Lovastatin ameliorates α-synuclein accumulation and oxidation in transgenic mouse models of α-synucleinopathies

Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many diseases including Dementia with Lewy Bodies (DLB) and Parkinson's Disease (PD), collectively termed the α-synucleinopathies. The mechanisms underlying α-syn aggregation remain elusive though emerging science has hypothesized that the interaction between cholesterol and α-syn may play a role. Cholesterol has been linked to α-synucleinopathies by recent work suggesting cholesterol metabolites appear to accelerate α-syn fibrillization. Consistent with these findings, cholesterol-lowering agents have been demonstrated to reduce α-syn accumulation and the associated neuronal pathology in vitro. In this context, this study sought to investigate the in vivo effects of the cholesterol synthesis inhibitor lovastatin on α-syn aggregation in two different transgenic (Tg) mouse models that neuronally overexpress human α-syn. Lovastatin-treated mice displayed significantly reduced plasma cholesterol levels and levels of oxidized cholesterol metabolites in the brain in comparison to saline-treated controls. Immunohistochemical analysis demonstrated a significant reduction of neuronal α-syn aggregates and α-syn immunoreactive neuropil in the temporal cortex of lovastatin-treated Tg mice in comparison to saline-treated α-syn Tg controls. Consistently, immunoblot analysis of mouse brain homogenates showed a reduction in levels of total and oxidized α-syn in lovastatin-treated α-syn Tg mice in comparison to saline-treated α-syn Tg controls. The reduced α-syn accumulation in lovastatin-treated mice was associated with abrogation of neuronal pathology. The results from this study demonstrate that lovastatin administration can reduce α-syn aggregation and associated neuropathology and support the possibility that treatment with cholesterol-lowering agents may be beneficial for patients with PD and/or DLB.     

Benefit of statins in daily practice? A six-year retrospective observational study

This observational retrospective study analysed the association of adherence to statins with the achievement of a target total cholesterol level (CL, <200 mg/dl), and any association of adherence with the time to first hospital admission for coronary event in hypercholesterolemic patients treated with statins, in one Italian Local Health Authority between 1998 and 2003. The study population consisted of 3516 patients who were prescribed statins and for whom full cholesterol results were available. After three months of treatment, there were significant reductions in CL (p < 0.001) in the three treatment groups stratified by adherence (good adherents −24%, poor adherents −22%, and nonadherents −14%). Patients more likely to achieve the target CL were older, male and more adherent to the statins. The risk of first hospitalization was associated positively with increased age and male gender. Patients with co-treatments were more likely to be hospitalized. Surprisingly, better adherence to statin treatment increased the risk of hospitalization.     

Low density lipoprotein cholesterol, statins and cardiovascular events: a meta–analysis

Summary A recent meta–analysis of the Cholesterol Treatment Trialists’ (CTT) Collaboration comes to the clear conclusion that a reduction in LDL–C using statins of 1 mmol/l (39 mg/dl) leads to a decrease in overall mortality by 12%, in coronary mortality by 19% and in the incidence of strokes by 17%, independent of the LDL–C level prior to the start of treatment. We conducted a systematic review retrieving 18 studies with a total of 97 861 participants. Differences in average LDL–C reductions between the intervention and control groups during the follow–up and relative risks according to different clinical endpoints were extracted from the original publications. Metaregression analyses showed that reduction in LDL–C accounted for more than 75% of the variance in risk reductions for overall mortality and cardiovascular endpoints. On the basis of our estimates, a reduction in LDL–C of 1 mmol/l (39 mg/dl) leads to reductions in overall mortality, coronary mortality, incidence of non–fatal myocardial infarction, the combination of coronary mortality and non–fatal myocardial infarction, stroke and any vascular event by 15% (95% CI: 11–20%), 24% (95% CI: 20–28%), 27% (95% CI: 20–32%), 25% (95% CI: 22–29%), 24% (18–29%) and 22% (95% CI: 19–26%), respectively. We conclude that the extent to which statins lower LDL–C is strongly related to the improvement of clinical outcomes achieved by this class of drugs. An erratum to this article is available at .     

扩张型心肌病患者外周血单个核细胞NF-κB/p65的表达及阿托伐他汀钙的影响

目的探讨扩张型心肌病（DCM）患者外周血单个核细胞（PBMCs）核转录因子xappaB（NF—κB）／p65的表达及阿托伐他汀钙（Ale）的干预作用。方法对25例DCM患者和18名健康对照者分离出的PBMCs进行培养，共培养24h，并将培养的PBMCs分成3组：空白对照组、脂多糖（LPS）组和Ale组。对3组培养后的PBMCsNF—κB／p65的表达进行免疫组化染色检测和半定量分析。结果DCM患者PBMCsNF—κB／p65胞核染色阳性率明显高于健康对照者[（14．86±3．21）％比（6．32±2．25）％，P〈0.01]；脂多糖组DCM患者和健康对照者PBMCsNF—κB／p65胞核染色阳性率与空白对照组比较均显著增加（P〈O．01）；Ale组DCM患者和健康对照者PBMCsNF—κB／p65胞核染色阳性率与脂多糖组比较则显著下降（P〈0．01）。结论DCM患者NF—κB／p65表达增高，而Ale可下调脂多糖刺激下NF-κB／p65表达增高。     

Current approaches in the treatment of Alzheimer's disease.

The management of Alzheimer's disease (AD) has been a long-standing challenge and area of interest. Advances in knowledge of the pathogenesis of disease and an increase in disease burden have prompted investigation into innovative therapeutics over the last two decades. This article reviews the various treatments of AD including those targeted towards cholinergic deficiency, oxidative stress, the amyloid cascade, inflammation, and excitotoxicity. Second generation cholinesterase inhibitors remain the preferred therapy for early and intermediate AD while the glutamate antagonist, memantine, is also approved for advanced stages of disease. Antioxidants may delay disease progression, while data on other experimental therapies remain equivocal at best. Gene therapy directed at neurotropins is currently under investigation with some intriguing preliminary results; however, the number of patients examined is too few to be conclusive. Drugs directly targeting amyloid-beta, particularly the amyloid-beta vaccine, continue to be investigated and their forthcoming results are eagerly anticipated.     

Spontaneous compartment syndrome in a patient with diabetes and statin administration: a case report

Compartment syndrome is a condition characterized by pressure increasing in the inextensible muscular compartments that leads to a decrease of capillary perfusion with consequent ischemic lesions of the logia elements. The authors report a case of an unusual compartment syndrome with spontaneous onset in a patient with type II diabetes and chronic therapy with statins (Atorvastatin). The condition was successfully treated by a fasciotomy and medical support. The importance of a correct anamnesis and a high level of suspicion is emphasized.     

他汀类药物联合抗血小板药物降低冠状动脉搭桥术后血管再狭窄的研究

冠状动脉旁路移植术（CABG）是治疗冠心病有效手段之一,但是其术后易发生桥静脉再狭窄甚至闭塞,发生复发性心绞痛、心肌梗死以及再次血运重建的风险增加。抗血小板药物和他汀类药物是临床提高桥血管通畅率的常用药物,抗血小板药物能减少早期的血栓形成,他汀类药物能够延缓中期的内膜增厚和晚期的粥样斑块的形成。本文就联合使用抗血小板药物和他汀类药物降低CABG术后血管再狭窄的研究作一综述,并对综合治疗CABG术后血管再狭窄的方法进行展望。