Mechanisms of Action of Cognitive Enhancers on Neuroreceptors

Abstract

No strategies for curing Alzheimer's disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer's disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients' cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer's disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long. Thus new approaches are needed. One approach is to stimulate directly nicotinic acetylcholine (nACh) receptors in the brain, and another is to stimulate NMDA receptors which are also known to be downregulated in Alzheimer's patients. Nefiracetam has been shown to potentiate ACh currents in the a a4b b2 receptor of rat cortical neurons with a bell-shaped dose-response relationship and the maximum effect at 1 nM. This effect was exerted via G s proteins. The a a7 receptor was almost unaffected by nefiracetam. Nefiracetam also potentiated NMDA currents with the maximum effect at 10 nM via interaction with the glycine-binding site of the receptor. Galantamine had a moderate potentiating effect on the a a4b b2 receptor and potentiated NMDA currents with the maximum effect at 1 m mM. However, galantamine did not interact with the glycine-binding site. Donepezil, a potent anticholinesterase, also potentiated NMDA currents at 1-10000 nM. In conclusion, these three drugs potentiate the activity not only of the cholinergic system but also of the NMDA system, thereby stimulating the downregulated nACh receptors and NMDA receptors to improve patients' learning, cognition, and memory.

Combination of Rimonabant and Donepezil Prolongs Spatial Memory Duration

“…Specifically, it has been suggested that mechanisms other than enhancement of cholinergic function may be involved in the pharmacology of donepezil efficacy in improving cognition (Narahashi et al, 2004;Moriguchi et al, 2005). Systemic administration of donepezil has been found to increase levels of norepinephrine, dopamine, and serotonin, in addition to its effects on acetylcholine (Cuadra et al, 1994;Giacobini et al, 1996;Shearman et al, 2006).…”

Depressão vascular no idoso: resposta ao tratamento antidepressivo associado a inibidor das colinesterases

“…Sintomas não cognitivos presentes em casos de DA, como ansiedade e depressão, são usualmente descritos como secundários a uma disfunção nos sistemas desses neurotransmissores (Assal e Cummings, 2002;Erkinjuntti, 2002), o que torna essa hipótese ainda mais relevante. Além disso, um estudo com pacientes deprimidos, utilizando fluoxetina, citalopram e paroxetina, sugeriu a hipótese da sensibilização dos receptores "D2-like" como efeito central da ação antidepressiva dos ISRS (Narahashi, 2004).…”

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

“…Tacrine directly enhances acetylcholine transmission by inhibition of AChE while deprenyl will increase acetylcholine activity indirectly via improved dopamine function (Tariot et al, 1987;Piccinin et al, 1990;Mangoni et al, 1991;Molinengo and Ghi, 1997). Nefiracetam also exerts strong effects on cholinergic function and, in vitro, this nootrope has been shown to enhance neuritogenesis and NCAM PSA expression (Odumeru et al, 1997;Woodruff Pak and Hinchliffe, 1997;Oyaizu and Naharishi, 1999;Nishizaki et al, 2000;Narahashi et al, 2004). It is also likely that other transmitter systems enhancing neural activity will contribute to this neuroplastic response as previous studies have suggested activation of NMDA receptors to result in increased polysialylation in ex vivo preparations of neural tissue (Bouzioukh et al, 2001).…”

“…Moreover, several such potential Alzheimer's treatments have been shown to augment cholinergic function. For example, the nootropic antidementia agent nefiracetam stimulates nicotinic receptors as efficiently as galantamine and donepezil, an effect that is dependent on Gs protein(s) (Nishizaki et al, 2000;Shorvon, 2001;Narahashi et al, 2004). Also, the procognitive action of the monoamine oxidase B inhibitor, l-deprenyl, in aged rats and Alzheimer's patients is thought to result from monoaminergic-driven enhancement of cholinergic function, in particular, in the hippocampus (Tariot et al, 1987;Piccinin et al, 1990;Mangoni et al, 1991;Molinengo and Ghi, 1997).…”