目的 探究Anle138b对慢性β淀粉样蛋白(Aβ)诱导的海马神经元线粒体功能损伤的影响.方法 取出生24 h以内的SD乳鼠,原代培养海马神经元,待细胞成熟将其分为对照组(不进行任何处理)、oAβ1-42组(100 nmol/L oAβ1-42处理 7 d)、oAβ1-42+Anle138b 组(100 nmol/L oAβ1-42+100 nmol/L Anle138b 共处理 7 d)、An-le138b组(100 nmol/L Anle138b处理7 d).各组处理结束后,应用流式细胞术检测活性氧(ROS)和线粒体膜电位(Δ φm)阳性细胞的变化.结果 析因设计的方差分析显示,oAβ1-42和Anle138b的主效应明显(FoAβ1-42=14.149、38.209,FAn1e138b=1.942、24.871,P＜0.01),oAβ1-42 和 Anle138b 之间有交互性作用(F交互=18.425、21.904,P＜0.01).单独效应分析显示,用oAβ1-42处理时,Anle138b的处理效应明显(F=16.483、19.148,P＜0.01);不用An-le138b处理时,oAβ1-42的处理效应明显(F=14.149、38.209,P＜0.01).结论 Anle138b可以减轻oAβ1-42引起的海马神经元氧化应激和线粒体损伤,抑制oAβ1-42对海马神经元的损伤.

Parkinson's disease, the second most prevalent neurodegenerative disorder worldwide, is characterized by a progressive loss of dopaminergic neurons in substantia nigra pars compacta, causing motor symptoms. This disorder's main hallmark is the formation of intraneuronal protein inclusions, named Lewy bodies and neurites. The major component of these arrangements is α-synuclein, an intrinsically disordered and soluble protein that, in pathological conditions, can form toxic and cell-to-cell transmissible amyloid structures. Preventing α-synuclein aggregation has attracted significant effort in the search for a disease-modifying therapy for Parkinson's disease. Small molecules like SynuClean-D, epigallocatechin gallate, trodusquemine, or anle138b exemplify this therapeutic potential. Here, we describe a subset of compounds containing a single aromatic ring, like dopamine, ZPDm, gallic acid, or entacapone, which act as molecular chaperones against α-synuclein aggregation. The simplicity of their structures contrasts with the complexity of the aggregation process, yet the block efficiently α-synuclein assembly into amyloid fibrils, in many cases, redirecting the reaction towards the formation of non-toxic off-pathway oligomers. Moreover, some of these compounds can disentangle mature α-synuclein amyloid fibrils. Their simple structures allow structure-activity relationship analysis to elucidate the role of different functional groups in the inhibition of α-synuclein aggregation and fibril dismantling, making them informative lead scaffolds for the rational development of efficient drugs.

目的 观察二苯基吡唑化合物Anle138b对β淀粉样蛋白寡聚体(AβOs)诱导的海马神经元毒性作用的影响.方法 原代培养的海马神经元细胞成熟后,将其分为空白对照组、AβOs处理组(用0.1μmol/L AβOs处理7 d)和Anle138b处理组(用0.1μmol/L AβOs处理7 d,在AβOs处理的后2 d加用0.1μmol/L Anle138b).使用乳酸脱氢酶(LDH)试剂盒检测细胞损伤情况,采用蛋白质免疫印迹(Western blot)法检测凋亡蛋白cleaved caspase-3的表达.结果 与空白对照组相比较,AβOs处理组海马神经元细胞LDH释放量增加(F=14.810,q=7.481,P<0.01),凋亡蛋白cleaved caspase-3的表达升高(F=6.677,q=4.816,P<0.05).与AβOs处理组相比,Anle138b处理组海马神经元细胞LDH释放量降低(q=5.310,P<0.05),凋亡蛋白cleaved caspase-3的表达有下降趋势,但差异无统计学意义(P>0.05).结论 Anle138b在慢性AβOs诱导的海马神经元凋亡模型中具有一定的保护作用.

β-淀粉样蛋白(Aβ)产生的神经毒性是阿尔茨海默症(Alzheimer's disease,AD)的主要发病机理.Aβ发挥毒性的一种机制是形成离子通道从而破坏细胞内Ca2+动态平衡.研究表明,Aβ与质膜的相互作用定位于高胆固醇的脂筏结构域,Aβ通道形成与质膜上胆固醇的含量变化密切相关,胆固醇参与Aβ寡聚化,并形成神经毒性淀粉样蛋白通道,从而破坏了膜的完整性,改变了细胞内钙稳态.本综述将从Aβ通道的定位,装配,研究方法,作用机制,相关药物等方面论述,还总结了AD研究最新进展,阐明目前关于AD假说与离子通道假说之间的内部联系,为阐明AD发病机制并开发治疗阿尔茨海默症新型药物的研究方向提供思路.