Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine

Mesulam, M-Marsel; Guillozet, Angela L.; Shaw, Pamela L; Levey, Aĺlan I.; Duysen, Ellen G.; Lockridge, Oksana

doi:10.1016/s0306-4522(01)00613-3

Cited by 582 publications

(335 citation statements)

References 31 publications

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“…The field excitatory postsynaptic potentials (fEPSPs) were recorded in CA1 stratum radiatum with electrodes containing ACSF (impedance of 2-4 M⍀) using an Axopatch-1D amplifier (Axon Instruments). The presence of BChE in the neuropil of rodent hippocampus has been confirmed (11).…”

Section: Ex Vivo Long-term Potentiation (Ltp)mentioning

confidence: 80%

Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent

Greig

Utsuki

Ingram

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

664

433

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Like acetylcholinesterase , butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused longterm inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra-and extracellular ␤-amyloid precursor protein, and secreted ␤-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower ␤-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.anticholinesterase ͉ long-term potentiation ͉ dementia ͉ memory ͉ neurodegeneration

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Section: Ex Vivo Long-term Potentiation (Ltp)mentioning

confidence: 80%

Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent

Greig

Utsuki

Ingram

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

664

433

View full text Add to dashboard Cite

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“…The survival and 'normality' of the brain of AChE knockout (AChE−/−) versus normal (AChE+/+) mice, together with the distinct and overlapping distribution patterns of AChE-and BuChE-positive neurons, supports the opinion that BuChE is involved in neural function (Mesulam et al 2002;Rice et al 2007), for example co-regulation of cholinergic and non-cholinergic neurotransmission Giacobini 2003;). This viewpoint is fortified by animal studies indicating that selective BuChE-Is, cymserine analogues, elevate brain levels of ACh in AChE+/+ and −/− animals, augment LTP in brain slice preparations and improve cognitive performance of aged rodents without adverse actions (Greig et al 2005c;Hartmann et al 2007).…”

Section: Introductionmentioning

confidence: 84%

“…The recent development of AChE−/− mice that readily survive with normal levels and localization of BuChE (Mesulam et al 2002) and no neuronal, dendritic, astrocytic, synaptic, microglial or endothelial differences (Rice et al 2007), together with the development of entirely selective BuChE-Is, such as (−)-N1-phenethylcymserine (PEC) (Yu et al 1999), that elevate brain ACh levels in normal and AChE−/− mice (Greig et al 2005c;Hartmann et al 2007), indicates that brain BuChE has a physiological function. The relevance of this can be assessed from recent studies by Cerbai et al (2007), where donepezil (AChE selective), rivastigmine (AChE/BuChE unselective) and PEC (BuChE selective) were administered systemically to normal healthy rats to achieve similar twofold to threefold elevations in brain extracellular ACh levels, as determined by in vivo microdialysis and HPLC.…”

Section: Discussionmentioning

confidence: 99%

Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis

Kamal

et al. 2008

J Neural Transm

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Synaptic loss, particularly related to the forebrain cholinergic system, is considered to be an early event that leads to Alzheimer's disease (AD) and has led to the development of acetylcholinesterase inhibitors (AChE-Is) as the mainstay of treatment for several degenerative disorders that culminate in dementia. The primary dose-limiting toxicities of all clinically available AChE-Is are, similar to useful actions on cognition, cholinergically mediated and they ultimately limit the value of this drug class in achieving anything but symptomatic improvements. In addition, AChE levels in brain areas associated with AD decline with disease progression, which likely ultimately limits the therapeutic utility of this drug class. New research indicates that selective inhibition of butyrylcholinesterase (BuChE), a closely related enzyme that is markedly elevated in AD brain, increases acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of AChE-Is. BuChE inhibition hence represents an innovative treatment approach for AD, and agents are currently being synthesized to optimally achieve this. The novel compound, tetrahydrofurobenzofuran cymserine (THFBFC), is derived from our effort to produce a potent and BuChE-selective inhibitor as a candidate to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. Herein, we applied innovative enzyme kinetic analyses to characterize the quantitative interaction of THFBFC with human BuChE. These provided values for the agent's IC50, together with specific new kinetic constants, such as KT50, KT1/2, RI, oKRT, oPmax, KPT and PT1/2, to aid define target concentrations for clinical translation. Additional classical kinetic parameters, including Ki, Km or Ks, kcat or Vmax and Vmi were also determined. THFBFC proved to be a potent competitive inhibitor of human BuChE and, like its isomer dihydrobenzodioxepine cymserine, is a potentially interesting AD drug candidate.

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“…However, we also noted that BChE activity increased significantly (P< 0.02) in sham controls relative to nonimplanted controls. These observations are of particular interest in view of the recent work conducted with AChE knockout mice indicating a previously unrecognized and potentially important role for BChE in the brain (Li et al, 2000;Mesulam et al, 2002). Animals were exposed to PB and/or stress for 7 days.…”

Section: Validation Of the Modelmentioning

confidence: 90%

Low Level Chemical Toxicity: Relevance to Chemical Agent Defense

Morris¹

2003

PsycEXTRA Dataset

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Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine

Cited by 582 publications

References 31 publications

Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent

Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer β-amyloid peptide in rodent

Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis

Low Level Chemical Toxicity: Relevance to Chemical Agent Defense

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