不同剂量阿托伐他汀对急性脑梗死患者血脂水平和神经功能的影响

目的 探讨不同剂量阿托伐他汀对急性脑梗死患者血脂水平以及神经功能的影响.方法 分别应用阿托伐他汀10、20和40mg/d对急性脑梗死患者进行血脂调节治疗,观察治疗前后血脂水平和神经功能缺损程度的变化.结果 阿托伐他汀治疗后,各组患者血清总胆固醇水平均较治疗前下降(P<0.05),且随药物剂量的增加而逐渐降低(P<0.05),其中以20 mg/d组和40 mg/d组下降最为显著(均P<0.05);与治疗前比较,治疗后各组患者血清低密度脂蛋白-胆固醇水平均明显下降(P<0.05),其中10、20和40 mg/d组均显著低于基础治疗组(P<0.05).各组患者阿托伐他汀治疗前后血清甘油三酯和高密度脂蛋白-胆固醇水平无明显变化(均P>0.05),组间差异无统计学意义(均P>0.05).各组治疗前后神经功能缺损评分差异具有统计学意义(P<0.05),但组间差异无统计学意义(P>0.05).结论 急性脑梗死患者应用阿托伐他汀(10、20和40mg/d)进行调脂治疗安全有效,推荐以20mg/d作为适宜剂量.     

他汀类药物在缺血性卒中和短暂性脑缺血发作二级预防中的应用现状及其依从性

目的 了解他汀类药物在缺血性卒中和TIA二级预防的不同危险因素分层中的应用现状,分析影响他汀类药物依从性的因素.方法 从2009年4月至2010年1月前瞻性登记在郑州大学第一附属医院神经内科连续入院的缺血性卒中和TIA患者,收集其临床特征及可能影响他汀类药物依从性的因素,随访发病后3个月时他汀类药物的应用情况,使用多元Logistic回归进行统计学分析.结果 共纳入缺血性卒中和TIA患者369例.住院期间有52.8％ (195/369)的患者应用他汀类药物.高危组、极高危Ⅱ组及极高危Ⅰ组他汀类药物应用的指南符合率分别为25.0％ (16/64),44.1％ (30/68)和71.4％(135/189),Logistic回归分析发现住院期间使用他汀类药物与糖尿病病史(P =0.032,OR=1.789,95％ CI 1.052～3.043)及颈动脉易损斑块的存在相关(P=0.000,OR=5.308,95％ CI3.340～8.434).3个月时他汀类药物总体应用率为22.3％(81/363),明显低于住院期间他汀类药物的应用率(P=0.000).3个月时高危组、极高危Ⅱ组及极高危Ⅰ组他汀类药物应用的指南符合率分别为9.7％ (6/62),25.8％ (17/66)和29.4％( 55/187).Logistic回归分析发现3个月随访时他汀类药物依从性好与出院医嘱相关(P =0.000,OR=34.852,95％ CI14.673 ～ 175.452).结论 他汀类药物在缺血性卒中和TIA二级预防中的依从性差,与指南存在差距;出院医嘱是二级预防中他汀类药物依从性好的促进因素.     

瑞舒伐他汀逆转动脉粥样硬化斑块及其与斑块稳定性的实验研究

目的 探讨动脉粥样硬化斑块发生、发展和破裂机制,以及瑞舒伐他汀对动脉粥样硬化斑块及其稳定性的影响.方法 18只普通健康大耳白兔随机分为对照组(6只)、高脂组(6只)和瑞舒伐他汀干预治疗组(6只).建立动脉粥样硬化动物模型.分别采用酶比色法、氧化酶终点法检测血清甘油三脂(TG)、总胆固醇(TC)、高密度脂蛋白-胆固醇(HDL-C)和低密度脂蛋白-胆固醇(LDL-C)水平;双抗体夹心酶联免疫吸附(ELISA)法、HE染色和免疫组织化学染色检测血清白细胞介素-6(IL-6)和热休克蛋白60(hsp60)表达水平;图像分析软件计算血管面积、斑块面积、斑块比例及hsp60阳性表达面积.结果 至实验结束时,瑞舒伐他汀干预治疗组动物血清甘油三脂、总胆固醇和低密度脂蛋白-胆固醇水平以及IL-6和hsp60表达水平均低于高脂组(P相似文献   

阿托伐他汀对β淀粉样蛋白1-42诱导阿尔茨海默病大鼠模型的抗炎作用

目的 探讨阿托伐他汀对β淀粉样蛋白1-42(β-amyloid 1-42,Aβ1-42)诱导阿尔茨海默病(Alzheimer's disease,AD)大鼠模型学习记忆功能及脑内炎性因子的分泌、神经细胞损伤的影响.方法 将60只Wistar大鼠(体重300～350 g)完全随机分为对照组、模型组、他汀对照组和治疗组,每组各15只.服用阿托伐他汀(每天5 mg/kg)3周为治疗组,采用侧脑室注射Aβ1-42的方法制备大鼠痴呆模型,设假手术组为对照组.水迷宫实验观测大鼠的行为学变化,免疫组织化学方法测定海马区炎性因子IL-1β、IL-6、TNF-α的表达,HE染色观察海马区形态结构的变化,透射电镜观察海马区神经元和小胶质细胞超微结构的变化.结果 模型组大鼠的学习记忆成绩下降(逃避潜伏期:对照组12.0±1.2,模型组41.3±3.4,t=18.0363,P<0.01),海马区炎性因子IL-1β、IL-6、TNF-α分泌增多(IL-1β:对照组53.5±2.4,模型组101.0±3.8,t=23.8246,P<0.01);阿托伐他汀治疗组与模型组大鼠相比较,学习和记忆成绩有所改善(逃避潜伏期:25.7±1.6,41.3±3.4,t=9.1076,P<0.01),海马区IL-1β、IL-6、TNF-α分泌减少(IL-1β:60.0±3.4,101.0±3.8,t=18.0231,P<0.01).细胞形态学观察显示,与模型组相比,阿托伐他汀治疗组模型海马区神经细胞损伤减轻,胶质细胞增生减少.结论 阿托伐他汀可以减少大鼠AD模型海马区胶质细胞炎性因子的分泌,减轻神经细胞损伤,改善其学习和记忆能力.     

抗N-甲基-D-天冬氨酸受体脑炎的抗体检测及临床意义

目的探讨抗N-甲基-D-天冬氨酸受体(NMDAR)脑炎的抗体检测意义及临床特征。方法选取本院收治的脑炎病人35例及对照组30例,分析临床资料,采用转染细胞间接免疫荧光法检测两组患者其血清及脑脊液抗NMDAR机体结果抗NMDAR抗体检测仅1例边缘叶脑炎患者结果阳性,该患者腑脊液细胞数增多、蛋白轻度升高、脑电图见双侧慢波、其余检查无异常。精神症状及意识水平障碍明显,免疫治疗有效。结论抗NMDAR脑炎发病率低,临床表现复杂多样,怀疑该病时需行抗NMDAR抗体检测。     

抗α-氨基-3-羟基-5-甲基-4-异唑丙酸受体抗体脑炎3例分析

目的分析抗α-氨基-3-羟基-5-甲基-4-异唑丙酸受体(AMPAR)抗体脑炎的临床特点。方法回顾性总结2020年1月至2021年5月空军军医大学唐都医院诊治的3例抗AMPAR抗体脑炎患者的临床资料, 对其临床表现、辅助检查、治疗及预后进行分析。结果 3例抗AMPAR抗体脑炎(年龄12～70岁)均急性起病, 首发症状包括认知减退、性格改变及少见的头痛、运动障碍, 其中例1肺部占位性病变经病理证实为小细胞肺癌, 血清及脑脊液抗AMPAR抗体、抗Y染色体性别决定区相关高迁移率组盒蛋白1抗体阳性, 激素联合肿瘤化学治疗后症状仍持续存在, 无临床复发;例2责任病灶位于双侧额颞叶、半卵圆中心及侧脑室旁, 同时合并低颅压综合征典型影像学特征, 血清抗AMPAR抗体阳性, 激素治疗后症状部分改善;例3颅内病灶位于脑桥及右侧小脑中脚, 伴显著小脑萎缩, 脊髓磁共振成像提示颈2～胸10水平脊髓病变, 血清及脑脊液抗AMPAR抗体阳性, 激素联合静脉滴注人免疫球蛋白治疗后症状显著改善。结论抗AMPAR抗体脑炎临床表现异质性高, 除边缘系统外, 尚可波及脑干、脊髓, 出现脑萎缩;存在多重抗神经元抗体尤其是抗...     

Insights in the molecular mechanisms of the anti-angiogenic effect of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduce the risk of coronary event by cholesterollowering dependent and independent mechanisms. We have already described that the inhibitory effect of cerivastatin on angiogenesis contribute to the cholesterol-independent beneficial effect and was due to the inhibition of the cell signaling cascade RhoA/FAK/Akt. In this study, new insights in the molecular mechanism of action were provided. It indicates an inhibition of exposure of alpha V beta 3 integrin on cell membrane and a modification of gene expression. The inhibition of angiogenesis could be related to 1) an increase in genes involved in the inhibition of cell proliferation (p19(INK4), p21(Waf/Cip1),Wnt-5a), the inhibition of cell migration (Rho-GDI 1, alpha E-catenin) and 2) a downregulation of genes involved in angiogenesis (PAI-1, Vitronectin, HoxD3, Notch4) or in cell invasion (Semaphorin E). In addition, DNA repair protein genes (MLH1, XRCC1) were increased. This study may indicate new biological interest of genes involved in angiogenesis control.     

Therapeutic potential of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors for the treatment of retinal and eye diseases

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, generically termed statins, are widely prescribed for their cholesterol-lowering properties. In addition to lipid-lowering properties, statins have pleiotropic effects including anti-inflammatory, anti-apoptotic, and antiproliferative effects. Recently, data from experimental and observational studies have indicated that statins could also become a treatment option for diseases of the central nervous system (CNS). Many neurodegenerative diseases particularly affect the retina and other ocular structures and are the cause for blindness. This review, focused on recent clinical and experimental data, discusses known and putative mechanisms of statin actions underlying neuroprotective effects in relevant retinal and eye diseases. In addition, it presents evidence for the role of heat shock proteins (Hsps) as target of statin-mediated neuroprotective effects in ocular diseases.     

Regulation of sterol synthesis and of 3-hydroxy-3-methylglutaryl coenzyme a reductase by lipoproteins in glial cells in primary culture

Although plasma lipoproteins have been demonstrated to have a major role in regulating cholesterol biosynthesis in extraneural cells, no data concerning such regulation are available for developing brain, when cholesterol synthesis is especially active. Glial primary cultures derived from neonatal rat brain and by morphological and biochemical criteria essentially exclusively composed of astrocytes were utilized to examine such regulation. When the primary cultures, which had been maintained in 10% fetal calf serum, were placed in 10% lipoprotein-poor serum on day 7 of culture, an induction of sterol synthesis (1.6–2.2-fold) and of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-specific activity (1.5-2-fold) resulted after 24 hr. Addition of low-density lipopro-tein (LDL) to the 10% lipoprotein-poor serum prevented the induction of both sterol synthesis and HMG-CoA reductase. However, addition of high-den-sity lipoprotein (HDL) to the 10% lipoprotein-poor serum caused a 1.5–2-fold further induction of sterol synthesis relative to that in cultures containing 10% lipoprotein-poor serum alone. In contrast to the glial primary cultures, cultures of C-6 glioma cells responded to replacement of 10% fetal calf serum with 10% lipoprotein-poor serum with much more marked increases of sterol synthesis and HMG-CoA reductase. Although, as with the primary cultures, addition of LDL to the C-6 glioma cell cultures prevented the increases in sterol synthesis and reductase activity, addition of HDL had no effect. Thus, these results indicate that in developing glial cells in primary culture, cholesterol synthesis and HMG-CoA reductase are capable of responsiveness to both LDL and HDL. Moreover, at least in terms of regulation of sterol synthesis, C-6 glioma cells and developing glia in primary culture clearly are not identical.     

Concurrent positive anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase antibody with reducing body myopathy: Possible double trouble

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy is less common in children but has been associated with more favorable prognosis than adult patients after immunotherapies. We report anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody positivity in a 6-year-old boy with progressive muscle weakness, scoliosis, spinal rigidity, multiple joint contractures, mild left ventricular hypertrophy, and elevated serum creatine kinase. In contrast to most of previously reported pediatric anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy, he showed little response to immunotherapies. Muscle biopsy contained changes suggestive of myofiber necrosis and regeneration and reducing bodies. The diagnosis of reducing body myopathy was later confirmed by reported c.368A>G (p.His123Arg) mutation in the FHL1 gene. Although the level of association between these two conditions is still inconclusive, this is the first report of concurrent positive anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody with reducing body myopathy emphasizing the possibility of co-occurrence of immune mediated necrotizing myopathy and muscular dystrophy and importance of comprehensive diagnostic investigations in unusual cases.     

Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors

CONTEXT: Increasing evidence suggests that cholesterol plays a role in the pathophysiology of Alzheimer disease (AD). For instance, an elevated serum cholesterol level has been shown to be a risk factor for AD. OBJECTIVE: To determine whether patients taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are a group of medicines that inhibit the synthesis of cholesterol, have a lower prevalence of probable AD. DESIGN: The experiment uses a cross-sectional analysis comparing the prevalence of probable AD in 3 groups of patients from hospital records: the entire population, patients receiving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (hereafter referred to as the statins), and patients receiving medications used to treat hypertension or cardiovascular disease. PATIENTS: The subjects studied were those included in the computer databases of 3 different hospitals for the years October 1, 1996, through August 31, 1998. MAIN OUTCOME MEASURES: Diagnosis of probable AD. RESULTS: We find that the prevalence of probable AD in the cohort taking statins during the study interval is 60% to 73% (P < .001) lower than the total patient population or compared with patients taking other medications typically used in the treatment of hypertension or cardiovascular disease. CONCLUSIONS: There is a lower prevalence of diagnosed probable AD in patients taking 2 different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors-lovastatin and pravastatin. While one cannot infer causative mechanisms based on these data, this study reveals an interesting association in the data, which warrants further study. Arch Neurol. 2000;57:1439-1443     

Protective effect of fluvastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on MPP(+)-induced hydroxyl radical in the rat striatum

We examined whether fluvastatin, an inhibitor of low-density lipoprotein (LDL) oxidation, can resist 1-methyl-4-phenylpyridine (MPP⁺)-induced hydroxyl radical generation (·OH) in the extracellular fluid of rat striatum. Rats were anesthetized and sodium salicylate in Ringer's solution (0.5 nmol/μl/min) was infused through a microdialysis probe to detect the generation of ·OH as reflected by the nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. MPP⁺ (5 mM; total dose 75 nmol) clearly produced an increase in ·OH formation. However, fluvastatin (100 μM) reduced the ·OH formation by the action of MPP⁺. These results indicated that fluvastatin, a potent inhibitor of LDL oxidation, may resist the formation of ·OH products of MPP⁺.     

Mitophagy in three cases of immune-mediated necrotizing myopathy associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase autoantibodies: ultrastructural and immunohistochemical studies

Immune-mediated necrotizing myopathy (IMNM) associated with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies occurs in patients both with and without history of statin-intake. The mechanisms of muscle fiber degeneration in this condition remain unknown. We studied pathological changes in muscle biopsies from three patients lacking history of statin-intake. Ultrastructural observations showed accumulation of degenerating mitochondria, glycogen granules and autophagic vacuoles, forming large composites in three cases, along with various nonspecific changes. The autophagic vacuoles often contained remnants of mitochondria, indicating mitophagy. Furthermore, upregulation of B-cell lymphoma 2/adenovirus E1B 19 kD-interacting protein 3 (BNIP3), a protein involved in mitophagy, was observed in two cases examined. In three cases of sporadic inclusion body myositis, two polymyositis, and three IMNM with anti-signal recognition particle antibody, BNIP3 was upregulated less frequently, and ultrastructural change of mitophagy was rarely seen. These findings suggested that mitophagy plays an important role in muscle fiber degeneration in IMNM with anti-HMGCR autoantibodies.     

Synthesis of arachidonoyl coenzyme A and docosahexaenoyl coenzyme A in synaptic plasma membranes of cerebrum and microsomes of cerebrum, cerebellum, and brain stem of rat brain

Synthesis of arachidonoyl CoA and docosahexaenoyl CoA in homogenates and microsomes from cerebrum, cerebellum, and brain stem and in synaptic plasma membranes from cerebrum of control rats and rats undergoing bicuculline-induced status epilepticus were studied. Arachidonoyl CoA synthesis was 3-5 times higher than docosahexaenoyl CoA in homogenates and microsomes. The synaptic plasma membranes showed only 1.5- to 2.5-fold higher activity. The presence of Triton X-100 (0.1%) in the incubation medium did not alter the activity of arachidonoyl CoA synthesis but did increase the synthesis of docosahexaenoyl CoA in homogenates, microsomes, and especially in synaptic plasma membranes. The synthesis of these polyenoic fatty acyl CoAs were 4-6 times higher in microsomes than in homogenates. Synaptic plasma membranes exhibited about the same amount of activity as homogenates in the synthesis of docosahexaenoyl CoA, but only half the activity of the latter in arachidonoyl CoA synthesis. The synthesis of arachidonyl CoA and docosahexaenoyl CoA in cerebral homogenates and microsomes was higher than that of cerebellum and brain stem. The apparent Km values for labeled arachidonic acid (17 microM) and docosahexaenoic acid (12 microM) in synaptic plasma membranes were lower than the values for microsomes isolated from different brain regions. The Vmax values were also 4-10 times lower. Microsomes from different regions did not differ in their apparent Km values, but did show variations in apparent Vmax values. Cerebellar microsomes showed lower Vmax values than the other two regions. The presence of Triton X-100 caused a significant decrease in the apparent Km values with little change in the Vmax values. Bicuculline-induced seizures did not alter the kinetic properties of arachidonoyl CoA and docosahexaenoyl CoA synthesis, except there was a significant decrease in the apparent Km and Vmax values for cerebellar microsomal docosahexaenoyl CoA synthesis. In conclusion, there were marked differences in the activation of polyenoic fatty acids in different parts of the brain and in subcellular fractions. Although bicuculline-induced convulsions accumulate free polyenoic fatty acids in the brain, no changes were detected when the fatty activation was assayed with exogenous cofactors, except in cerebellum.