Excessive hippocampal acetylcholine levels in acetylcholinesterase‐deficient mice are moderated by butyrylcholinesterase activity

Journal of Neurochemistry - Tập 100 Số 5 - Trang 1421-1429 - 2007
Joachim Hartmann1, Cornelia Kiewert2, Ellen G. Duysen3, Oksana Lockridge4, Nigel H. Greig5, Jochen Klein3
1Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, Amarillo, Texas 79106, USA.
2Texas Tech University Health Sciences Center
3University of Nebraska Medical Center
4Eppley Institute for Cancer Research
5NATIONAL INSTITUTES OF HEALTH

Tóm tắt

AbstractCentral cholinergic systems are involved in a plethora of brain functions and are severely and selectively damaged in neurodegenerative diseases such as Alzheimer’s disease and dementia with Lewy bodies. Cholinergic dysfunction is treated with inhibitors of acetylcholinesterase (AChE) while the role of butyrylcholinesterase (BChE) for brain cholinergic function is unclear. We have usedin vivomicrodialysis to investigate the regulation of hippocampal acetylcholine (ACh) levels in mice that are devoid of AChE (AChE‐/‐ mice). Extracellular ACh levels in the hippocampus were 60‐fold elevated in AChE‐/‐ mice compared with wild‐type (AChE+/+) animals. In AChE‐/‐ mice, calcium‐free conditions reduced hippocampal ACh levels by 50%, and infusion of tetrodotoxin by more than 90%, indicating continuous ACh release. Infusion of a selective AChE inhibitor (BW284c51) caused a dose‐dependent, up to 16‐fold increase of extracellular ACh levels in AChE+/+ mice but did not change ACh levels in AChE‐/‐ mice. In contrast, infusion of a selective inhibitor of BChE (bambuterol) caused up to fivefold elevation of ACh levels in AChE‐/‐ mice, but was without effect in AChE+/+ animals. These results were corroborated with two other specific inhibitors of AChE and BChE, tolserine and bis‐norcymserine, respectively. We conclude that lack of AChE causes dramatically increased levels of extracellular ACh in the brain. Importantly, in the absence of AChE, the levels of extracellular ACh in the brain are controlled by the activity of BChE. These results point to a potential usefulness of BChE inhibitors in the treatment of central cholinergic dysfunction in which brain AChE activity is typically reduced.

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Tài liệu tham khảo

10.1177/0891988704267463

10.1002/mus.20099

10.1016/0197-0186(92)90189-X

10.2174/1567205054367838

10.1038/nn788

10.1016/S1044-7431(03)00034-4

10.1042/bj2600625

10.1016/0306-4522(86)90002-3

10.1002/cne.10751

10.1038/nrn1035

10.1152/physrev.1995.75.2.393

10.1016/S0165-3806(02)00367-X

10.1146/annurev.psych.48.1.649

10.1136/jnnp.66.2.137

Gauthier S., 2002, Advances in the pharmacotherapy of Alzheimer’s disease, CMAJ, 166, 616

10.1185/030079903125002450

10.1023/A:1022869222652

10.1016/j.phrs.2003.11.017

10.1016/j.nlm.2003.07.003

10.1002/cne.901890409

10.1073/pnas.0508575102

10.1016/j.neuroscience.2004.02.038

10.1016/0024-3205(77)90437-4

10.1046/j.1471-4159.2002.00791.x

10.1073/pnas.95.7.4029

10.1038/npp.1993.81

10.1016/S0197-0186(97)00123-X

10.1016/j.neulet.2004.04.046

10.1016/S0167-4838(99)00124-7

10.1046/j.1471-4159.2000.751320.x

10.1016/S0091-3057(03)00022-4

10.1016/S1474-4422(03)00619-7

10.1016/S0306-4522(01)00613-3

10.1111/j.1365-2990.1978.tb00545.x

10.1097/00005072-199705000-00006

10.1016/j.coph.2005.01.014

10.1038/35067589

10.1586/14737175.5.1.101

10.1001/archpsyc.59.10.946

10.1002/ana.10589

10.1016/S0165-0270(01)00401-0

Xie W., 2000, Postnatal developmental delay and supersensitivity to organophosphate in gene‐targeted mice lacking acetylcholinesterase, J. Pharmacol. Exp. Ther., 293, 896, 10.1016/S0022-3565(24)39312-7

10.1021/jm980459s

10.1523/JNEUROSCI.22-05-01709.2002

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Journal of Neurochemistry

Tập 100 Số 5

1421-1429

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