Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease

Cerebrolysin is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative pathology in Alzheimer's disease (AD). We have previously shown in an amyloid protein precursor (APP) transgenic (tg) mouse model of AD-like neuropathology that Cerebrolysin ameliorates behavioral deficits, is neuroprotective, and decreases amyloid burden; however, the mechanisms involved are not completely clear. Cerebrolysin might reduce amyloid deposition by regulating amyloid-beta (Abeta) degradation or by modulating APP expression, maturation, or processing. To investigate these possibilities, APP tg mice were treated for 6 months with Cerebrolysin and analyzed in the water maze, followed by RNA, immunoblot, and confocal microscopy analysis of full-length (FL) APP and its fragments, beta-secretase (BACE1), and Abeta-degrading enzymes [neprilysin (Nep) and insulin-degrading enzyme (IDE)]. Consistent with previous studies, Cerebrolysin ameliorated the performance deficits in the spatial learning portion of the water maze and reduced the synaptic pathology and amyloid burden in the brains of APP tg mice. These effects were associated with reduced levels of FL APP and APP C-terminal fragments, but levels of BACE1, Notch1, Nep, and IDE were unchanged. In contrast, levels of active cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3beta [GSK-3beta; but not stress-activated protein kinase-1 (SAPK1)], kinases that phosphorylate APP, were reduced. Furthermore, Cerebrolysin reduced the levels of phosphorylated APP and the accumulation of APP in the neuritic processes. Taken together, these results suggest that Cerebrolysin might reduce AD-like pathology in the APP tg mice by regulating APP maturation and transport to sites where Abeta protein is generated. This study clarifies the mechanisms through which Cerebrolysin might reduce Abeta production and deposition in AD and further supports the importance of this compound in the potential treatment of early AD.     

Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy

To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.     

外伤性脑水肿神经元胞浆游离钙浓度及Ca~(2+)—ATP酶活性变化

本文研究大鼠脑损伤后皮质神经元突触体胞浆中游离钙浓度([Ca~(2+)]i),Ca~(2+)—ATP酶活性及脑组织水含量变化。并选用脑活素治疗,观察其对神经细胞Ca~(2+)超载及Ca~(2+)—ATP酶活性改变和脑水肿的影响。结果:脑损伤后神经元Ca~(2+)通道开放,伤后仅0.5小时,突触体胞浆中游离[Ca~(2+)]i已升高至1095.42±76.15nmol/L水平,为对照值的10倍;伤后6,24,48和72小时,[Ca~(2+)]i持续处于高水平,为对照值的16～17倍。与之相反,神经细胞线粒体Ca~(2+)—ATP酶活性显著下降。脑损伤后脑组织水含量增加,以脑白质增加较为明显。应用脑活素治疗后,线粒体Ca~(2+)—ATP酶活性有明显回升,神经元胞浆Ca~(2+)超载有所减轻,脑水肿有一定改善。     

施普善与胞二磷胆碱合用治疗新生儿缺血缺氧性脑病84例疗效观察

目的:探讨施普善与胞二磷胆碱合用对新生儿缺血缺氧性脑病的临床疗效与安全性。方法:84例病人随机分为治疗组(47例)和对照组(37例),治疗组在一般治疗基础上加用施普善(脑活素)1ml/kg和胞二磷胆碱(CTC)100～125mg/d加入10%葡萄糖注射液静滴,qd,疗程为7d。对照组在一般治疗基础上加用胞二磷胆碱(CTC)100～125mg/d加入10%葡萄糖注射液静滴,qd,疗程为7d。结果:治疗组痊愈率为76.6%,有效率为95.7%;对照组痊愈率为35.1%,有效率为75.7%。经统计学处理两组有效率和显效率均有显著性差异(P<0.05)。结论:施普善是治疗新生儿缺血缺氧性脑病较理想的药物。     

三磷酸胞苷二钠与脑活素治疗急性脑血管病的疗效对比

目的:评价三磷酸胞苷二钠的安全性和有效性,并与脑活素比较。方法:236例急性脑血管疾病患者随机分成两组,使用三磷酸胞苷二钠和脑活素进行治疗。结果:治疗组和对照组有效率分别为74.2％和50.9％,两者有显著性差异。不良反应率分别为13.3％和19.0％。结论:三磷酸胞苷二钠是治疗急性脑血管病安全有效的药物。     

施普善(脑活素)对急性缺血性卒中的临床疗效研究

目的 观察施普善治疗急性缺血性卒中的疗效和安全性.方法 采用开放、随机、对照研究,选择航天中心医院神经内科自2008年1月至2011年1月收治的发病在48 h内的急性缺血性卒中患者108例,随机数字表法分成治疗组(64例)和对照组(44例),对照组给予常规治疗,治疗组在常规治疗基础上给予30 mL施普善(内含于250 mL氯化钠注射液),连续14d.依据美国国立卫生院卒中量表(NIHSS)评分及日常生活能力评分(BI指数)评定患者神经功能缺损程度,并监测肝肾功能、血尿常规及心电图.结果 与对照组相比,治疗组NIHSS评分、BI分值在治疗后差异均有统计学意义(P＜0.05).结论 施普善能有效改善急性缺血性卒中患者的神经功能缺损.     

脑活素对原代培养大鼠小脑颗粒神经元影响的研究

目的研究脑活素(现药名施普善)对原代培养的大鼠小脑颗粒神经元的影响。方法采用原代培养的大鼠小脑颗粒神经元,观察脑活素对细胞形态学及生存的影响。用噻唑蓝(MTT)法测定细胞存活率。结果脑活素在0～40mL/L浓度下,剂量依赖性诱导小脑颗粒神经元死亡。兴奋性氨基酸受体拮抗剂地佐环平(MK-801)可保护低浪度脑活素(＜50mL/L)的神经毒性。脑活素浓度＞50mL/L时MK-801无明显保护作用。而对照药物胞二磷胆碱(0～10g/L)、单唾液酸四己糖神经糖甙脂(GM-1,0～20mg/L)两者被认为具有护脑作用的药物,对小脑颗粒细胞均无毒性作用。结论脑活素对原代培养的大鼠小脑颗粒神经元具有毒性作用,其机制部分是通过兴奋性氨基酸介导的。提示脑活素的神经药理作用值得进一步探讨。     

几种脑组织注射液药理作用的比较研究

目的 :对国产和进口的脑组织注射液的药理作用进行比较。方法 :采用断头、结扎双侧带迷走神经颈总动脉、结扎双侧颈总动脉致动物脑急性缺氧缺血 ,测定动物张口喘息时间、脑血管通透性、脑指数、脑含水量、血清中磷酸肌酸激酶和乳酸脱氢酶水平 ;测定由东莨菪碱、NaNO2 及乙醇致记忆障碍小鼠的错误潜伏期和错误次数。结果 :国产和进口脑组织注射液均能显著延长小鼠断头张口喘息时间和结扎双侧带迷走神经颈总动脉小鼠的存活时间 ;对结扎大鼠双侧颈总动脉引起的脑血管通透性、脑指数和脑含水量的增高以及血清中磷酸肌酸激酶和乳酸脱氢酶水平的升高等均有明显的抑制作用 ;可显著抑制由东莨菪碱、NaNO2 及乙醇致记忆障碍小鼠的错误潜伏期和错误次数。结论 :国产脑组织注射液的药理作用与进口产品脑活素注射液相当     

脑活素抗局灶脑缺血再灌流损伤的实验研究

目的观察脑活素对局部脑缺血再灌流损伤的保护作用。方法以易卒中型肾血管性高血压大鼠复制可再灌流的ＭＣＡＯ模型，用光镜、电镜及图像分析比较了脑活素和对照组的脑梗死灶及脑微血管超微结构改变。结果脑活素组大鼠死亡数下降，并发脑出血例数减少。再灌流７～１４天，脑梗死灶面积较对照组的小，脑微血管损害减轻。结论脑活素可减轻局灶脑缺血再灌流后脑水肿，缩小梗死灶，对脑微血管损伤有一定保护作用