. Rats were sacrificed and their hippocampal tissues were taken out for testing. H600 transmission electron microscope was used to observe the ultrastructure of neuronal cells and glial cells in the hippocampus of rats. The protein and phosphorylation of NRG1 and ErbB4 in the hippocampus of each group were measured by Western bloting. Results: Sixty minutes after modeling, there were significant differences in the stereotyped behavior of rats in all groups except F group(P<0.01). Compared with the B group, the apoptosis of neurons and glial cells in the hippocampus of D and E rats decreased significantly, and the expressions of NRG1 and ErbB4 protein decreased significantly and the expression of phosphorylation increased significantly(P<0.01). Conclusion: Wendan Decoction may regulate the function of NRG1-ErbB4 signaling pathway and improve the ultrastructure of hippocampal tissue by regulating the protein and phosphorylation of NRG1 and ErbB4 in the rat model of schizophrenia, and improve the ultrastructure of the hippocampus to prevent schizophrenia.
Objective: To study the effect of Wendan Decoction on the NRG1-ErbB4 signaling pathway and the ultrastructure of hippocampus in schizophrenic model rats. Methods: Sixty experimental rats were randomly divided into normal group(A), model group(B), clozapine group(C), Wendan Decoction 40 mg/kg group(D), Wendan Decoction 20 mg·kg~(-1 )group(E) and Wendan Decoction 10 mg/kg group(F). Group D, E and F were given Wendan Decoction by gavage. Each dose was given 20 mL·kg~(-1)(equivalent to D, E, F in group 40, 20, 10 g·kg~(-1)). The C group was given the clozapine original medicine for the stomach, A and B were given the same amount of normal saline, once a day. In addition to the A group, the other 5 groups were injected MK-801(0.6 mg·kg~(-1)) in the left abdominal cavity after the last dose of 2 h in the left abdominal cavity to induce the rat model of schizophrenia, and the A group was given the same amount of saline injection. After modeling, stereotyped behavior changes were observed and recorded in different groups of rats. Rats were sacrificed and their hippocampal tissues were taken out for testing. H600 transmission electron microscope was used to observe the ultrastructure of neuronal cells and glial cells in the hippocampus of rats. The protein and phosphorylation of NRG1 and ErbB4 in the hippocampus of each group were measured by Western bloting. Results: Sixty minutes after modeling, there were significant differences in the stereotyped behavior of rats in all groups except F group(P<0.01). Compared with the B group, the apoptosis of neurons and glial cells in the hippocampus of D and E rats decreased significantly, and the expressions of NRG1 and ErbB4 protein decreased significantly and the expression of phosphorylation increased significantly(P<0.01). Conclusion: Wendan Decoction may regulate the function of NRG1-ErbB4 signaling pathway and improve the ultrastructure of hippocampal tissue by regulating the protein and phosphorylation of NRG1 and ErbB4 in the rat model of schizophrenia, and improve the ultrastructure of the hippocampus to prevent schizophrenia.
引文
[1] Moller H.Management of the negative symptoms of schizophrenia[J].CNS drugs,2003,17(11):793-823.
[2] Ddington J,Addington D,Matickatyn-Dale E.Cognitive functioning and positive and negative symptoms in schizophrenia[J].Schizophr Res,1991,5(2):123-134.
[3] 李贤佐,田明萍.中西医结合治疗精神分裂症26例[J].中华全科医师杂志,2005,4(6):384.
[4] Birchmeier C.ErbB receptors and the development of the nervous system[J].Exp Cell Res,2009,315(4):611-618.
[5] Pan B,Huang XF,Deng C.Antipsychotic treatment and neuregulin1-ErbB4 signalling in schizophrenia[J].Prog Neuropsychopharmacol Biol Psychiatry,2011,35(4):924-930.
[6] 吴金华,邹洪,于军,等.用不同实验小鼠品系建立精神分裂症的动物模型[J].生理学报,2003,55(4):35.
[7] 李晓白,方贻儒,王祖承.精神分裂症动物模型研究进展[J].上海精神医学,2004,16(3):184-185.
[8] 刘娟,韩怀钦,文玉军,等.大鼠精神分裂症后自发性运动量及海马神经发生的改变[J].神经解剖学杂志,2010,26(3):314-318.
[9] Tanimura A,Liu J,Namba T,et al.Prenatal phencyclidine exposure alters hippocampal cell proliferation in offspring rats[J],Synapse,2009,63(9):729-736.
[10] 郑艳宇,张义伟,马江波,等.青春期大鼠癫痫发作后海马齿状回颗粒细胞层神经细胞增殖的改变[J].神经解剖学杂志,2012,28(1):55-58.
[11] 刘水平,郭薇,陈玉川.精神分裂症的神经病理学研究进展[J].法医学杂志,2001,17(3):18.
[12] 高维娟,黄启福,贾旭.益肾降浊汤对脑缺血再灌注大鼠海马组织超微结构的影响[J].河北医学,2001,7(8):682.
[13] Giaume C,Venance L.Intercellular calcium signaling and gap junctional communication in astrocytes[J].Glia,1998,24(1):50-64.
[14] Martin AO,Mathieu MN,Chevillard C,et al.Gap junctions mediate electrical signaling and ensuing cytosolic Ca2+ increases between chromaffin cells in adrenal slices:A role in catecholamine release[J].Journal of Neuroscience the Official Journal of the Society for Neuroscience,2001,21(15):5397-5405.
[15] Longuemare M,Rose CK,Ransom B,et al.K(+)-induced reversal of astrocyte glutamate uptake is limited by compensatory changes in intracellular Na+[J].Neuroscience,1999,93(1):285-292.
[16] 王晓东,司天梅.NRG1-ErbB信号转导系统与精神分裂症[J].国际精神病学杂志,2007,34(4):198-201.
[17] Hahn CG,Wang HY,Cho DS,et al.Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia[J].Nat Med,2006,12(7):824-828.
[18] Du Y,Dreyfus CF.Oligodendrocytes as providers of growth factors[J].Neurosci Res,2002,68(6):647-654.
[19] Hobbs SS,Coffing SL,Le AT,et al.Neuregulin isoforms ex-hibit distinct patterns of ErbB family receptor activation[J].Oncogene,2002,21(55):8442-8452.
[20] Michailov GV,Sereda MW,Brinkmann BG.Axonal neuregulin-1 regulates myelin sheath thickness[J].Science,2004,304(5671):700-703.
[21] Ullian EM,Sapperstein SK,Christopherson KS,et al.Control of synapse number by glia[J].Science,2001,291(5504):657.
[22] Mei L,Xiong WC.Neuregulin 1 in neural development,synaptic plasticity and schizophrenia[J].Nat Rev Neurosci,2008,9(6):437-452.
[23] Lu CL,Wang YC,Chen JY,et al.Support for the involvement of the ERBB4 gene in schizophrenia:a genetic association analysis[J].Neurosci Lett,2010,481(2):120-125.
[24] Neddens J,Buonanno A.Selective populations of hippocampal interneurons express Erb B4 and their number and distribution is altered in Erb B4 knockout mice[J].Hippocampus,2010,20(6):724-744.
[25] Deakin IH,Nissen W,Law AJ,et al.Transgenic overexpression of the type I isoform of neuregulin1 affects working memory and hippocampal oscillations but not long-term potentiation[J].Cereb Cortex,2012,22(7):1520-1529.
[26] 王继堃,许秀峰,杨建中.精神分裂症与NRG1基因的研究进展[J].国际精神病学杂志,2007,34(1):9-11.
[27] Law AJ,Lipska BK,Weickert CS,et al.Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5’SNP associated with the disease[J].Proc Natl Acad Sci USA,2006,103(17):6747-6752.
[28] Hashimoto R,Straub RE,Weickert CS,et al.Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia[J].Mol Psychiatry,2004,9(3):299-307.
[29] Yin DM,Chen YJ,Lu YS,et al.Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1[J].Neuron,2013,78(4):644.
[30] Kato T,Kasai A,Mizuno M,et al.Phenotypic characterization of transgenic mice overexpressing neuregulin-1[J].Plos One,2010,5(12):e14185.
[31] 万红娇,何欢,刘圣徽,等.温胆汤对精神分裂症模型大鼠海马组织NRG1、ErbB4蛋白表达的影响[J].中药药理与临床,2016,32(3):12-16.
[32] Pan B,Huang XF,Deng C.Antipsychotic treatment and neuregulin1-ErbB4 signalling in schizophrenia[J].Prog Neuropsychopharmacol Biol Psychiatry,2011,35(4):924-930.
[33] Barros CS,Calabrese B,Chamero P,et al.Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system[J].Proc Natl Acad Sci USA,2009,106(11):4507-4512.
[34] 郭汝金,敖丽娟,李咏梅,等.神经调节蛋1-ErbB信号通路的研究进展[J].中国康复医学杂志,2014,29(7):679-684.
[2] Ddington J,Addington D,Matickatyn-Dale E.Cognitive functioning and positive and negative symptoms in schizophrenia[J].Schizophr Res,1991,5(2):123-134.
[3] 李贤佐,田明萍.中西医结合治疗精神分裂症26例[J].中华全科医师杂志,2005,4(6):384.
[4] Birchmeier C.ErbB receptors and the development of the nervous system[J].Exp Cell Res,2009,315(4):611-618.
[5] Pan B,Huang XF,Deng C.Antipsychotic treatment and neuregulin1-ErbB4 signalling in schizophrenia[J].Prog Neuropsychopharmacol Biol Psychiatry,2011,35(4):924-930.
[6] 吴金华,邹洪,于军,等.用不同实验小鼠品系建立精神分裂症的动物模型[J].生理学报,2003,55(4):35.
[7] 李晓白,方贻儒,王祖承.精神分裂症动物模型研究进展[J].上海精神医学,2004,16(3):184-185.
[8] 刘娟,韩怀钦,文玉军,等.大鼠精神分裂症后自发性运动量及海马神经发生的改变[J].神经解剖学杂志,2010,26(3):314-318.
[9] Tanimura A,Liu J,Namba T,et al.Prenatal phencyclidine exposure alters hippocampal cell proliferation in offspring rats[J],Synapse,2009,63(9):729-736.
[10] 郑艳宇,张义伟,马江波,等.青春期大鼠癫痫发作后海马齿状回颗粒细胞层神经细胞增殖的改变[J].神经解剖学杂志,2012,28(1):55-58.
[11] 刘水平,郭薇,陈玉川.精神分裂症的神经病理学研究进展[J].法医学杂志,2001,17(3):18.
[12] 高维娟,黄启福,贾旭.益肾降浊汤对脑缺血再灌注大鼠海马组织超微结构的影响[J].河北医学,2001,7(8):682.
[13] Giaume C,Venance L.Intercellular calcium signaling and gap junctional communication in astrocytes[J].Glia,1998,24(1):50-64.
[14] Martin AO,Mathieu MN,Chevillard C,et al.Gap junctions mediate electrical signaling and ensuing cytosolic Ca2+ increases between chromaffin cells in adrenal slices:A role in catecholamine release[J].Journal of Neuroscience the Official Journal of the Society for Neuroscience,2001,21(15):5397-5405.
[15] Longuemare M,Rose CK,Ransom B,et al.K(+)-induced reversal of astrocyte glutamate uptake is limited by compensatory changes in intracellular Na+[J].Neuroscience,1999,93(1):285-292.
[16] 王晓东,司天梅.NRG1-ErbB信号转导系统与精神分裂症[J].国际精神病学杂志,2007,34(4):198-201.
[17] Hahn CG,Wang HY,Cho DS,et al.Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia[J].Nat Med,2006,12(7):824-828.
[18] Du Y,Dreyfus CF.Oligodendrocytes as providers of growth factors[J].Neurosci Res,2002,68(6):647-654.
[19] Hobbs SS,Coffing SL,Le AT,et al.Neuregulin isoforms ex-hibit distinct patterns of ErbB family receptor activation[J].Oncogene,2002,21(55):8442-8452.
[20] Michailov GV,Sereda MW,Brinkmann BG.Axonal neuregulin-1 regulates myelin sheath thickness[J].Science,2004,304(5671):700-703.
[21] Ullian EM,Sapperstein SK,Christopherson KS,et al.Control of synapse number by glia[J].Science,2001,291(5504):657.
[22] Mei L,Xiong WC.Neuregulin 1 in neural development,synaptic plasticity and schizophrenia[J].Nat Rev Neurosci,2008,9(6):437-452.
[23] Lu CL,Wang YC,Chen JY,et al.Support for the involvement of the ERBB4 gene in schizophrenia:a genetic association analysis[J].Neurosci Lett,2010,481(2):120-125.
[24] Neddens J,Buonanno A.Selective populations of hippocampal interneurons express Erb B4 and their number and distribution is altered in Erb B4 knockout mice[J].Hippocampus,2010,20(6):724-744.
[25] Deakin IH,Nissen W,Law AJ,et al.Transgenic overexpression of the type I isoform of neuregulin1 affects working memory and hippocampal oscillations but not long-term potentiation[J].Cereb Cortex,2012,22(7):1520-1529.
[26] 王继堃,许秀峰,杨建中.精神分裂症与NRG1基因的研究进展[J].国际精神病学杂志,2007,34(1):9-11.
[27] Law AJ,Lipska BK,Weickert CS,et al.Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5’SNP associated with the disease[J].Proc Natl Acad Sci USA,2006,103(17):6747-6752.
[28] Hashimoto R,Straub RE,Weickert CS,et al.Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia[J].Mol Psychiatry,2004,9(3):299-307.
[29] Yin DM,Chen YJ,Lu YS,et al.Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1[J].Neuron,2013,78(4):644.
[30] Kato T,Kasai A,Mizuno M,et al.Phenotypic characterization of transgenic mice overexpressing neuregulin-1[J].Plos One,2010,5(12):e14185.
[31] 万红娇,何欢,刘圣徽,等.温胆汤对精神分裂症模型大鼠海马组织NRG1、ErbB4蛋白表达的影响[J].中药药理与临床,2016,32(3):12-16.
[32] Pan B,Huang XF,Deng C.Antipsychotic treatment and neuregulin1-ErbB4 signalling in schizophrenia[J].Prog Neuropsychopharmacol Biol Psychiatry,2011,35(4):924-930.
[33] Barros CS,Calabrese B,Chamero P,et al.Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system[J].Proc Natl Acad Sci USA,2009,106(11):4507-4512.
[34] 郭汝金,敖丽娟,李咏梅,等.神经调节蛋1-ErbB信号通路的研究进展[J].中国康复医学杂志,2014,29(7):679-684.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |