A new acetylcholinesterase inhibitor with anti-PAF activity modulates oxidative stress and pro-inflammatory mediators release in stimulated RAW 264.7 macrophage cells. Comparison with tacrine

Ezoulin, Miezan J.; Liu, Z.; Dutertre-Catella, H.; Wu, Guangdong; Dong, Chang‐Zhi; Heymans, Françoise; Ombetta, Jean-Edouard; Rat, Patrice; Massicot, France

doi:10.1016/j.intimp.2007.08.023

Cited by 12 publications

(6 citation statements)

References 59 publications

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“…Next, the macrophages were starved in RPMI 1640 medium supplemented with 2% FBS under humidified 5% CO 2 air at 37°C for at least 24 h. Next, the macrophages were stimulated for 8 min with mCRP (for Western blotting based on our previously published observations) and 24 h for inflammation assays following 2 h pre-incubation with acetylcholine (10–100 μM), nicotine (0.93 μM) or tacrine (1 μM). Concentrations of small molecules were chosen based on published literature showing their use as inhibitors in macrophages/glia, [acetylcholine, ( 8 )]; [nicotine, ( 9 )]; [tacrine, ( 10 )] and our own pilot observations and optimization (toxicity assay assessment of viability using a range of concentrations for the three molecules showed that the concentrations above were non-toxic to the U937 cells). For the monocyte-EC adhesion assay, immortalized human brain microvascular EC cells (HbMEC), were kindly donated by Prof. Babette Weksler (Division of Hematology and Medical Oncology, Weill Medical College, Cornell University, New York).…”

Section: Methodsmentioning

confidence: 99%

Acetylcholine Inhibits Monomeric C-Reactive Protein Induced Inflammation, Endothelial Cell Adhesion, and Platelet Aggregation; A Potential Therapeutic?

et al. 2018

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Objectives: In this study, we examined the possibility of using targeted antibodies and the potential of small molecular therapeutics (acetylcholine, nicotine and tacrine) to block the pro-inflammatory and adhesion-related properties of monomeric C-reactive protein (mCRP).Methods: We used three established models (platelet aggregation assay, endothelial leucocyte binding assay and monocyte inflammation via ELISA and Western blotting) to assess the potential of these therapeutics.Results: The results of this study showed that monocyte induced inflammation (raised tumor necrosis factor-alpha-TNF-α) induced by mCRP was significantly blocked in the presence of acetylcholine and nicotine, whilst tacrine and targeted antibodies (clones 8C10 and 3H12) had less of or no significant effects. Western blotting confirmed the ability of acetylcholine to inhibit mCRP-induced cell signaling phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), p38 and nuclear factor-kappa B (NF-κB). There was no evidence of direct binding between small molecules and mCRP. mCRP also induced endothelial cell-monocyte adhesion in a dose dependent fashion, however, both acetylcholine and nicotine as well as targeting antibodies notably inhibited adhesion. Finally, we investigated their effects on mCRP-induced platelet aggregation. All three small molecules significantly attenuated platelet aggregation as did the antibody 8C10, although 3H12 had a weaker effect.Discussion: Acetylcholine and to a lesser extent nicotine show potential for therapeutic inhibition of mCRP-induced inflammation and cell and platelet adhesion. These results highlight the potential of targeted antibodies and small molecule therapeutics to inhibit the binding of mCRP by prevention of membrane interaction and subsequent activation of cellular cascade systems, which produce the pro-inflammatory effects associated with mCRP.

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Section: Methodsmentioning

confidence: 99%

Acetylcholine Inhibits Monomeric C-Reactive Protein Induced Inflammation, Endothelial Cell Adhesion, and Platelet Aggregation; A Potential Therapeutic?

et al. 2018

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“…PMS777 (1-100 µM) could dose-dependently inhibit PAF-induced rabbit platelet aggregation and markedly inhibit brain AChE activity in mice with a modest selectivity for AChE [ 48 ]. It was also able to fight oxidative injury [ 49 , 50 ], modulate the release of pro-inflammatory mediators [ 51 ], attenuate PAF-induced neurocytotoxicity and neuroinflammation [ 52 , 53 ], and regulate APP processing in vitro [ 54 ]. Additionally, in vivo study found that PMS777 could reverse spatial memory deficits induced by scopolamine in mouse model [ 48 ].…”

Section: The Multi-target Directed Ligands (Mtdls) a New Paradigm Fomentioning

confidence: 99%

AChE Inhibition-based Multi-target-directed Ligands, a Novel Pharmacological Approach for the Symptomatic and Disease-modifying Therapy of Alzheimer's Disease

Wang¹,

Wang

Chen

2016

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Alzheimer's disease (AD) is the most common form of dementia in elder people, characterised by a progressive decline in memory as a result of an impairment of cholinergic neurotransmission. To date acetylcholinesterase inhibitors (AChEIs) have become the most prescribed drugs for the symptomatic treatment of mild to moderate AD. However, the traditional “one molecule-one target” paradigm is not sufficient and appropriate to yield the desired therapeutic efficacy since multiple factors, such as amyloid-β (Aβ) deposits, neuroinflammation, oxidative stress, and decreased levels of acetylcholine (ACh) have been thought to play significant roles in the AD pathogenesis. New generation of multi-target drugs is earnestly demanded not only for ameliorating symptoms but also for modifying the disease. Herein, we delineated the catalytic and non-catalytic functions of AChE, and summarized the works of our group and others in research and development of novel AChEI-based multi-target-directed ligands (MTDLs), such as dual binding site AChEIs and multi-target AChEIs inhibiting Aβ aggregation, regulating Aβ procession, antagonizing platelet-activating factor (PAF) receptor, scavenging oxygen radical, chelating metal ions, inhibiting monoamine oxidase B (MAO-B), blocking N-methyl-D-aspartic acid (NMDA) receptor and others.

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“…ROS formation is a process that starts very early and worsens over the course of the disease (Amaral et al, 2008). Recently the anti-cholinesterase drug tacrine (the same chemical class as neuromidin) was found to decrease ROS production and TNF alpha level without preventing loss of mitochondrial activity (Ezoulin et al, 2007). Another explanation of the efficacy of neuromidin in the diabetic neuropathy model can be associated with its eventual influence on sodium ion channels.…”

Section: Discussionmentioning

confidence: 99%

Neuromidin Attenuates Neuropathic Pain in the Streptozocin-Induced Diabetes Model in Rats

Kluša¹,

Rumaks²,

Karajeva³

2008

Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences.

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A new acetylcholinesterase inhibitor with anti-PAF activity modulates oxidative stress and pro-inflammatory mediators release in stimulated RAW 264.7 macrophage cells. Comparison with tacrine

Cited by 12 publications

References 59 publications

Acetylcholine Inhibits Monomeric C-Reactive Protein Induced Inflammation, Endothelial Cell Adhesion, and Platelet Aggregation; A Potential Therapeutic?

Acetylcholine Inhibits Monomeric C-Reactive Protein Induced Inflammation, Endothelial Cell Adhesion, and Platelet Aggregation; A Potential Therapeutic?

AChE Inhibition-based Multi-target-directed Ligands, a Novel Pharmacological Approach for the Symptomatic and Disease-modifying Therapy of Alzheimer's Disease

Neuromidin Attenuates Neuropathic Pain in the Streptozocin-Induced Diabetes Model in Rats

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