Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system.     

Exploration of a Library of 3,4‐(Methylenedioxy)aniline‐Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design,Synthesis, and Evaluation

A library of 3,4‐(methylenedioxy)aniline‐derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO‐B and AChE, with IC₅₀ values in the micro‐ or nanomolar ranges. Compound 16 , 1‐(2,6‐dichlorobenzylidene)‐4‐(benzo[1,3]dioxol‐5‐yl)semicarbazide presented a balanced multifunctional profile of MAO‐A (IC₅₀=4.52±0.032 μm ), MAO‐B (IC₅₀=0.059±0.002 μm ), and AChE (IC₅₀=0.0087±0.0002 μm ) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAO‐A and MAO‐B, and mixed‐type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme–inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug‐like characteristics.     

沙棘叶提取物的体外抗氧化及乙酰胆碱酯酶抑制能力

以沙棘叶为原料,以DPPH?清除能力、总还原力为指标,评估沙棘叶提取物的体外抗氧化活性,并以沙棘叶提取物对乙酰胆碱酯酶的抑制能力为指标,考察其成为乙酰胆碱酯酶抑制剂的潜力。研究结果表明：5种不同乙醇体积分数的（40%、50%、60%、70%、80%）沙棘叶提取物均有较好的抗氧化活性与对乙酰胆碱酯酶抑制能力。以60%乙醇提取的沙棘叶提取物的DPPH?清除率、总还原力及乙酰胆碱酯酶抑制能力最强,分别为（85.80±1.39）%,3.06±0.18,（97.14±0.809）%,可作为抗氧化剂与乙酰胆碱酯酶抑制剂。筛选后的沙棘叶提取物对乙酰胆碱酯酶有较强的抑制能力,半数抑制质量浓度（IC50）值为（1.086±0.144）mg/mL,并且根据酶的抑制动力学分析得出对乙酰胆碱酯酶是竞争性大于非竞争性的混合可逆抑制类型。AutoDock分子对接结果也表明,沙棘叶活性成分与乙酰胆碱酯酶具有一定的对接亲和力。剂效相关性分析表明沙棘叶提取物的抗氧化、酶抑制活性与功能成分之间均存在良好的正相关性（P<0.05）,沙棘叶提取物中起主要抗氧化与酶抑制作用的成分为多酚类化合物.     

Interaction of Cucurbit[7]uril with Oxime K027, Atropine,and Paraoxon: Risky or Advantageous Delivery System?

Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood–brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC—pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.     

Correlation of the dynamics of native human acetylcholinesterase and its inhibited huperzine A counterpart from sub-picoseconds to nanoseconds

It is a long debated question whether catalytic activities of enzymes, which lie on the millisecond timescale, are possibly already reflected in variations in atomic thermal fluctuations on the pico- to nanosecond timescale. To shed light on this puzzle, the enzyme human acetylcholinesterase in its wild-type form and complexed with the inhibitor huperzine A were investigated by various neutron scattering techniques and molecular dynamics simulations. Previous results on elastic neutron scattering at various timescales and simulations suggest that dynamical processes are not affected on average by the presence of the ligand within the considered time ranges between 10 ps and 1 ns. In the work presented here, the focus was laid on quasi-elastic (QENS) and inelastic neutron scattering (INS). These techniques give access to different kinds of individual diffusive motions and to the density of states of collective motions at the sub-picoseconds timescale. Hence, they permit going beyond the first approach of looking at mean square displacements. For both samples, the autocorrelation function was well described by a stretched-exponential function indicating a linkage between the timescales of fast and slow functional relaxation dynamics. The findings of the QENS and INS investigation are discussed in relation to the results of our earlier elastic incoherent neutron scattering and molecular dynamics simulations.     

Perspectives on Inhibiting β‐Amyloid Aggregation through Structure‐Based Drug Design

Targeting β‐amyloid (Aβ) remains the most desired strategy in Alzheimer’s disease (AD) drug discovery research. Many peptides that specifically target Aβ aggregates are known, encompassing efforts from both industrial and academic research settings. However, in clinical terms, not much success has been gained with peptide research; in turn, small drug‐like molecules are already globally recognized as showing promise as an alternate approach. Aβ aggregation inhibitors are the most important part of the multifunctional drug design regimen for treating AD. Unfortunately, rational drug design approaches with small molecules are still in the initial stages. Herein we highlight, update, and elaborate on the structural anatomy of Aβ and known Aβ aggregation inhibitors in hopes of helping to optimize their use in structure‐based drug design approaches toward inhibitors with greater specificity. Furthermore, we present the first review of efforts to target a previously uncharacterized region of acetylcholinesterase: the N‐terminal 7–20 sub‐region, which was experimentally elucidated to participate in Aβ aggregation and deposition.     

EPA对大鼠学习记忆、血脂与抗氧化功能的影响

研究二十碳五烯酸(EPA)对大鼠空间学习记忆能力、抗氧化功能以及血脂的影响。将24只初断乳雄性SD大鼠随机分成阴性对照组、EPA低剂量组(150 mg/(kg·d))、中剂量组(300mg/(kg·d))、高剂量组(600 mg/(kg·d))。连续饲养30 d,进行Morris水迷宫实验测试,并同步测定脑组织乙酰胆碱酯酶、一氧化氮合酶、超氧化物歧化酶和丙二醛的含量以及血清总胆固醇、高密度脂蛋白胆固醇、甘油三酯的含量。结果显示:与阴性对照组相比,EPA低剂量组丙二醛含量显著降低;EPA高剂量组逃避潜伏期、丙二醛含量显著增高;EPA中剂量组超氧化物歧化酶活力增高、丙二醛含量显著降低。研究表明EPA不能提高大鼠的空间学习记忆能力,若剂量过大还会降低大鼠的空间学习记忆功能,但一定剂量的EPA能够改善大鼠的血脂水平与抗氧化功能。