Biochemical and neurobehavioral profile of CHF2819, a novel, orally activeacetylcholinesterase inhibitor for Alzheimer's disease

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.