Butyrylcholinesterase inhibition (MoA of Exelon) ameliorates cognitive dysfunction induced by amyloid-ß peptide in mice.
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Moussaoui, Saliha (2011) Butyrylcholinesterase inhibition (MoA of Exelon) ameliorates cognitive dysfunction induced by amyloid-ß peptide in mice. Behavioural Brain Research, 225 (1). pp. 222-229. ISSN 0166-4328
Abstract
The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl-norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-β peptide (Aβ(1-40)) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aβ(1-40) or the control peptide Aβ(40-1) on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0mg/kg), rivastigmine (0.03, 0.1, 0.3mg/kg) or PEC (1.0, 3.0mg/kg) 20min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aβ(1-40) induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in Aβ(1-40) challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aβ(1-40) induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.
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| Additional Information: | This a piece of key very recent information that shows for the first time that not only acetylcholinesterase inhibition, but also butyrylcholinesterase (BChE) inhibition mechanism of Exelon (rivastigmine) is linked to improve cognition in mice. This is in agreement with another of our studies using KO AChE and BChE mice that both enzymes are responsible of degradation of acetylcholine and that inhibition of both enzymes should increase acetylcholine and therefore the cholinergic neurotransmission at the synaptic level. In addition, BChE enzyme increases with disease severity in Alzheimer's disease. Rivastigmine being the only marketed dual BChE+ AChE inhibitor, and not competitors (donepezil and galantamine which are selective AChE inhibitors), may be associated with better efficacy in severe Alzheimer's and other conditions where BChE enzyme increases. |
| Keywords: | Exelon, rivastigmine, butyrylcholinesterase, cognition, Alzheimer's disease |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/8264 |