Effects of rivastigmine and donepezil on brain acetylcholine levels in acetylcholinesterase-deficient mice.
OBJECTIVE
Alzheimer s disease is characterized by a dysfunction of central cholinergic systems and is treated by inhibitors of acetylcholinesterase (AChE). This study tests the effect of two AChE inhibitors in therapeutic use, rivastigmine and donepezil, in mice that are devoid of AChE (AChE-/- mice). Rivastigmine is an inhibitor of both AChE and butyrylcholinesterase (BChE) whereas donepezil is a selective inhibitor of AChE.


METHODS
We have used in vivo microdialysis to investigate the effects of the two drugs on the extracellular concentration of acetylcholine (ACh) in the hippocampus of AChE-/- mice.


RESULTS
Extracellular ACh levels in the hippocampus were 30-fold elevated in AChE-/- mice compared to wild-type (AChE+/+) animals. Infusion of rivastigmine (1 and 10 microM) caused a further doubling of ACh levels in AChE-/- mice within 90-120 min. In contrast, infusion of donepezil (1 microM) did not affect hippocampal ACh levels in AChE-/- mice although it increased ACh levels more than twofold in wild-type mice.


CONCLUSIONS
In the absence of AChE, rivastigmine enhances the levels of extracellular ACh by inhibiting BChE. This finding may be of therapeutic relevance because BChE activity is preserved, but AChE activity is strongly decreased, in late-stage Alzheimer s disease.
Naik
Runa S
RS
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, 1300 Coulter Dr, Amarillo, TX 79106, USA.
Hartmann
Joachim
J
Kiewert
Cornelia
C
Duysen
Ellen G
EG
Lockridge
Oksana
O
Klein
Jochen
J
D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000172:deficiency*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077265:Donepezil; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D048448:Phenylcarbamates / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D000068836:Rivastigmine
D002800:Cholinesterase Inhibitors; D007189:Indans; D048448:Phenylcarbamates; D010880:Piperidines; D000077265:Donepezil; D000110:Acetylcholinesterase; D000109:Acetylcholine; D000068836:Rivastigmine