曲唑酮对脑卒中后抑郁大鼠学习记忆功能及海马区BDNF、受体TrkB表达的影响
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摘要
目的:探讨曲唑酮对脑卒中后抑郁大鼠学习记忆功能及海马区脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)、受体酪氨酸激酶B(TrkB)蛋白表达的影响。方法:选取雄性SD大鼠72只随机分为6组(对照组、模型对照组、阳性对照组、曲唑酮小、中、大剂量组),每组均为12只。选择右侧大脑中动脉进行栓塞,并连续给予慢性无法预见性的应激(3周)建立大鼠卒中后抑郁模型(对照组除外)。在给予慢性应激的同时,曲唑酮小、中、大剂量组分别给予曲唑酮(8,13,20 mg·kg~(-1))灌胃,阳性对照组给予文拉法辛(20 mg·kg~(-1))灌胃,均每天1次,连用21 d。Morris水迷宫试验对大鼠空间学习记忆功能进行评价,免疫组化法对海马区BDNF表达进行检测。免疫印迹法对BDNF及其受体TrkB蛋白表达进行检测。结果:模型组、曲唑酮中剂量组、大剂量组在用药第7,14,21天大鼠糖水偏爱情况与模型对照组比较,差异有显著性(P<0.05);大剂量组在用药第14天、第21天大鼠糖水偏爱情况与小剂量组比较,差异有显著性(P<0.05);曲唑酮小、中、大剂量组逃避潜伏期、穿平台次数、空间探索时间与模型对照组比较,差异均有显著性(P<0.05);中、大剂量组逃避潜伏期、穿越平台次数、空间探索时间与小剂量组比较,差异有显著性(P<0.05);模型对照组BDNF、TrkB阳性细胞数明显低于对照组(P<0.05);曲唑酮小、中、大剂量组BDNF、TrkB阳性细胞数、BDNF及TrkB蛋白表达明显高于模型对照组(P<0.05);大剂量组BDNF、TrkB阳性细胞数、BDNF及TrkB蛋白表达明显高于小、中剂量组(P<0.05)。结论:大、中、小剂量曲唑酮能改善脑卒后抑郁大鼠的空间学习及记忆功能,以大剂量曲唑酮效果最明显,其作用机制可能与同时上调海马BDNF及其受体TrkB的表达有关。
OBJECTIVE To investigate the effect of trozodone on the learning and memory function of post-stroke depression rats and the expression of brain-derived neurotrophic factor(BDNF) and receptor tyrosine kinase B(TrkB) in the hippocampus. METHODS 72 male SD rats were randomly divided into 6 groups(control group, model control group,positive control group, trazodone low, medium and high dose group), 12 rats in each group. Right middle cerebral artery was selected for embolization, and chronic unpredictable stress(3 weeks) was continuously administered to establish a post-stroke depression model in rats(Control group excluded). While chronic stress was given, trazodone small, medium and high dose groups were given trazodone(8,13,20 mg·kg~(-1)) by gavage, respectively, and the positive control group was given venlafaxine(20 mg·kg~(-1)) by gavage, all once a day for 21 days. Morris water maze test was used to evaluate the spatial learning and memory function of rats, and immunohistochemical method was used to detect the expression of BDNF in the hippocampus. BDNF and its receptor TrkB protein expression were detected by Western blot. RESULTS There was significant difference in sugar water preference between the rats in the model group and the control group on the 7 th, 14 th and 21 st days of medication(P<0.05); there was significant difference in sugar water preference between the rats in the medium and high dose trazodone groups and the model control group on the 7 th, 14 th and 21 st days of medication(P<0.05); there was significant difference in sugar water preference between the rats in the high dose group and the low dose group on the 14 th and 21 st days of medication(P<0.05); there was significant difference in escape latency, number of platform crossings and space exploration time between the small, medium and high dose trazodone groups and the model control group(P<0.05); The difference was significant(P<0.05); the number of BDNF and TrkB positive cells in the model control group was significantly lower than that in the control group(P<0.05); the number of BDNF, TrkB positive cells, BDNF and TrkB protein expression in the trazodone small, medium and high dose groups was significantly higher than that in the model control group(P<0.05); the number of BDNF, TrkB positive cells, BDNF and TrkB protein expression in the high dose group was significantly higher than that in the low and medium dose groups(P<0.05). CONCLUSION High, medium and low doses of trazodone can improve spatial learning and memory function in rats with post-stroke depression, the effect of high dose of trazolone is the most obvious, in which the mechanism may be related to the simultaneous up-regulation of hippocampal BDNF and its receptor TrkB expression.
OBJECTIVE To investigate the effect of trozodone on the learning and memory function of post-stroke depression rats and the expression of brain-derived neurotrophic factor(BDNF) and receptor tyrosine kinase B(TrkB) in the hippocampus. METHODS 72 male SD rats were randomly divided into 6 groups(control group, model control group,positive control group, trazodone low, medium and high dose group), 12 rats in each group. Right middle cerebral artery was selected for embolization, and chronic unpredictable stress(3 weeks) was continuously administered to establish a post-stroke depression model in rats(Control group excluded). While chronic stress was given, trazodone small, medium and high dose groups were given trazodone(8,13,20 mg·kg~(-1)) by gavage, respectively, and the positive control group was given venlafaxine(20 mg·kg~(-1)) by gavage, all once a day for 21 days. Morris water maze test was used to evaluate the spatial learning and memory function of rats, and immunohistochemical method was used to detect the expression of BDNF in the hippocampus. BDNF and its receptor TrkB protein expression were detected by Western blot. RESULTS There was significant difference in sugar water preference between the rats in the model group and the control group on the 7 th, 14 th and 21 st days of medication(P<0.05); there was significant difference in sugar water preference between the rats in the medium and high dose trazodone groups and the model control group on the 7 th, 14 th and 21 st days of medication(P<0.05); there was significant difference in sugar water preference between the rats in the high dose group and the low dose group on the 14 th and 21 st days of medication(P<0.05); there was significant difference in escape latency, number of platform crossings and space exploration time between the small, medium and high dose trazodone groups and the model control group(P<0.05); The difference was significant(P<0.05); the number of BDNF and TrkB positive cells in the model control group was significantly lower than that in the control group(P<0.05); the number of BDNF, TrkB positive cells, BDNF and TrkB protein expression in the trazodone small, medium and high dose groups was significantly higher than that in the model control group(P<0.05); the number of BDNF, TrkB positive cells, BDNF and TrkB protein expression in the high dose group was significantly higher than that in the low and medium dose groups(P<0.05). CONCLUSION High, medium and low doses of trazodone can improve spatial learning and memory function in rats with post-stroke depression, the effect of high dose of trazolone is the most obvious, in which the mechanism may be related to the simultaneous up-regulation of hippocampal BDNF and its receptor TrkB expression.
引文
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[2] Tang Y,Meng XL,Tang R.Effects of trazodone replacement therapy on cognitive function of patients[J].Pharma Care Res(药学服务与研究),2016,16(3):190-191.
[3] Hou YY.Changes of plasma Hcy and BDNF in patients with depression after ischemic stroke[J].Med J Chin People Health(中国民康医学),2015,27(22):65-67.
[4] Wang Y,Xiao W,Zhang XB,et al.Establishment and evaluation of stress animal models[J].J Gansu College Tradit Chin Med(甘肃中医学院学报),2015,32(2):70-71.
[5] Dai MH,Li DQ,HanY.Effects of venlafaxine on learning and memory and hippocampal brain-derived neurotrophic factor in rats with poststroke depression[J].J Zhejiang Univ (Med Sci) (浙江大学学报·医学版),2011,10(5):528-530.
[6] Li Y,Peng C,You JJ,et al.Expression of thalamic neurotrophic factor and tyrosine kinase receptor B protein in depressed rats after stroke[J].Chin J Geriatric Cardiovascular Dis(中华老年心血管疾病杂志),2014,16(5):526-528.
[7] Huang JH,Huang XH,Chen ZY,et al.Equivalent dose conversion between animals and between animals and humans in pharmacological tests[J].Chin Clin Pharm Therapeutics(中国临床药理学与治疗学),2014,9(9):1069-1072.
[8] Si XM.Study on the role of P13K/Akt/mTOR mediated BDNF/TrkB signaling pathway in the antidepressant effect of votecetine[D].Qingdao :Qingdao university (青岛大学),2018.
[9] Cheng ZX,Liang XJ,Gao CY,et al.The clinical effect of trazodone combined with cognitive behavioral therapy on posttraumatic stress disorder[J].Pharm J Chin PLA(解放军药学学报),2014,30(6):559-560.
[10] Huang YH,Wu GX,Yang GY.Clinical observation of trazodone in the treatment of poststroke depression[J].J Clin Psychiatry Med,2012,22(2):88-89.
[11] Shi XL,DuZY,Xia M,et al.Effects of total flavonoids from albiflora on expression of BDNF and TrkB in hippocampus CA3 of depression model rats[J].Chi J Exp Formul (中国实验方剂学杂志),2013,19(18):198-199.
[12] Peng SQ,Xu XD,Zhao HX.Effects of Four inverse powder on HPA axis,hippocampal BDNF and its receptor TrkB in depression model rats[J].Chin J Exp Formul (中国实验方剂学杂志),2014,20(5):146-147.
[13] Liang HX,Li F,Liu SS,et al.Analysis of the application of antidepressants in a hospital from 2011 to 2013[J].Central South Pharm(中南药学),2014,107(12):1260-1264.
[14] Yi XY,Ni SF,Ghadami MR,et al.Trazodone for the treatment of insomnia:a meta-analysis of randomized placebocontrolled trials[J].Sleep Med,2018,45:25-32.
[15] Liu DH,Cai LQ.A clinical study of trazodone on perimenopause turbid sleep disorder with anxiety and depression[J].J Int Intensive Med (内科急危重症杂志),2016,22(1):28-29.
[16] Li Y.Correlation analysis of serum BDNF content and depression in convalescent stroke patients[J].Chin J Practl Neurological Dis (中国实用神经疾病杂志),2012,15(20):6-8.
[17] Ting S,Yu YY,Chitra J,et al.BDNF Polymorphism:A review of its diagnostic and clinical relevance in neurodegenerative disorders[J] Aging Dis,2018,9(3):523-536.
[18] Jantas D,Krawczyk S,lason W.The predominant protective effect of tianeptine over other antidepressants in models of neuronal apoptosis:the effect blocked by inhibitors of MAPK/ERK1/2 and PI3-K/Akt pathways[J].Neurotoxicity Res,2014,25(2):208-225.
[19] Gupta VK,You Y,Gupta VB,et al.TrkB receptor signalling:implications in neurodegenerative,psychiatric and proliferative disorders[J].Int J Mol Sci,2013,14(5):10122-10142.
[20] Yu B,Shen XC,Liang T,et al.Study on the combination of Borneol on specific brain region[J].Chin Hosp Pharm(中国医院药学杂志),2017,37(18):1792-1796.