1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo¿2,3-bĭndol-5-ol 2-ethylphenylcarbamate N-oxide hydrochloride (3aS-cis) (CHF2819) is a novel acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral administration in rats. In vivo studies show that CHF2819 (0.5, 1.5, and 4.5 mg/kg p.o.) significantly increases acetylcholine levels in young adult rat hippocampus in a dose-dependent manner. Moreover, aged animals, which show a significant decrease in basal acetylcholine levels with respect to young adult rats, also exhibit a marked increase in the hippocampal concentrations of this neurotransmitter after the administration of CHF2819. This compound (1.5 mg/kg p.o.) significantly attenuates scopolamine-induced amnesia in a passive avoidance task. Furthermore, CHF2819 induces a significant decrease in dopamine levels and a significant elevation of extracellular concentrations of 5-hydroxytryptamine, whereas it does not modify norepinephrine 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 points (body weight and temperature). However, this compound induces involuntary 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 serotonergic functions, might have a therapeutic potential mainly for the symptomatic treatment of Alzheimer's disease patients in which the cognitive impairment is accompanied by a depressive syndrome.

Biochemical and neurobehavioral profile of CHF2819, a novel orally active acethylcholinesterase inhibitor for Alzheimer’s disease / Trabace, L.; Cassano, T.; Steardo, Luca; Pietra, C.; Villetti, G.; Kendrick, K. M.; Cuomo, Vincenzo. - In: THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - STAMPA. - 294(1):(2000), pp. 187-194.

Biochemical and neurobehavioral profile of CHF2819, a novel orally active acethylcholinesterase inhibitor for Alzheimer’s disease

STEARDO, LUCA;CUOMO, VINCENZO
2000

Abstract

1,2,3,3a,8,8a-Hexahydro-1,3a,8-trimethylpyrrolo¿2,3-bĭndol-5-ol 2-ethylphenylcarbamate N-oxide hydrochloride (3aS-cis) (CHF2819) is a novel acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral administration in rats. In vivo studies show that CHF2819 (0.5, 1.5, and 4.5 mg/kg p.o.) significantly increases acetylcholine levels in young adult rat hippocampus in a dose-dependent manner. Moreover, aged animals, which show a significant decrease in basal acetylcholine levels with respect to young adult rats, also exhibit a marked increase in the hippocampal concentrations of this neurotransmitter after the administration of CHF2819. This compound (1.5 mg/kg p.o.) significantly attenuates scopolamine-induced amnesia in a passive avoidance task. Furthermore, CHF2819 induces a significant decrease in dopamine levels and a significant elevation of extracellular concentrations of 5-hydroxytryptamine, whereas it does not modify norepinephrine 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 points (body weight and temperature). However, this compound induces involuntary 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 serotonergic functions, might have a therapeutic potential mainly for the symptomatic treatment of Alzheimer's disease patients in which the cognitive impairment is accompanied by a depressive syndrome.
2000
FREELY MOVING RATS; CORTEX IN-VIVO; AGED RATS; EXTRACELLULAR ACETYLCHOLINE; EVOKED RELEASE; DOPAMINE; STRIATUM; TACRINE; MEMORY; METRIFONATE
01 Pubblicazione su rivista::01a Articolo in rivista
Biochemical and neurobehavioral profile of CHF2819, a novel orally active acethylcholinesterase inhibitor for Alzheimer’s disease / Trabace, L.; Cassano, T.; Steardo, Luca; Pietra, C.; Villetti, G.; Kendrick, K. M.; Cuomo, Vincenzo. - In: THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. - ISSN 0022-3565. - STAMPA. - 294(1):(2000), pp. 187-194.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/252944
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