Acetylcholinesterase: A Primary Target for Drugs and Insecticides

Thapa, Sunita; Lv, Min; 徐, 会連

doi:10.2174/1389557517666170120153930

Cited by 92 publications

(49 citation statements)

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“…With respect to its termination of synaptic transmission, inhibition of AChE produces an excess accumulation of ACh and overstimulation of its receptors, causing uncoordinated neuromuscular function that often results in death due to respiratory paralysis [ 14 ]. As such, AChE inhibitors are widely used as pesticides [ 15 ] and anthelmintics [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

et al. 2017

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BackgroundSchistosomiasis affects over 200 million people and there are concerns whether the current chemotherapeutic control strategy (periodic mass drug administration with praziquantel (PZQ)—the only licenced anti-schistosome compound) is sustainable, necessitating the development of new drugs.Methodology/Principal findingsWe investigated the anti-schistosome efficacy of polypyridylruthenium(II) complexes and showed they were active against all intra-mammalian stages of S. mansoni. Two compounds, Rubb12-tri and Rubb7-tnl, which were among the most potent in their ability to kill schistosomula and adult worms and inhibit egg hatching in vitro, were assessed for their efficacy in a mouse model of schistosomiasis using 5 consecutive daily i.v. doses of 2 mg/kg (Rubb12-tri) and 10 mg/kg (Rubb7-tnl). Mice treated with Rubb12-tri showed an average 42% reduction (P = 0.009), over two independent trials, in adult worm burden. Liver egg burdens were not significantly decreased in either drug-treated group but ova from both of these groups showed significant decreases in hatching ability (Rubb12-tri—68%, Rubb7-tnl—56%) and were significantly morphologically altered (Rubb12-tri—62% abnormal, Rubb7-tnl—35% abnormal). We hypothesize that the drugs exerted their activity, at least partially, through inhibition of both neuronal and tegumental acetylcholinesterases (AChEs), as worms treated in vitro showed significant decreases in activity of these enzymes. Further, treated parasites exhibited a significantly decreased ability to uptake glucose, significantly depleted glycogen stores and withered tubercules (a site of glycogen storage), implying drug-mediated interference in this nutrient acquisition pathway.Conclusions/SignificanceOur data provide compelling evidence that ruthenium complexes are effective against all intra-mammalian stages of schistosomes, including schistosomula (refractory to PZQ) and eggs (agents of disease transmissibility). Further, the results of this study suggest that schistosome AChE is a target of ruthenium drugs, a finding that can inform modification of current compounds to identify analogues which are even more effective and selective against schistosomes.

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Section: Introductionmentioning

confidence: 99%

Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

et al. 2017

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“…Acetylcholinesterase is a serine hydrolase that is vital for regulating the neurotransmitter acetylcholine in insects. This enzyme is an excellent molecular target for the development of insecticides [56,57]. The well-known active site has a deep and narrow gorge, with a catalytic site at the bottom and a peripheral site at the entrance.…”

Section: Discussionmentioning

confidence: 99%

In Silico Studies on Compounds Derived from Calceolaria: Phenylethanoid Glycosides as Potential Multitarget Inhibitors for the Development of Pesticides

Loza-Mejía¹,

Salazar²,

Sánchez-Tejeda³

2018

Biomolecules

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An increasing occurrence of resistance in insect pests and high mammal toxicity exhibited by common pesticides increase the need for new alternative molecules. Among these alternatives, bioinsecticides are considered to be environmentally friendly and safer than synthetic insecticides. Particularly, plant extracts have shown great potential in laboratory conditions. However, the lack of studies that confirm their mechanisms of action diminishes their potential applications on a large scale. Previously, we have reported the insect growth regulator and insecticidal activities of secondary metabolites isolated from plants of the Calceolaria genus. Herein, we report an in silico study of compounds isolated from Calceolaria against acetylcholinesterase, prophenoloxidase, and ecdysone receptor. The molecular docking results are consistent with the previously reported experimental results, which were obtained during the bioevaluation of Calceolaria extracts. Among the compounds, phenylethanoid glycosides, such as verbascoside, exhibited good theoretical affinity to all the analyzed targets. In light of these results, we developed an index to evaluate potential multitarget insecticides based on docking scores.

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“…Ion channels have a key role in maintaining normal CNS function. The channel hypothesis supports that ion channels constructed by Aβ on the nerve cell membrane allow abnormal flows of intracellular and extracellular ions, destroy the dynamic balance of ions and leads to nerve cell death (Thapa et al, 2017). Kem et al (1997) found that alkaloids in marine-derived larvae regulated ion channels.…”

Section: Ion Channel Regulatormentioning

confidence: 93%

Current anti-Alzheimer's disease effect of natural products and their principal targets

2019

Journal of Integrative Neuroscience

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Various bioactive substances isolated from natural products play a pivotal role in the prevention and cure of neurodegenerative diseases, such as Alzheimer's disease. Currently, there are many theories about the pathogenesis of this disease. In this review we discuss among them, the cholinergic hypotheses, the Aβ toxicity hypothesis, and the tau dysfunction hypothesis. Multiple potential targets are a focus for the development of anti-AD drugs. There is an urgent need to develop more effective therapies to treat and delay the onset of the disease and to find safe and effective drugs. In this review, the recent progress of anti-AD effects and their principal targets are updated.

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Acetylcholinesterase: A Primary Target for Drugs and Insecticides

Cited by 92 publications

References 0 publications

Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases

In Silico Studies on Compounds Derived from Calceolaria: Phenylethanoid Glycosides as Potential Multitarget Inhibitors for the Development of Pesticides

Current anti-Alzheimer's disease effect of natural products and their principal targets

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