缺血再灌注联合慢性不可预知刺激构建卒中后抑郁新模型
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摘要
背景:国内外卒中后抑郁动物模型主要以脑卒中叠加抑郁造模方式构建,但其各种造模方式都有其优缺点,在此基础上对卒中后抑郁造模方式进行新的探讨。目的:采用行为学评估及脑组织神经介质检测,探究一种稳定、可复制的卒中后抑郁造模方式。方法:雄性SD大鼠90只,体质量(200±20)g,由西安交通大学动物实验中心提供。(1)将60只大鼠随机分为3组,行30,60,90min的缺血再灌注,24h后观察大鼠存活率,并行神经功能缺损评分及脑梗死体积的评定,确定最佳缺血再灌注的时间点;(2)另将30只大鼠随机分为假手术组、大脑中动脉栓塞组、卒中后抑郁组,于刺激前及刺激的第1,2,3周进行强迫游泳实验、敞箱实验、糖水消耗实验、新奇抑制摄食实验、体质量变化评价大鼠的抑郁行为;运用ELisa法检测脑组织中的5-羟色胺、去甲肾上腺素及脑源性神经营养因子水平。结果与结论:(1)确定了60 min为后续缺血再灌注的时间点;(2)行为学评估显示,与大脑中动脉栓塞组相比,卒中后抑郁大鼠的体质量、糖水消耗实验和敞箱运动垂直及水平运动得分均于第2周开始降低(P <0.05),新奇抑制摄食实验潜伏时间、强迫游泳实验不动时间出现明显升高(P<0.05);(3)Elisa检测显示,与大脑中动脉栓塞组相比,卒中后抑郁组大鼠的5-羟色胺、去甲肾上腺素及脑源性神经营养因子水平均降低(P <0.05);(4)结果说明,采用60 min的缺血再灌注联合慢性不可预知的刺激,建立卒中后抑郁模型,可表现出明显的抑郁状态,同时,模型稳定、存活率高,符合卒中后抑郁的多种临床特征,可能成为研究卒中后抑郁一种新的、可靠的造模方式。
BACKGROUND: Animal models of post-stroke depression are established by stroke combined with depression induction, and each modeling method has its own advantages and shortcomings. A new modeling method is needed. OBJECTIVE: To explore a stable and replicable model of post-stroke depression through behavioral assessment and brain tissue neurotransmitter detection. METHODS: Ninety male Sprague-Dawley rats weighting(200±20) g provided by Laboratory Animal Center of Xi'an Jiaotong University were enrolled. Sixty rats were randomly divided into three groups and then underwent 30, 60 and 90 minutes of ischemia/reperfusion. The survival rate of rats was observed after 24 hours, and the scores of neurological function deficit and the volume of cerebral infarct were evaluated. The optimal time points of ischemia/reperfusion were determined. The remaining 30 rats were randomly divided into sham, middle cerebral artery occlusion, and post-stroke depression groups. Forced swimming test, open field test, the novelty-suppressed feeding test, sucrose preference test and body mass change were used to evaluate rat depression behaviors before and 1, 2, and 3 weeks after stimulation. The levels of 5-hydroxytryptamine, norepinephrine, and brain-derived neurotrophic factor in brain tissue were detected by ELISA. RESULTS AND CONCLUSION: The optimal time point 60 minutes was determined for subsequent ischemia/reperfusion. Behavioral evaluation showed that compared with the middle cerebral artery occlusion group, body mass, sucrose preference test and the vertical and horizontal movement scores of the open field test began to decrease at 2 weeks in the post-stroke depression group(P < 0.05). The latency of the novelty-suppressed feeding and the time of forced swimming test were significantly increased(P < 0.05). The results of ELISA showed that 5-hydroxytryptamine, norepinephrine, and brain-derived neurotrophic factor levels in the post-stroke depression group were significantly lower than those in the middle cerebral artery occlusion group(P < 0.05). Our findings imply that the post-stroke depression model can be established by 60-minute ischemia/reperfusion combined with chronic unpredictable mild stress. The models are stable, have a high survival rate and many clinical characteristics of post-stroke depression. It may become a new and reliable model for the study of post-stroke depression.
BACKGROUND: Animal models of post-stroke depression are established by stroke combined with depression induction, and each modeling method has its own advantages and shortcomings. A new modeling method is needed. OBJECTIVE: To explore a stable and replicable model of post-stroke depression through behavioral assessment and brain tissue neurotransmitter detection. METHODS: Ninety male Sprague-Dawley rats weighting(200±20) g provided by Laboratory Animal Center of Xi'an Jiaotong University were enrolled. Sixty rats were randomly divided into three groups and then underwent 30, 60 and 90 minutes of ischemia/reperfusion. The survival rate of rats was observed after 24 hours, and the scores of neurological function deficit and the volume of cerebral infarct were evaluated. The optimal time points of ischemia/reperfusion were determined. The remaining 30 rats were randomly divided into sham, middle cerebral artery occlusion, and post-stroke depression groups. Forced swimming test, open field test, the novelty-suppressed feeding test, sucrose preference test and body mass change were used to evaluate rat depression behaviors before and 1, 2, and 3 weeks after stimulation. The levels of 5-hydroxytryptamine, norepinephrine, and brain-derived neurotrophic factor in brain tissue were detected by ELISA. RESULTS AND CONCLUSION: The optimal time point 60 minutes was determined for subsequent ischemia/reperfusion. Behavioral evaluation showed that compared with the middle cerebral artery occlusion group, body mass, sucrose preference test and the vertical and horizontal movement scores of the open field test began to decrease at 2 weeks in the post-stroke depression group(P < 0.05). The latency of the novelty-suppressed feeding and the time of forced swimming test were significantly increased(P < 0.05). The results of ELISA showed that 5-hydroxytryptamine, norepinephrine, and brain-derived neurotrophic factor levels in the post-stroke depression group were significantly lower than those in the middle cerebral artery occlusion group(P < 0.05). Our findings imply that the post-stroke depression model can be established by 60-minute ischemia/reperfusion combined with chronic unpredictable mild stress. The models are stable, have a high survival rate and many clinical characteristics of post-stroke depression. It may become a new and reliable model for the study of post-stroke depression.
引文
[1]Wei C,Zhang F,Chen L,et al.Factors associated with post-stroke depression and fatigue:lesion location and coping styles.J Neurol.2016;263(2):269-276.
[2]Howells DW,Porritt MJ,Rewell SS,et al.Different strokes for different folks:the rich diversity of animal models of focal cerebral ischemia.J Cereb Blood Flow Metab.2010;30(8):1412-1431.
[3]Sehara Y,Inaba T,Urabe T,et al.Survivin Overexpression via Adeno-Associated Virus Vector Rh10 Ameliorates Ischemic Damage after Middle Cerebral Artery Occlusion in Rats.Eur JNeurosci.2018 Sep 25.
[4]Yan Y,Fan W,Liu L,et al.The effects of Xingnao Jieyu capsules on post-stroke depression are similar to those of fluoxetine.Neural Regen Res.2013;(19):1765-1772.
[5]Yan Y,Li T,Liu L,et al.Effect of tonifying liver and kidney-essence herbs on expression of Nogo-A and p75(NTR)in cerebral ischemic stroke rats model.J Tradit Chin Med.2012;32(4):664-668.
[6]范文涛,闫咏梅,别玉龙,等.脑卒中后抑郁症患者肠道菌群的多样性分析[J].南方医科大学学报,2016,36(10):1305-1311.
[7]范文涛,闫咏梅,别玉龙,等.大鼠卒中后肠道菌群紊乱与抑郁的关系[J].中国脑血管病杂志,2016(12):644-649.
[8]张慧,闫咏梅,谢福恒,等.醒脑解郁胶囊干预卒中后抑郁及与NEI网络关系的临床研究[J].现代中医药,2016;36(4):46-48.
[9]Longa EZ,Weinstein PR,Carlson S,et al.Reversible middle cerebral artery occlusion without craniectomy in rats.Stroke.1989;20(1):84-91.
[10]Qi X,Hosoi T,Okuma Y,et al.Sodium 4-phenylbutyrate protects against cerebral ischemic injury.Mol Pharmacol.2004;66(4):899-908.
[11]常晓波,王舒,樊小农,等.脑梗死大鼠模型神经功能缺损评分的动态变化分析[J].中华中医药杂志,2015,30(11):4053-4056.
[12]Willner P,Towell A,Sampson D,et al.Reduction of sucrose preference by chronic unpredictable mild stress,and its restoration by a tricyclic antidepressant.Psychopharmacology(Berl).1987;93(3):358-364.
[13]Gaur V,Kumar A.Behavioral,biochemical and cellular correlates in the protective effect of sertraline against transient global ischemia induced behavioral despair:possible involvement of nitric oxide-cyclic guanosine monophosphate study pathway.Brain Res Bull.2010;82(1-2):57-64.
[14]Yan B,Wang DY,Xing DM,et al.The antidepressant effect of ethanol extract of radix puerariae in mice exposed to cerebral ischemia reperfusion.Pharmacol Biochem Behav.2004;78(2):319-325.
[15]Zhang G,Chen L,Yang L,et al.Combined use of spatial restraint stress and middle cerebral artery occlusion is a novel model of post-stroke depression in mice.Sci Rep.2015;5:16751.
[16]Luo L,Deng S,Yi J,et al.Buyang Huanwu Decoction Ameliorates Poststroke Depression via Promoting Neurotrophic Pathway Mediated Neuroprotection and Neurogenesis.Evid Based Complement Alternat Med.2017;2017:4072658.
[17]de Oliveira GS,Cereser KM,Fernandes BS,et al.Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients.J Psychiatr Res.2009;43(14):1171-1174.
[18]Pinnock SB,Herbert J.Brain-derived neurotropic factor and neurogenesis in the adult rat dentate gyrus:interactions with corticosterone.Eur J Neurosci.2008;27(10):2493-2500.
[19]Boyko M,Kutz R,Gruenbaum BF,et al.The influence of aging on poststroke depression using a rat model via middle cerebral artery occlusion.Cogn Affect Behav Neurosci.2013;13(4):847-859.
[20]Ji XW,Wu CL,Wang XC,et al.Monoamine neurotransmitters and fibroblast growth factor-2 in the brains of rats with post-stroke depression.Exp Ther Med.2014;8(1):159-164.
[21]Yan HC,Cao X,Das M,et al.Behavioral animal models of depression.Neurosci Bull.2010;26(4):327-337.
[22]Abelaira HM,Reus GZ,Quevedo J.Animal models as tools to study the pathophysiology of depression.Rev Bras Psiquiatr.2013;35 Suppl 2:S112-S120.
[23]Nestler EJ,Hyman SE.Animal models of neuropsychiatric disorders.Nat Neurosci.2010;13(10):1161-1169.
[24]Astrom M,Adolfsson R,Asplund K.Major depression in stroke patients.A 3-year longitudinal study.Stroke.1993;24(7):976-982.
[25]Ren L,Qian X,Zhai L,et al.Loss of Ahi1 impairs neurotransmitter release and causes depressive behaviors in mice.PLoS One.2014;9(4):e93640.
[26]Lin R,Li X,Liu W,et al.Electro-acupuncture ameliorates cognitive impairment via improvement of brain-derived neurotropic factor-mediated hippocampal synaptic plasticity in cerebral ischemia-reperfusion injured rats.Exp Ther Med.2017;14(3):2373-2379
[2]Howells DW,Porritt MJ,Rewell SS,et al.Different strokes for different folks:the rich diversity of animal models of focal cerebral ischemia.J Cereb Blood Flow Metab.2010;30(8):1412-1431.
[3]Sehara Y,Inaba T,Urabe T,et al.Survivin Overexpression via Adeno-Associated Virus Vector Rh10 Ameliorates Ischemic Damage after Middle Cerebral Artery Occlusion in Rats.Eur JNeurosci.2018 Sep 25.
[4]Yan Y,Fan W,Liu L,et al.The effects of Xingnao Jieyu capsules on post-stroke depression are similar to those of fluoxetine.Neural Regen Res.2013;(19):1765-1772.
[5]Yan Y,Li T,Liu L,et al.Effect of tonifying liver and kidney-essence herbs on expression of Nogo-A and p75(NTR)in cerebral ischemic stroke rats model.J Tradit Chin Med.2012;32(4):664-668.
[6]范文涛,闫咏梅,别玉龙,等.脑卒中后抑郁症患者肠道菌群的多样性分析[J].南方医科大学学报,2016,36(10):1305-1311.
[7]范文涛,闫咏梅,别玉龙,等.大鼠卒中后肠道菌群紊乱与抑郁的关系[J].中国脑血管病杂志,2016(12):644-649.
[8]张慧,闫咏梅,谢福恒,等.醒脑解郁胶囊干预卒中后抑郁及与NEI网络关系的临床研究[J].现代中医药,2016;36(4):46-48.
[9]Longa EZ,Weinstein PR,Carlson S,et al.Reversible middle cerebral artery occlusion without craniectomy in rats.Stroke.1989;20(1):84-91.
[10]Qi X,Hosoi T,Okuma Y,et al.Sodium 4-phenylbutyrate protects against cerebral ischemic injury.Mol Pharmacol.2004;66(4):899-908.
[11]常晓波,王舒,樊小农,等.脑梗死大鼠模型神经功能缺损评分的动态变化分析[J].中华中医药杂志,2015,30(11):4053-4056.
[12]Willner P,Towell A,Sampson D,et al.Reduction of sucrose preference by chronic unpredictable mild stress,and its restoration by a tricyclic antidepressant.Psychopharmacology(Berl).1987;93(3):358-364.
[13]Gaur V,Kumar A.Behavioral,biochemical and cellular correlates in the protective effect of sertraline against transient global ischemia induced behavioral despair:possible involvement of nitric oxide-cyclic guanosine monophosphate study pathway.Brain Res Bull.2010;82(1-2):57-64.
[14]Yan B,Wang DY,Xing DM,et al.The antidepressant effect of ethanol extract of radix puerariae in mice exposed to cerebral ischemia reperfusion.Pharmacol Biochem Behav.2004;78(2):319-325.
[15]Zhang G,Chen L,Yang L,et al.Combined use of spatial restraint stress and middle cerebral artery occlusion is a novel model of post-stroke depression in mice.Sci Rep.2015;5:16751.
[16]Luo L,Deng S,Yi J,et al.Buyang Huanwu Decoction Ameliorates Poststroke Depression via Promoting Neurotrophic Pathway Mediated Neuroprotection and Neurogenesis.Evid Based Complement Alternat Med.2017;2017:4072658.
[17]de Oliveira GS,Cereser KM,Fernandes BS,et al.Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients.J Psychiatr Res.2009;43(14):1171-1174.
[18]Pinnock SB,Herbert J.Brain-derived neurotropic factor and neurogenesis in the adult rat dentate gyrus:interactions with corticosterone.Eur J Neurosci.2008;27(10):2493-2500.
[19]Boyko M,Kutz R,Gruenbaum BF,et al.The influence of aging on poststroke depression using a rat model via middle cerebral artery occlusion.Cogn Affect Behav Neurosci.2013;13(4):847-859.
[20]Ji XW,Wu CL,Wang XC,et al.Monoamine neurotransmitters and fibroblast growth factor-2 in the brains of rats with post-stroke depression.Exp Ther Med.2014;8(1):159-164.
[21]Yan HC,Cao X,Das M,et al.Behavioral animal models of depression.Neurosci Bull.2010;26(4):327-337.
[22]Abelaira HM,Reus GZ,Quevedo J.Animal models as tools to study the pathophysiology of depression.Rev Bras Psiquiatr.2013;35 Suppl 2:S112-S120.
[23]Nestler EJ,Hyman SE.Animal models of neuropsychiatric disorders.Nat Neurosci.2010;13(10):1161-1169.
[24]Astrom M,Adolfsson R,Asplund K.Major depression in stroke patients.A 3-year longitudinal study.Stroke.1993;24(7):976-982.
[25]Ren L,Qian X,Zhai L,et al.Loss of Ahi1 impairs neurotransmitter release and causes depressive behaviors in mice.PLoS One.2014;9(4):e93640.
[26]Lin R,Li X,Liu W,et al.Electro-acupuncture ameliorates cognitive impairment via improvement of brain-derived neurotropic factor-mediated hippocampal synaptic plasticity in cerebral ischemia-reperfusion injured rats.Exp Ther Med.2017;14(3):2373-2379