The butyrylcholinesterase knockout mouse a research tool in the study of drug sensitivity, bio-distribution, obesity and Alzheimer's disease

Duysen, Ellen G.; Li, Bin; Lockridge, Oksana

doi:10.1517/17425250902915555

Cited by 33 publications

(20 citation statements)

References 33 publications

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“…BChE-K increases the risk for early onset cardiac disease (28), suggesting that other, rare BChE mutations with yet lower hydrolytic activities (for example, "atypical" D70G BChE [17]; or null BChE mutations [29]) may entail yet poorer recovery. Thanks to the slower hydrolytic pace of BChE compared with AChE, this increase can protect from the lethal consequences of cholinergic crisis due to AChE decline while preventing the debilitating outcome of failed cholinergic neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

Serum Cholinesterase Activities Distinguish between Stroke Patients and Controls and Predict 12-Month Mortality

Assayag

Shenhar‐Tsarfaty

Ofek

et al. 2010

Mol Med

100

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To date there is no diagnostic biomarker for mild stroke, although elevation of inflammatory biomarkers has been reported at early stages. Previous studies implicated acetylcholinesterase (AChE) involvement in stroke, and circulating AChE activity reflects inflammatory response, since acetylcholine suppresses inflammation. Therefore, carriers of polymorphisms that modify cholinergic activity should be particularly susceptible to inflammatory damage. Our study sought diagnostic values of AChE and Cholinergic Status (CS, the total capacity for acetylcholine hydrolysis) in suspected stroke patients. For this purpose, serum cholinesterase activities, butyrylcholinesterase-K genotype and inflammatory biomarkers were determined in 264 ischemic stroke patients and matched controls during the acute phase. AChE activities were lower (P < 0.001), and butyrylcholinesterase activities were higher in patients than in controls (P = 0.004). When normalized to sampling time from stroke occurrence, both cholinergic parameters were correlated with multiple inflammatory biomarkers, including fibrinogen, interleukin-6 and C-reactive protein (r = 0.713, r = 0.607; r = 0.421, r = 0.341; r = 0.276, r = 0.255; respectively; all P values < 0.001). Furthermore, very low AChE activities predicted subsequent nonsurvival (P = 0.036). Also, carriers of the unstable butyrylcholinesterase-K variant were more abundant among patients than controls, and showed reduced activity (P < 0.001). Importantly, a cholinergic score combining the two cholinesterase activities discriminated between 94.3% matched pairs of patients and controls, compared with only 75% for inflammatory measures. Our findings present the power of circulation cholinesterase measurements as useful early diagnostic tools for the occurrence of stroke. Importantly, these were considerably more distinctive than the inflammatory biomarkers, albeit closely associated with them, which may open new venues for stroke diagnosis and treatment.

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Section: Discussionmentioning

confidence: 99%

Serum Cholinesterase Activities Distinguish between Stroke Patients and Controls and Predict 12-Month Mortality

Assayag

Shenhar‐Tsarfaty

Ofek

et al. 2010

Mol Med

100

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“…BuChE deficient individuals are generally healthy with no manifest signs of disease 4 . The case is similar for mice with a damaged BuChE gene 5,6 . BuChE deficient individuals have increased sensitivity to muscle relaxants such as succinylcholine, resulting in lasting breath insufficiency 7 .…”

Section: Butyrylcholinesterasementioning

confidence: 90%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

320

219

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Background. Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology.Methods and Results. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium).Conclusions. The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

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“…BChE is less efficient in hydrolyzing Ach and less abundant in cholinergic synapses than AChE (Duysen et al. ; Johnson and Moore ). Mice with BChE genetic depletion have normal cholinergic function (Duysen et al.…”

Section: Discussionmentioning

confidence: 99%

Reduced vagal control of the heart in high-fat diet mice: a potential role of increased butyrylcholinesterase

et al. 2015

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Suppressed parasympathetic function is commonly present in cardiovascular diseases, aging, obesity, and various other health conditions. Impaired parasympathetic action is known as a detrimental factor and contributes to the adverse outcomes in these conditions. However, the underlying mechanisms remain to be fully addressed. In this study, using high-fat diet (HFD)-induced obese mice as a model, the potential peripheral mechanisms underlying the impaired parasympathetic vagal control of the heart was examined. The HFD induced obesity and metabolic disorder in mice. These obese mice exhibited an attenuated response in heart rate to vagal stimulation, indicating impairment of peripheral parasympathetic activity in the heart. In cholinergic function-related proteins in the atria, protein levels of choline transporter and vesicular acetylcholine transporter were not decreased but increased, and type 2 muscarinic receptors showed a trend toward a reduction in HFD mice atria as compared with regular diet (RD) mice controls. While the protein level of acetylcholinesterase was not different, butyrylcholinesterase (BChE) protein level showed a twofold increase in HFD mice atria as compared with RD mice. Functionally, inhibition of BChE activity partially and significantly improved the attenuated response in heart rate to vagal stimulation in HFD mice. Collectively, these data suggest that increased BChE activity in the atria may contribute to the decreased parasympathetic function in HFD-induced obese mice.

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The butyrylcholinesterase knockout mouse a research tool in the study of drug sensitivity, bio-distribution, obesity and Alzheimer's disease

Cited by 33 publications

References 33 publications

Serum Cholinesterase Activities Distinguish between Stroke Patients and Controls and Predict 12-Month Mortality

Serum Cholinesterase Activities Distinguish between Stroke Patients and Controls and Predict 12-Month Mortality

Cholinesterases, a Target of Pharmacology and Toxicology

Reduced vagal control of the heart in high-fat diet mice: a potential role of increased butyrylcholinesterase

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