“益气调血、扶本培元”药线灸对多发梗死性痴呆大鼠海马乙酰胆碱、乙酰胆碱酯酶、胆碱乙酰转移酶含量的影响

目的观察"益气调血、扶本培元"药线灸对多发梗死性痴呆(MID)大鼠海马乙酰胆碱(ACh)、乙酰胆碱酯酶(AChE)、胆碱乙酰转移酶(ChAT)含量的影响。方法 100只雄性大鼠经MID造模、痴呆筛选后,随机分为正常组、模型组、假手术组、药线灸组、药物组和药线非穴组6组,各组10只;药线灸组予壮医药线点灸治疗,药物组给予多奈哌齐口服治疗,药线非穴组给予针刺两肋下非穴点治疗,余3组未给予特别治疗。经4 w干预后处死动物,分离海马,匀浆、分离上清,检测ACh、AChE与ChAT含量。结果模型组ACh、ChAT含量较正常组显著降低,AChE含量显著升高(P<0.05);药线穴组与模型组ACh、AChE无统计学差异(P>0.05),药线灸组能显著升高ACh、ChAT和降低AChE含量,而药物组只显著升高ACh和降低AChE含量(P<0.05);药物组与药线灸组比较无差异(P>0.05)。结论 "益气调血、扶本培元"药线灸可以全面改善MID大鼠海马ACh代谢障碍,且较多奈哌齐有疗效优势。     

不同年龄组抑郁症模型大鼠脑乙酰胆碱酯酶及乙酰胆碱转移酶活性的变化

目的从生化和形态两个方面探讨不同年龄组抑郁症模型大鼠脑乙酰胆碱酯酶及乙酰胆碱转移酶活性的变化。方法 Sprague-Dawley雄性大鼠,按照年龄分为幼年、成年和中年组共3组,每组20只。采用慢性轻度不可预见性应激刺激(chronic mild unp redictable stress,CMUS)与孤养相结合的方法建立抑郁症动物模型,运用敞箱实验(Open-Field)与糖水消耗量评定大鼠行为学改变,用比色法和免疫组化法测量大鼠大脑皮层、海马区乙酰胆碱转移酶(Choline acetyltransferase,ChAT)与乙酰胆碱酯酶(Acetylcholinesterase,AChE)活性,并用电镜观察大鼠脑海马CA3区超微结构变化。结果造模21 d后,与对照组相比,模型组水平运动得分、垂直运动得分、体重和糖水偏爱度明显降低(P<0.05);与对照组比较,模型组大鼠ChAT与AChE活性均升高(P<0.05);与幼年模型组、成年模型组相比,中年模型组两个酶活性均升高(P<0.05),与幼年模型组相比,成年模型组两个酶活性均升高(P<0.05)。电镜观察结果显示,海马凋亡细胞主要集中在幼年、成年和中年模型组。结论抑郁症模型ChAT与AChE活性升高,并且随着年龄的增长升高尤为显著,胆碱能神经系统与抑郁症发生发展有密切关系。     

不可预见刺激对大鼠行为学及HPA轴功能的影响

目的 探讨慢性轻度不可预见刺激(CUMS)对大鼠行为学和下丘脑-垂体-肾上腺皮质(HPA)轴功能的影响及其机制.方法 20只SD雄性大鼠随机分为正常对照组与模型组.模型组大鼠给予孤养加慢性轻度不可预见性刺激,用糖水消耗实验和高架十字迷宫检测大鼠行为学改变;试剂盒测定血清丙二醛(MDA)水平与超氧化物歧化酶(SOD)活性,以观察机体氧化应激能力改变;放射免疫法分析地塞米松抑制实验中血清皮质酮(corticosterone,CORT)浓度;免疫组化SP法检测下丘脑促肾上腺皮质激素释放因子(corticotrophin-releasing factor,CRF)表达变化.结果 与正常对照组相比,模型组大鼠糖水消耗量明显下降,在高架迷宫开放臂内的活动及停留时间亦明显减少,血清MDA水平增加,SOD活力减弱,CORT水平显著升高,下丘脑CRF表达明显增强.结论 CUMS致大鼠产生抑郁行为,其发生机制至少部分与体内自由基水平升高及HPA轴功能受损有关.     

血管性认知功能障碍大鼠胆碱酯酶及胆碱乙酰化酶的表达

目的观察乙酰胆碱酯酶(AChE)和胆碱乙酰化酶(ChAT)在血管性认知障碍(VCI)大鼠脑内表达的变化。方法采用四血管法复制大鼠轻度认知功能障碍模型,并使用Morris水迷宫检测假手术组和造模2 w,1个月,3个月模型鼠的学习和记忆功能,对假手术组和造模2 w,1个月,3个月模型鼠脑内神经元的变化用苏木素-伊红(HE)染色和尼氏染色进行鉴定,然后用酶标仪测定大鼠血浆和海马AChE、ChAT酶活性,Western印迹检测大鼠大脑皮层AChE及ChAT蛋白的表达变化,免疫组织化学检测大鼠大脑皮层不同的区域AChE及ChAT的表达变化。结果在造模2 w模型鼠中未出现明显学习记忆障碍,1个月后出现记忆障碍和学习障碍,模型建立后1～3个月痴呆状况仍然持续并有下降趋势,且出现相应的神经细胞损伤及尼氏小体的丢失。与假手术组比较,模型组血浆中AChE酶活性下降,ChAT则相反。模型组脑内AChE蛋白表达增加,ChAT蛋白的表达减少;通过免疫组化结果显示,随着造模时间的延长,AChE的表达逐渐增加,ChAT则呈现逐渐减少趋势。结论持续的脑缺血、缺氧即可导致大鼠海马及血AChE表达升高,ChAT表达下降,且随着缺血时间的延长,这些改变更为明显,据此可初步认为胆碱能神经系统的改变与VCI发生发展密切相关。     

不同年龄组大鼠抑郁症模型评价

目的 观察年龄对抑郁模型大鼠行为及生化方面的影响.方法 选取SD雄性大鼠,按照年龄分为幼年、成年和中年,采用慢性轻度不可预见性应激刺激与孤养相结合的方法 建立抑郁症动物模型,运用开野法(Open-Field)与糖水消耗量评定大鼠行为学改变,用比色法测量大鼠海马区单胺氧化酶(monoamine oxidase,MAO)活性,用酶联免疫吸附法检测血清促肾上腺皮质激素释放激素(CRH)、促肾上腺皮质激素(ACTH)、皮质酮(CORT)含量.结果 与对照组相比,各组模型组糖水消耗量与OpeIl-Field得分均下降(P<0.05),成年抑郁组比幼年抑郁组均下降(P<0.05),中年抑郁组比成年抑郁组均下降(P<0.05);MAO活性与CRH、ACTH、CORT含量,模型组比对照组均升高(P<0.05),中年抑郁组比幼年抑郁组、成年抑郁组均升高(P<0.05),成年抑郁组与幼年抑郁组没有显著性变化(P>0.05).结论 刺激强度相等条件下,年龄的增长与抑部模型大鼠行为学指标呈负相关,与生化指标呈正相关.     

芬戈莫德对抑郁大鼠行为学及单胺类神经递质的影响

目的 观察芬戈莫德(FTY720)对抑郁大鼠行为学及单胺类神经递质的影响并探索其作用机制。方法 50只SD大鼠依照随机对照方法分为对照(Con)组、慢性不可预见的温和性应激(CUMS)组及FTY720低、中、高剂量(FTY-L、M、H)组(分别给予0.5、1.0、2.0 mg/kg FTY720)。采取CUMS建立抑郁模型。记录大鼠每周体质量，运用敞箱实验和糖水消耗实验评估大鼠抑郁症状；苏木素-伊红(HE)染色观察大鼠海马组织形态；Western印迹法检测大鼠海马组织中多巴胺(DA)、血清5-羟色胺(HT)和去甲肾腺素(NE)的表达水平；酶联免疫吸附试验(ELISA)检测大鼠血清中白细胞介素(IL)-1β、IL-6和肿瘤坏死因子(TNF)-α的含量。结果 与Con组相比，CUMS组体质量、敞箱实验得分及糖水消耗比例显著减低(P<0.05),HE染色显示海马组织CA1区呈现神经元萎缩、变性现象，大鼠海马组织中DA、5-HT及NE含量明显下降(P<0.05),血清TNF-α、IL-1β和IL-6水平均明显上升(P<0.05);与CUMS组相比，FTY-M和FTY-H组体质...     

氯沙坦对慢性不可预知温和应激模型大鼠的抗抑郁作用

目的探讨氯沙坦（Los）对慢性不可预知温和应激（CUMS）模型大鼠抑郁行为的影响,对其抗炎和抗氧化作用进行考察,探究其潜在的抗抑郁机制。 方法将24只SD大鼠随机分为4组：对照组（Control）、氯沙坦组（Los）、抑郁组（CUMS）、抑郁+氯沙坦组（CUMS+ Los）,每组6只。Los组、CUMS+Los组每天灌胃10 mg/kg的Los溶液,Control组和CUMS组每日灌胃等体积的生理盐水,连续8周。采用糖水偏好实验、强迫游泳实验和高架十字迷宫实验评估大鼠抑郁样行为。酶联免疫吸附法检测大鼠海马的血管紧张素Ⅱ（Ang Ⅱ）的含量。荧光定量PCR检测血管紧张素Ⅱ1型受体（AT1R）和炎性因子白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α）的表达量。分光光度法检测海马的超氧化物歧化酶（SOD）活性及丙二醛（MDA）含量。 结果Los组较Control组糖水的消耗量、进入开放臂的时间、进入开放臂次数以及比率、强迫游泳不动时间、Ang Ⅱ含量、AT1R、IL-6、TNF-α表达量、SOD活性、MDA含量差异均无统计学意义（P>0.05）。CUMS组较Control组糖水的消耗量、进入开放臂的时间、进入开放臂次数以及比率、SOD活性显著降低,强迫游泳不动时间、Ang Ⅱ含量和AT1R、IL-6、TNF-α表达量及MDA含量显著升高,差异具有统计学意义（P<0.05）。CUMS+Los组较CUMS组糖水的消耗量、进入开放臂的时间、进入开放臂次数以及比率、SOD活性均升高,而强迫游泳不动时间、Ang Ⅱ含量和AT1R、IL-6、TNF-α表达量及MDA含量均降低,差异均具有统计学意义（P<0.05）。 结论Los能明显改善CUMS所致的大鼠抑郁样行为,降低炎症反应、减轻氧化损伤降低,且该作用与脑内肾素-血管紧张素系统有关,为抗抑郁的靶向治疗提供了新的方向。     

通经补肾复方对铝诱导阿尔茨海默病模型大鼠海马乙酰胆碱酯酶、胆碱乙酰转移酶、乙酰胆碱的影响

目的 观察通经补肾中药方对铝诱导的AD模型大鼠海马组织中乙酰胆碱酯酶(AchE)和胆碱乙酰转移酶(ChAT)活性及乙酰胆碱(Ach)含量变化.方法 选择健康3月龄SD大鼠84只,随机分为对照组、模型组(分为低、中、高剂量铝饲料组)、中药组(分为低、中、高剂量中药组),每组各12只.模型组在常规饲料中添加不同剂量A1C13·6H20喂饲大鼠,持续染毒3个月,制作AD动物模型.中药组大鼠喂饲含铝饲料,并以通经补肾中药方灌胃.上述实验结束后,处死大鼠,取海马组织,测定海马中的AchE和ChAT的活性及Ach含量.结果 与对照组比较,中、高剂量铝饲料组大鼠海马中AchE的活性明显增高(P＜0.01),ChAT活性明显降低(P＜0.01),Ach含量显著减少(P＜0.01).与高剂量铝饲料组比较,中、高剂量中药组大鼠海马中AchE活性明显降低(P＜0.01),ChAT活性明显升高(P＜0.01),Ach含量明显增加(P＜0.01).结论 铝的过多摄入使大鼠海马Ach减少可能是AD发病的机制之一,中药方可提高海马中ChAT活性,抑制AchE活性,增加Ach的含量,改善大鼠中枢胆碱能系统失衡状况.     

雌激素对抑郁大鼠海马单胺类神经递质含量的影响及缰核在其中的作用

目的 探讨雌激素对抑郁大鼠海马内单胺类递质含量的调节以及缰核在其中的作用.方法 雌性Wistar大鼠随机被分成6组:正常对照组( Control)、抑郁模型组(Depression)、假手术组(SHAM)、去卵巢组(OVX)、雌二醇组(OV/ER)、缰核损毁组(Hb lesion).用高效液相色谱法( HPLC)检测各组海马内5-羟色胺(5-HT)、去甲肾上腺素(NE)、多巴胺(DA)递质的含量.结果 OVX组大鼠海马内5-HT、NE和DA含量与SHAM组大鼠相比降低,OV/ER组大鼠海马内5-HT、NE和DA含量与OVX组大鼠相比均显著回升.Depression组大鼠海马内5-HT、NE和DA含量与Control组相比明显降低;抑郁大鼠外侧缰核损毁后,海马内的5-HT、NE和DA含量均升高.结论 缰核可以通过对海马功能的影响介导雌激素改善抑郁行为的作用.     

柴胡疏肝散对抑郁症模型大鼠海马单胺氧化酶与乙酰胆碱酯酶活性的影响

目的 观察柴胡疏肝散对大鼠大脑海马乙酰胆碱酯酶(AChE)与单胺氧化酶(MAO)活性的影响.方法 选取60只4～5月龄的SD大鼠随机分为正常组、模型组、氟西汀组和中药组,共4组,每组15只.利用孤养结合慢性轻度不可预见性应激刺激制造抑郁症模型.21 d后,采用敞箱实验、糖水消耗量检测和体重检测等指标评定大鼠行为学改变,并用免疫组织化学染色法观察大鼠大脑海马区AChE的蛋白表达变化,利用比色法检测大鼠大脑海马区MAO活性.结果 与正常组相比,模型组水平运动得分、垂直运动得分、体重和糖水偏爱度均明显降低(P<0.01),与模型组比较,氟西汀组和中药组水平运动得分、垂直运动得分、糖水偏爱度与体重均明显升高(P<0.05～0.001);免疫组化结果显示,与正常组相比,模型组海马区AChE的蛋白表达均明显升高(P<0.05),与模型组相比,氟西汀组和中药组大鼠海马区AChE的蛋白表达均明显降低(P<0.05);比色法结果显示,与正常组相比,模型组海马区MAO活性明显升高(P<0.05),与模型组相比,氟西汀组、中药组海马区MAO活性明显下降(P<0.05).结论 柴胡疏肝散抗抑郁症的作用可能与其降低大脑组织海马区AChE蛋白表达和MAO活性有关.     

Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior

Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety- and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety- and depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety- and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.     

运动对慢性应激所致抑郁样老年大鼠行为异常及神经内分泌的影响

目的探讨运动对慢性不可预见温和应激(CUMS)抑郁老年大鼠行为学及血清皮质醇和促肾上腺皮质激素(ACTH)浓度的影响。方法 50只雄性老年SD大鼠随机分为对照组、CUMS组、低强度跑台运动训练(LITT)组、中等强度跑台运动训练(MITT)组、高强度跑台运动训练(HITT)组。采用CUMS加孤养复制老年大鼠抑郁模型。采用旷场实验得分和强迫游泳实验评价各组大鼠行为学改变,分别采用ELISA和放射免疫方法检测血清皮质醇、ACTH浓度。结果与对照组比较,CUMS组大鼠血清皮质醇和ACTH浓度增高(P<0.01);与CUMS组比较,LITT组、MITT组和HITT组大鼠水平运动和垂直运动增多、清理次数增加,中央格停留时间缩短,血清皮质醇和ACTH浓度降低(P<0.05,P<0.01)。结论 CUMS可使老年大鼠行为及内分泌发生异常改变,引起抑郁;适度的运动可调节CUMS引起的下丘脑-垂体-肾上腺轴功能亢进,具有抗抑郁及降低抑郁程度的作用。     

Protective effect of recombinant human somatotropin on amyloid beta-peptide induced learning and memory deficits in mice.

This study aimed to examine the effects of the recombinant human somatotropin (rhGH) on protecting neuronal function, and improving learning and memory deficits in mice. Mice were intracerebroventricularly (icv) injected with the aggregated amyloid beta-peptide (Abeta) to mimic the Alzheimer's disease (AD). The learning and memory functions in mice were examined by the step through test (an index of long-term memory) and the water maze performance (an index of spatial recognition memory). The results indicated that the mice treated with rhGH showed significant reduction of the error counts and the long memory retentions in the step-through test, and short swimming times in the water maze performance. Toxic effects of free radicals, damages of cholinergic neurons, and increased lipid peroxidation appeared in the cerebra of Abeta-treated mice, manifesting an increase of malondialdehyde (MDA) and decline of glutathione (GSH) level, an increment of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities, and a reduction of the acetylcholine (ACh) level. The gel electrophoresis pattern of the cerebra of mice treated with Abeta showed a typical DNA ladder of apoptosis. The in vivo experiments showed that the rhGH treatment significantly reversed the elevated MDA, ChAT, AChE, and the decreased GSH, ACh levels in the Abeta model mice. The results suggested that there were potential uses of the neuroprotective action of rhGH in the remedy of AD.     

Investigations of the cholinergic deficit hypothesis in the hippocampus of the aged rat brain with physostigmine and scopolamine

Using histochemically demonstrated acetylcholinesterase activity and (14)C-2-deoxyglucose uptake as the respective indices, a study was set up to determine whether cerebral (hippocampal) metabolism was stimulated by a cholinergic agonist and/or inhibited by a cholinergic antagonist. For this 36 12-month-old (adult) and 48 27-month-old (aged) Fischer 344 rats were given intraperitoneal injections of physostigmine 0.05, 0.1 or 0.2 mg/kg or scopolamine 0.01, 0.03 or 0.1 mg/kg for 5 days. In the aged rats there was a slight increase in acetylcholinesterase activity after physostigmine but no convincing evidence of enhanced (14)C-2-deoxyglucose uptake. In neither age group was glucose uptake significantly reduced by scopolamine; it was in fact increased, as was - slightly but significantly - acetylcholinesterase activity. Findings for acetylcholinesterase activity and (14)C-2-deoxyglucose uptake in aged Fischer 344 rats thus do not provide firm corroboration of physostigmine-induced stimulation of mental performance found in behavioural studies, while scopolamine did not adversely affect the hippocampal variables studied. It is concluded that cholinergic agents such as physostigmine and scopolamine have only a marginal effect on the functional and metabolic deficits associated with cerebral aging.     

Effect of treatment with the cholinesterase inhibitor rivastigmine on vesicular acetylcholine transporter and choline acetyltransferase in rat brain

A decline of cholinergic neurotransmission probably contributes to cognitive dysfunction occurring in Alzheimer's disease (AD) and vascular dementia (VaD). Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors are the only drugs authorized for symptomatic treatment of AD and are also under investigation for VaD. The present study has investigated the influence of two doses of the AChE inhibitor rivastigmine (0.625 mg/Kg/day and 2.5 mg/Kg/day) on vesicular acetylcholine transporter (VAChT) and on choline acetyltransferase (ChAT) expression in frontal cortex, hippocampus, striatum and cerebellum of normotensive and spontaneously hypertensive rats (SHR). Cholinergic markers were assessed by immunochemical (Western blotting) and immunohistochemical techniques. In frontal cortex and striatum of normotensive rats, treatment with the lower dose (0.625 mg/Kg/day) of rivastigmine had no effect on VAChT immunoreactivity and increased slightly ChAT protein immunoreactivity. The higher dose (2.5 mg/Kg/day) of the compound increased significantly VAChT and ChAT protein immunoreactivity. In hippocampus rivastigmine induced a concentration-dependent increase of VAChT protein expression and no significant changes of ChAT protein expression. A similar pattern of VAChT and ChAT protein expression was observed in control SHR, whereas treatment of SHR with rivastigmine induced a more pronounced increase of VAChT protein immunoreactivity in frontal cortex, hippocampus and striatum compared to normotensive rats. Our data showing an increase of VAChT after treatment with rivastgmine further support the notion of an enhancement of cholinergic neurotransmission by AChE/ChE inhibitors. The observation of a greater expression of this cholinergic marker in SHR suggest that AChE inhibition may provide beneficial effects on cholinergic neurotransmission in an animal model of VaD.     

尼麦角林通过调节海马 CA1区单胺类递质受体表达和血清载脂蛋白 E4水平改善血管性抑郁大鼠的抑郁行为

目的：探讨尼麦角林对血管性抑郁（vascular depression,VD）模型大鼠海马CA1区5-羟色胺1A受体（5-hydroxytryptamine 1A receptor,5-HT1A R）、多巴胺 D2受体（ D2 dopamine receptor, D2DR）、肾上腺素能α2A受体（α2A-adrenergic receptor,α2AAR）表达和血清载脂蛋白（apolipoprotein E4, ApoE4）水平的影响。方法48只雄性Sprague-Daw ley 大鼠随机分为正常对照组、模型组、氟西汀组以及尼麦角林小量组、中剂量组和大剂量组,每组8只。采用双侧颈总动脉结扎叠加慢性不可预见性温和应激（chronic unpredictable mild stress, CUMS ）加孤养建立VD模型。正常对照组不CUMS也不孤养,模型组CUMS 并孤养。氟西汀组在开始CUMS和孤养时给予氟西汀1.3 mg/（kg· d）灌胃,共3周;尼麦角林小剂量、中剂量和大剂量组在开始CUMS 和孤养时分别给予尼麦角林0.9、1.9和3.8 mg/（kg· d）灌胃,共3周;正常对照组和模型组等体积蒸馏水灌胃,1次/d,共3周。蔗糖溶液消耗和旷野试验评价抑郁样行为,免疫组化染色法和蛋白印迹法检测海马CA1区5-HT1AR、D2DR、α2AAR表达,酶联免疫法检测血清ApoE4水平。结果 CUMS 前,模型组、氟西汀组和各尼麦角林组水平运动和垂直运动评分、蔗糖溶液消耗均较正常对照组显著降低（P均＜0.01）;而CUMS 后21 d,氟西汀组和尼麦角林中剂量和大剂量组均显著高于模型组（P均＜0.05）,氟西汀组以及各尼麦角林组之间无统计学差异。模型组、氟西汀组和各尼麦角林组5-HT 1A R、D2 DR、α2A AR表达和血清ApoE4水平均显著高于正常对照组,氟西汀组、尼麦角林中剂量和大剂量组均显著低于模型组（P均<0.01）,而氟西汀组以及各尼麦角林组无统计学差异。结论尼麦角林可改善VD大鼠抑郁样行为,其机制可能与下调海马CA1区5-HT1AR、D2DR、α2AAR表达和血清ApoE4水平有关。     

艾司西酞普兰通过降低血清白细胞介素-18水平减轻大鼠卒中后抑郁

目的探讨艾司西酞普兰对卒中后抑郁（post—stroke depression,PSD）模型大鼠血清促炎细胞因子白细胞介素-6（Interleukin-6,IL-6）、肿瘤坏死因子-α（tumor necrosis factor-α,TNF-α）和IL-18水平的影响。方法24只雄性Sprague—Dawley大鼠随机分为假手术组、大脑中动脉闭塞（middlecerebralarteryocclusion,MCAO）组、PSD组和艾司西酞普兰组,每组6只。采用线栓法建立大鼠大脑中动脉闭塞（middle cerebral artery occlusion,MCAO）模型,并在此基础上结合慢性不可预见性温和应激（chronicunpredictablemildstress,CUMS）加孤养建立PSD模型。假手术组和MCAO组不CUMS也不孤养,PSD组CUMS并孤养,艾司西酞普兰组在开始CUMS和孤养时给予艾司西酞普兰干预[10mg／（kg·d）,腹腔注射,共3周]。在基线以及CUMS后7、14和21d利用蔗糖溶液消耗和旷野试验进行抑郁样行为学评估。应用酶联免疫吸附法检测CUMS后22d时血清促炎细胞因子IL-6、TNF—α和IL-18水平。结果CUMS后21d时,PSD组体重、蔗糖溶液消耗、垂直运动得分和水平运动距离均较假手术组和MCAO组显著性降低和缩短（P均〈0．01）,艾司西酞普兰组体重、蔗糖溶液消耗和水平运动距离均较PSD组显著性增加（P〈0．05或P〈0．01）。CUMS后22d时,PSD组血清IL-18水平较假手术组和MCAO组显著性升高（P〈0．05或P〈0．01）,艾司西酞普兰组血清IL-18水平较PSD组显著性降低（P〈0．05）,但各组间IL-6和TNF-α水平均无显著性差异。相关分析显示,CUMS后22d时,血清1L-18水平与蔗糖溶液消耗（r=-0．415,P=0．044）、旷野试验中水平运动距离（r=-0．508,P=0．011）均呈显著负相关,但与垂直运动得分（r=-0．390,P=0．059）和体重无显著相关性（r=-0．216,P=0．311）。结论PSD模型大鼠血清IL-18水平显著性升高,艾司西酞普兰能显著性降低PSD大鼠血清IL-18水平并改善抑郁样行为,提示IL-18可能在PSD的发病机制中起-定的作用。     

Effect of Treatment with the Cholinesterase Inhibitor Rivastigmine on Vesicular Acetylcholine Transporter and Choline Acetyltransferase in Rat Brain

A decline of cholinergic neurotransmission probably contributes to cognitive dysfunction occurring in Alzheimer's disease (AD) and vascular dementia (VaD). Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors are the only drugs authorized for symptomatic treatment of AD and are also under investigation for VaD. The present study has investigated the influence of two doses of the AChE inhibitor rivastigmine (0.625 mg/Kg/day and 2.5 mg/Kg/day) on vesicular acetylcholine transporter (VAChT) and on choline acetyltransferase (ChAT) expression in frontal cortex, hippocampus, striatum and cerebellum of normotensive and spontaneously hypertensive rats (SHR). Cholinergic markers were assessed by immunochemical (Western blotting) and immunohistochemical techniques. In frontal cortex and striatum of normotensive rats, treatment with the lower dose (0.625 mg/Kg/day) of rivastigmine had no effect on VAChT immunoreactivity and increased slightly ChAT protein immunoreactivity. The higher dose (2.5 mg/Kg/day) of the compound increased significantly VAChT and ChAT protein immunoreactivity. In hippocampus rivastigmine induced a concentration‐dependent increase of VAChT protein expression and no significant changes of ChAT protein expression. A similar pattern of VAChT and ChAT protein expression was observed in control SHR, whereas treatment of SHR with rivastigmine induced a more pronounced increase of VAChT protein immunoreactivity in frontal cortex, hippocampus and striatum compared to normotensive rats. Our data showing an increase of VAChT after treatment with rivastgmine further support the notion of an enhancement of cholinergic neurotransmission by AChE/ChE inhibitors. The observation of a greater expression of this cholinergic marker in SHR suggest that AChE inhibition may provide beneficial effects on cholinergic neurotransmission in an animal model of VaD.