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Abstract
E2020 is a piperidine cholinesterase inhibitor (ChEI) which is structurally distinct
from other compounds presently under study for treatment of Alzheimer's disease. We
studied the effect of this compound on acetylcholine (ACh), norepinephrine (NE), dopamine
(DA) and serotonin (5-HT; 5-hydroxytryptamine) by means of transcortical microdialysis
in the cortex of awake rats with no ChEI in the probe. We also compared the inhibition
of brain cholinesterase (ChE) by two different approaches. Following 0.5 and 2.0 mg/kg
s.c. administration, the increase in ACh was 200% (30 min) and 2100% (1 hr), respectively.
The maximal ChE inhibition at 30 min was 35.5% (2.0 mg/kg) and 15.6% (0.5 mg/kg) when
measured as ACh hydrolysis in the diluted homogenate. After the 2.0 mg/kg dose, phosphorylation
by DFP was completely blocked at 30 min. After 0.5 mg/kg, ChE phosphorylation was
maximally inhibited at 30 min (56%) and declined thereafter to negligible levels by
3 hr. In addition, E2020 increased extracellular levels of catecholamines in cortex
in agreement with our previous findings with carbamate ChEI. Following 2.0 mg/kg,
both NE (100%) and DA (80%) were elevated, whereas after 0.5 mg/kg only NE (50%) was
affected. Neither dose affected extracellular 5-HT. Thus, E2020, which inhibits brain
ChE by a novel, reversible mechanism, elevates extracellular ACh in a comparable manner
to other centrally-active ChEI, and this elevation of ACh is associated with stimulation
of catecholamine release.