CHF2819: pharmacological profile of a novel acetylcholinesterase inhibitor.
ABSTRACT CHF2819 is a novel orally active acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD). CHF2819 is a selective inhibitor of AChE, it is 115 times more potent against this enzyme than against butyrylcholinesterase (BuChE). Moreover, CHF2819 is more selective for inhibition of central (brain) AChE than peripheral (heart) AChE. In vivo CHF2819, 0.5, 1.5, and 4.5 mg/kg p.o., significantly and in dose-dependent manner increased acetylcholine (ACh) levels in hippocampus of young adult rats. Moreover, aging animals, with lower basal ACh levels than young adult rats, also exhibit a marked increase in hippocampal levels of this neurotransmitter after administration of CHF2819. At 1.5 mg/kg p.o. CHF2819 attenuated scopolamine-induced amnesia in a passive avoidance task. Furthermore, it decreased dopamine (DA) levels and increased extracellular levels of 5-hydroxytryptamine (5-HT) in the hippocampus, without modifying norepinephrine (NE) levels. By oral administration to young adult rats CHF2819 did not affect extracellular hippocampal levels of glutamate (Glu), aspartate (Asp), gamma-aminobutyric acid (GABA), taurine (Tau), arginine (Arg) or citrulline (Cit). Functional observational battery (FOB) screening demonstrated 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 endpoints (body weight and temperature). CHF2819 induced, however, involuntary motor movements (ranging from mild tremors to myoclonic jerks) in a dose-dependent manner. The neurochemical and behavioral profiles of CHF2819 suggest that this orally active novel AChEI could be of clinical interest for the treatment of Alzheimer-type dementia associated with multiple neurotransmitter abnormalities in the brain. In particular, CHF2819 might be a useful therapeutic drug for AD patients with cognitive impairment accompanied by depression.
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ABSTRACT: The present study examines whether tetrahydroaminoacridine (THA) can improve the deterioration in passive avoidance (PA) retention performance induced by medial septal (MS) and fimbria-fornix (FF) lesions in young rats or by aging. Retention of young MS-lesioned rats was improved by pretraining injection of THA at 3 mg/kg, but not by THA at 1 mg/kg or by either of the posttraining doses of THA (1 and 3 mg/kg). Pretraining injections of THA at 1 or 3 mg/kg had no effect on the PA retention performance of FF-lesioned rats. Age-induced PA failure was alleviated by pretraining administration of THA at 1 and 3 mg/kg. Posttraining injections of THA (1 or 3 mg/kg) had no effect on PA retention performance of aged rats. These results demonstrate that 1) THA may improve hippocampal cholinergic denervation-induced functional deficits and 2) some of the age-related PA deficits may be due to a cholinergic deficit and can be reversed with THA.Brain Research Bulletin 12/1991; 27(5):587-94. · 2.94 Impact Factor
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ABSTRACT: A dialysis loop cannula was implanted into rat striatum under anesthetized condition, and the area was perfused with Ringer's solution under freely moving condition after 3 days for surgical recovery. Dopamine (DA) and 3,4-dihydroxyphenylacetic acid recovered in the dialysate were measured by high-performance liquid chromatography with electrochemical detection. The effects of M1- and M2-muscarinic receptor agents, which were perfused continuously into the striatum through the dialysis membrane, were investigated. Continuous perfusion of AF102B, an M1-selective agonist, and oxotremorine, a non-selective agonist, resulted in a dose-dependent increase in the striatal DA release. Pirenzepine (10(-5) and 10(-7) M), an M1-selective antagonist, decreased the release of DA, and the stimulatory effect of AF102B (10(-5) M) was completely inhibited by 10(-5) and 10(-7) M pirenzepine, while the stimulatory effect of oxotremorine (10(-4) M) was only partly inhibited by 10(-5) M pirenzepine. AF-DX116 (10(-5) M), an M2-selective antagonist, increased the DA release, and showed an additive effect on the DA release evoked by AF102B (10(-5) M), whereas it produced no significant effect on oxotremorine (10(-5) M)-evoked DA release. These results suggest that in vivo DA release in the rat striatum is modulated by different subtypes of muscarinic receptors; i.e., the stimulatory effect is mainly mediated by M1-sites and inhibitory effect is mainly mediated by M2-sites. The changes in the DA release induced by the various drugs were prevented by pretreatment with tetrodotoxin (TTX). Since action potential-dependent DA release (exocytosis) is blocked by the pretreatment with TTX, those drugs affect DA release by means of action potential-dependent processes.Brain Research 09/1989; 495(2):232-42. · 2.88 Impact Factor
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ABSTRACT: Aged memory-impaired (AI) and unimpaired (AU) 24-25-month-old Long-Evans rats were used to investigate the integrity of various cholinergic markers during normal aging and to establish if alterations can possibly relate to cognitive disabilities. AI and AU rats were classified on the basis of their performance in the Morris swim maze task. Choline acetyltransferase activity (ChAT) was not differentially altered in various cortical and hippocampal areas between these two groups. Similarly, quantitative receptor autoradiography did not reveal significant differences in 3H-pirenzepine/muscarinic M1 and 3H-hemicholinium-3/high-affinity choline uptake binding sites in AI versus AU rats. In contrast, 3H-AF-DX 384/putative muscarinic M2 binding was significantly increased in certain cortical and hippocampal areas of the age-impaired animals. These increments were correlated with decreased in vivo acetylcholine (ACh) release capacity in the AI rats. Most interestingly, the muscarinic M2 antagonist BIBN-99 reversed, in a dose-dependent manner, the impaired ACh release as well as the cognitive deficits observed in the AI group. Similarly, BIBN-99 reversed scopolamine-induced amnesia in young animals. The efficacy of BIBN-99 likely relates to its antagonistic properties on negative muscarinic M2 autoreceptors that are apparently increased in the AI animals, leading to altered ACh release. Taken together, these findings strengthen the role of ACh in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic functions, such as Alzheimer's disease.Journal of Neuroscience 03/1995; 15(2):1455-62. · 6.91 Impact Factor