L. Trabace et al., Biochemical and neurobehavioral profile of CHF2819, a novel, orally activeacetylcholinesterase inhibitor for Alzheimer's disease, J PHARM EXP, 294(1), 2000, pp. 187-194
Citations number
47
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol 2-ethylphe
nylcarbamate N-oxide hydrochloride (3aS-cis) (CHF2819) is a novel acetylcho
linesterase inhibitor that produces central cholinergic stimulation after o
ral administration in rats. In vivo studies show that CHF2819 (0.5, 1.5, an
d 4.5 mg/kg p.o.) significantly increases acetylcholine levels in young adu
lt rat hippocampus in a dose-dependent manner. Moreover, aged animals, whic
h show a significant decrease in basal acetylcholine levels with respect to
young adult rats, also exhibit a marked increase in the hippocampal concen
trations of this neurotransmitter after the administration of CHF2819. This
compound (1.5 mg/kg p.o.) significantly attenuates scopolamine-induced amn
esia in a passive avoidance task. Furthermore, CHF2819 induces a significan
t decrease in dopamine levels and a significant elevation of extracellular
concentrations of 5-hydroxytryptamine, whereas it does not modify norepinep
hrine and gamma-aminobutyric acid levels in the hippocampus of young adult
rats. Functional observational battery screening demonstrates that CHF2819
(1.5 and 4.5 mg/kg p.o.) does not affect activity, excitability, autonomic,
neuromuscular, and sensorimotor domains, as well as physiological end poin
ts (body weight and temperature). However, this compound induces involuntar
y motor movements (ranging from mild tremors to myoclonic jerks) in a dose-
dependent manner. These findings suggest that the anti-amnestic properties
of CHF2819, together with its stimulatory effect on cholinergic and seroton
ergic functions, might have a therapeutic potential mainly for the symptoma
tic treatment of Alzheimer's disease patients in which the cognitive impair
ment is accompanied by a depressive syndrome.