亚慢性铝暴露对大鼠学习记忆能力及大脑皮质β-淀粉样蛋白表达的影响

目的研究铝对大鼠学习记忆能力及脑组织β-淀粉样蛋白(Aβ)表达的影响。方法选用健康清洁级雄性(SD)大鼠32只,按体质量随机分为4组,即对照组,麦芽酚铝[Al(mal)3]0.27,0.54,1.08mg/kg染毒组,每组8只,采用亚慢性腹腔注射方式染毒60d。采用Morris水迷宫测定大鼠学习记忆能力,采用酶联免疫吸附试验(ELISA)测定大鼠大脑皮质Aβ蛋白表达。结果 Morris水迷宫结果显示,亚慢性铝暴露可导致大鼠潜伏期和找到平台的时间逐渐延长,1.08mg/kg染毒组潜伏期与对照组比较差异有统计学意义(P<0.05),0.54,1.08mg/kg染毒组找到平台的时间与对照组比较差异具有统计学意义(P<0.05)。随染毒剂量的增加,0.54,1.08mg/kg染毒组大脑皮质Aβ40明显减少,各染毒组Aβ42显著升高,与对照组比较差异具有统计学意义(P<0.05)。结论铝对大鼠学习记忆能力具有明显损伤作用,其机制可能与脑内Aβ42生成增多有关。     

慢性铝中毒对大鼠肝脏功能及结构的影响

目的研究铝中毒对大鼠肝脏功能及结构的影响。方法 20只大鼠随机分组,实验组以AlCl3水溶液腹腔注射染毒,对照组以生理盐水腹腔注射;分别于第4和第8周末取血清检测丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)和γ-谷氨酰转移酶(GGT),在第8周末取肝组织作病理检查。结果与空白对照组相比,铝中毒组大鼠的血清中ALT、AST升高,肝细胞变性、坏死及纤维组织增生。结论铝中毒可使大鼠肝功能受损及肝细胞损伤。     

慢性铝暴露对成年大鼠海马LTP及谷氨酸含量的影响

目的采用慢性铝暴露大鼠模型来研究铝暴露对谷氨酸介导的神经传递的影响,进而从递质释放角度阐明在此阶段中铝影响LTP的机制。方法成年Wistar大鼠按体重随机分为3组,分别自由饮用:蒸馏水(对照组),0.2%AlCl3水溶液,0.4%AlCl3水溶液,染毒3个月后测定各项指标。结果随铝暴露剂量增大,大鼠海马齿状回群体峰电位幅值增强率逐渐减小,并呈剂量依赖性。免疫组化结果显示与对照组相比,铝暴露组的谷氨酸活性受到明显抑制,并且随着暴露剂量增大,谷氨酸活性降低,呈剂量依赖性。结论慢性铝暴露可损害成年大鼠海马LTP的诱导与维持,这可能与大鼠海马中谷氨酸的活性降低有关,对正常的学习记忆过程产生不利影响。     

NMDA对老年性痴呆大鼠βAPP及BACE1表达的影响

目的 探讨N-甲基-D-天冬氨酸(NMDA)受体抑制剂(盐酸美金刚)对老年性痴呆(AD)大鼠β-淀粉样前体蛋白(APP)及β分泌酶(BACE1)表达的影响。方法 30只SD大鼠随机分为假手术组,模型组,治疗组(盐酸美金刚组);除假手术组外,其余两组大鼠海马注射10 μg β淀粉样蛋白(Aβ)1-40构建AD大鼠模型,治疗组大鼠腹腔注射10 mg/(kg.d)盐酸美金刚,其余两组给予等量生理盐水,连续给药14 d,处死大鼠取血及海马组织。ELSIA法检测血清及海马组织中Aβ含量,western blot及RT-PCR法检测海马组织中APP和BACE1蛋白及mRNA表达量。结果 与假手术组比较,模型组中Aβ含量显著提高,APP及BACE1蛋白及mRNA含量显著提高;与模型组比较,治疗组中Aβ含量显著降低,APP及BACE1蛋白及mRNA含量显著下降。结论 盐酸美金刚能通过阻断APP裂解,从而抑制AD大鼠海马组织中Aβ沉积。     

冰片对长时连续作业大鼠觉醒能力及认知功能的影响

目的:探讨冰片对长时连续作业大鼠觉醒能力和认知功能损害的干预作用。方法:首先采取跑台作业方法建立大鼠长时连续作业模型,将模型大鼠分为跑台冰片组和跑台对照组,另设未跑台对照组。随后观察冰片对长时连续作业大鼠活动-静止行为、觉醒时间以及穿梭箱主动回避反应的影响。结果:3组纳入测试的大鼠各为6只。结果显示给予0.4g/kg冰片(经胃灌饲)可增加大鼠长时连续作业后的自主活动量(每分钟活动次数未跑台对照组为54.1±5.4,跑台对照组为15.5±8.3,跑台冰片组为26.8±7.8,3组之间两两比较,P均<0.05)和觉醒时间(未跑台对照组为639min±46min,跑台对照组为411min±36min,跑台冰片组为501min±52min,3组之间两两比较,P均<0.05),同时还可改善长时连续作业大鼠的认知功能(穿梭箱主动回避作为测试反应时间,未跑台对照组为5.63s±1.01s,跑台对照组为6.85s±1.24s,跑台冰片组为6.26s±0.96s,3组之间两两比较,P均<0.05)。结论:冰片可在一定程度上逆转长时连续作业对大鼠觉醒能力和认知功能的损害作用。     

慢性饮酒对大鼠肺组织TGF-β1和bFGF mRNA表达的影响

目的:观察慢性饮酒后大鼠肺组织中转化生长因子-β1(TGF-β1)和碱性成纤维细胞生长因子(bFGF)mRNA的表达,探讨慢性饮酒对肺间质的影响。方法:健康雄性Sprague-Dawley大鼠20只随机分为无乙醇液体饲料的对照组和乙醇液体饲料的乙醇组,每组10只。喂养16周后观察所有大鼠肺泡内炎性细胞浸润程度并评分,Masson染色观察肺间质胶原沉积情况,电镜观察肺组织超微结构变化,实时荧光定量PCR检测肺组织TGF-β1和bFGF mRNA的表达量。结果:光镜下肺泡内炎性细胞浸润程度评分乙醇组高于对照组,差异有统计学意义(Z=50,P<0.05)。乙醇组电镜可见线粒体膜和嵴均有不同程度融合、模糊不清,细胞间隔均可见不同程度的胶原纤维沉积。乙醇组肺组织中TGF-β1和bFGF mRNA表达量高于对照组,差异有统计学意义(t分别为3.702和3.487,均P<0.01)。结论:慢性饮酒可增加大鼠肺组织中TGF-β1、bFGF mRNA表达量,使肺组织胶原沉积,引起肺泡炎症和肺间质疾病。     

黄芩苷对牙周炎大鼠牙龈组织及外周血中IL-1β表达的影响

目的 采用大肠杆菌脂多糖诱导大鼠牙周炎模型,观察黄芩苷对牙周炎大鼠牙龈组织及外周血中白介素-1β(interleukin-1β,IL-1β)表达水平的影响.方法 选用50只8周龄SD大鼠,随机分成5组,每组10只,A组为对照组,B组为牙周炎组,C1、C2、C3组为黄芩苷治疗组,治疗1周后处死大鼠采取其外周血及牙龈组织,采用微量样本多重蛋白定量技术(CBA)检测外周血中IL-1β含量,采用RT-PCR法检测大鼠牙龈组织中IL-1βmRNA的表达水平.结果 B组大鼠牙龈组织中IL-1βmRNA及外周血中IL-1β表达含量均明显高于A组(P＜0.05),C1、C2、C3组大鼠牙龈组织中IL-1βmRNA和外周血中IL-1β表达含量均明显低于B组(P＜0.05).结论 黄芩苷可以降低牙周炎大鼠牙龈组织中IL-1βmRNA和外周血中IL-1β表达水平,抑制脂多糖对大鼠牙周组织的损伤作用.     

慢性饮酒对大鼠肺组织中TIMP-1表达的影响

目的:观察慢性饮酒大鼠的肺组织及基质金属蛋白酶抑制剂(TIMP)-1等指标的变化,探讨乙醇与肺纤维化之间的关系及可能的机制.方法:健康雄性SPF级Sprague-Dawley大鼠20只,随机分成2组,对照组10只,每日给予定量无乙醇液体饲料单笼喂养;乙醇组10只,每日给予定量乙醇液体饲料单笼喂养,不再提供饮水.16周后,处死大鼠,并获取其肺组织,通过Masson染色观察肺间质中胶原沉积的情况,用比色法计算大鼠肺组织中谷胱甘肽(GSH)和羟脯氨酸(HYP)的含量,通过ELISA方法检测肺组织TIMP-1的含量.结果:乙醇组较对照组在肺泡间隔中胶原纤维沉积增多.与对照组比较,乙醇组肺组织GSH含量减少,HYP和TIMP-1含量升高,差异均有统计学意义(P＜0.05或P＜0.01).结论:慢性摄入乙醇可以引起大鼠肺泡间隔胶原纤维沉积,肺组织中TIMP-1升高.饮酒可能是引起大鼠肺纤维化的原因之一.     

N-(3-(2-amino-6,6-difluoro-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-4-yl)-phenyl)-amides as BACE1 inhibitors: a patent evaluation of WO2013041499

A new series of oxazin amides have been synthesized from isoxazoles using a reaction to increase the heterocyclic ring size and were evaluated as BACE1 inhibitors. The innovative compounds were able to diminish amyloid-β peptide concentration in cell and proved to be selective toward peptidases from the same family. Further studies on the toxicity of this series showed that these new molecules were not recognized by P-glycoprotein and that they were unsusceptible to rapid metabolization by cytochrome P450 or glutathione conjugation. These results indicate that such compounds could be useful in developing drugs to fight Alzheimer's disease and that this novel oxazin scaffold should be considered as a starting point to tackle this pathology.     

Emerging and potential therapies for Alzheimer's disease

Background: The amyloid β (Aβ) peptide is critical to the development of Alzheimer's disease (AD), the major neurodegenerative disease of the elderly for which there is currently no cure. Objective: To review the literature on emerging treatments and potential therapeutic strategies for AD. Methods: Available published literature and information from pharmaceutical companies was utilised. Results/conclusion: Several of the current treatments to combat AD are aimed at inhibiting the production, blocking the oligomerisation/aggregation or enhancing the degradation of Aβ. In our opinion, albeit based on limited available data, a future potential therapeutic strategy is to mimic the mechanism by which the normal cellular form of the prion protein inhibits the β-secretase β-site amyloid precursor protein cleaving enzyme-1 (BACE1), and hence the production of Aβ.     

慢性氯化铝染毒对大鼠大脑皮层内钙稳态影响

目的研究铝对大鼠大脑皮层细胞内游离钙([Ca2 ]i)质量浓度的影响,探讨铝的神经毒性的机制。方法应用248.7、74.7和37.3 mg/kg AlCl3对Wistar大鼠经口灌胃染毒,分别在染毒45、75和120 d和染毒结束后30 d处死大鼠,取脑分离大脑皮层。将荧光染料Fura-2/AM与皮层细胞一起孵育,应用荧光分光光度计测定[Ca2 ]I质量浓度。应用Western Blot方法测定各组大鼠脑皮层中钙调蛋白(CaM)和钙调蛋白依赖性蛋白激酶Ⅱ(CaMKⅡ)表达情况。结果在染毒45、75和120 d时,74.7 mg/kg剂量组大鼠[Ca2 ]i质量浓度为(273.8±91.2)(、308.0±96.9)和(453.0±90.5)nmol/L,均显著高于对照组(P<0.05);染毒120 d时,高剂量组大鼠大脑皮层[Ca2 ]i质量浓度为(445.5±68.8)nmol/L,显著高于对照组(P<0.01);染毒结束后30 d,各染毒组大鼠大脑皮层[Ca2 ]i质量浓度高于对照组大鼠,但差异无显著性(P>0.05)。染毒457、5和120 d时,各染毒组大鼠大脑皮层中CaM表达与对照组相比均减少。各染毒组大鼠大脑皮层中CaMKⅡ表达与对照组相比,在不同染毒时期内均有不同程度上升。结论AlCl3可以增加皮层神经细胞内[Ca2 ]i质量浓度,同时引起CaM表达减少和CaMKⅡ表达增加,可见铝可使神经细胞内钙稳态失调而发挥神经毒作用。     

Statine-derived tetrapeptide inhibitors of β-secretase

Alzheimer’s disease (AD) is characterised by the accumulation of amyloid β-peptide (Aβ) within senile plaques in the brain. β-secretase is one of the enzymes necessary for the production of amyloid β-peptide from the amyloid precursor protein (APP), the other being γ-secretase. β-Secretase was recently characterised as a novel aspartyl protease. Statine-derived tetrapeptide inhibitors of this enzyme, described in this patent, may have therapeutic applications in AD.     

西红花酸对动脉粥样硬化大鼠血脂及LOX-1表达的影响

目的研究西红花酸对动脉粥样硬化大鼠血脂及LOX-1表达的影响。方法健康SD雄性大鼠,随机分为4组:空白对照组、模型组、西红花酸高剂量组、西红花酸低剂量组。高脂饲料建立大鼠实验性动脉粥样硬化模型,测定大鼠血清总胆固醇、甘油三酯、低密度脂蛋白、高密度脂蛋白。同时取主动脉做病理切片检查。RT-PCR、Westernblotting技术检测主动脉LOX-1的基因与蛋白表达水平,观察西红花酸对其血管平滑肌细胞LOX-1表达的影响。结果高、低剂量的西红花酸能显著降低动脉粥样硬化大鼠血清TC、TG和LDL-C含量;明显降低主动脉LOX-1的表达。结论西红花酸可明显下调动脉粥样硬化大鼠LOX-1的表达。     

Effects of maternal toluene exposure on testosterone levels in fetal rats

The goal of our study was to determine if toluene affected the synthesis and secretion of testosterone in fetal rats. Dams were exposed to atmospheres that contained 0.09 ppm, 0.9 ppm or 9 ppm of toluene for 90 min/day from gestational days (GDs) 14.5 to 18.5 via nasal inhalation. Fetal plasma testosterone concentrations determined by enzyme immunoassay were significantly reduced on GD18.5 after exposure to 0.9 and 9 ppm, but not to 0.09 ppm, of toluene in male, but not in female, fetuses. We measured, using real-time PCR methods, mRNA levels in fetal testes for several steroidogenic enzymes involved in testosterone synthesis and insulin-like 3 (Insl3), a maker of Leydig cell differentiation. The mRNA levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) were significantly reduced after exposure to 0.9-ppm toluene. However, the mRNA levels of cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17α-hydroxylase/c17-20 lyase, 17β-hydroxysteroid dehydrogenase, and Insl3 were not significantly altered by exposure to 0.9-ppm toluene. In addition, immunohistochemical analysis showed reduced 3β-HSD-immunoreactive areas in the interstitial region of fetal testes after exposure to 0.9 and 9 ppm, but not 0.09 ppm, toluene. These findings indicate that toluene reduced the synthesis and secretion of testosterone in fetal testes from rats possibly as a consequence of reduced 3β-HSD expression.     

高血氨对大鼠脑内NMDAR1 CREB表达的影响

目的探讨高血氨大鼠学习记忆能力改变的分子机制。方法雄性SD大鼠40只,随机分为2组,每组20只：正常对照组（A组）,高血氨模型组（B组）,Morris水迷宫观察动物学习记忆的变化,大鼠处死后,检测血氨,原位杂交检测N-甲基-D-天门冬氨酸受体1（NMDAR1）基因的表达,实时荧光定量聚合酶链反应（RTqPCR）检测大鼠脑组织环磷酸腺苷（cAMP）应答元件结合蛋白（CREB）基因的表达。结果与正常对照组比较,高血氨模型组大鼠血氨水平明显升高,其平均逃避潜伏期、游泳总距离均延长;并且大脑皮层、海马NMDAR1mRNA表达均下降,CREB基因表达亦均下降。结论高血氨模型大鼠学习记忆功能下降可能由于脑组织NMDAR1、CREB等基因表达下调所致。     

Behavioural effects of tetrachloroethylene exposure in rats: acute and subchronic studies

This study was carried out to compare the neurobehavioural profile of acute and subchronic tetrachloroethylene (perchloroethylene, PCE) exposure in rats. In the acute study, a single bolus of 50 and 500 mg/kg of PCE in corn oil was administered by gavage. In the subchronic experiments, rats were exposed to PCE at a dosage of 5 and 50 mg/kg in corn oil, 5 days per week for 8 weeks. Nociception, locomotion and seizure susceptibility was tested using open-field, tail immersion and hot plate and pentylenetetrazol-induced seizures, respectively. Subchronic PCE exposure exhibited higher antinociceptive effect and lower motor activity in comparison with acute exposure. Pentylenetetrazol-induced convulsion thresholds were elevated following acute PCE exposure. In contrast, subchronic PCE exposure only increased thresholds for myoclonic twitch and face and forelimb clonus without altering the thresholds for running and bouncing clonus and tonic hindlimb extension. These findings suggest that subchronic PCE exposure results in progressively greater toxic effects on nociception and locomotor activity. The differential effects on seizure susceptibility between acute and subchronic exposure may represent different alterations on neural circuits involved in seizure generation.     

An Orally Available BACE1 Inhibitor That Affords Robust CNS Aβ Reduction without Cardiovascular Liabilities

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