Chapter 33 The cholinergic receptor system of the human brain: neurochemical and pharmacological aspects in aging and Alzheimer

Giacobini, Ezio; DeSarno, Patrizia; Clark, Brent; McIlhany, Michael

doi:10.1016/s0079-6123(08)62493-0

Cited by 50 publications

(36 citation statements)

References 29 publications

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“…The data presented in Table 8 support the concept of an optimal brain ChE inhibition and functional ACh levels that might vary for each drug and relate to an optimal gain in cognitive and therapeutic effect (13, 34,35). This hypothesis is in accordance with pharmacological data in animals (3, 36) and in humans (34). The level of peripheral enzyme inhibition, which has been measured in patients (AChE activity in erythrocytes or plasma BuChE activity), producing maximal effect on cognitive testing varies between 30% and 60010 depending on kinetic and phar macological characteristics of the compound (Table 8).…”

Section: Molecular Design Of New Cholinesterase Inhibitorssupporting

confidence: 92%

“…However, for some drugs, (see E-2020 and metrifonate), this can be as high as 80%. As predicted by pharma cological and behavioral data, there is a clear correlation between ChE inhibition (or drug plasma concentration) and cognitive effect (36,37). Drugs producing only mild side effects at high dosage and causing high brain ChE inhibition have the advantage that they can be tested clinically within their full range of therapeutic potential.…”

Section: Molecular Design Of New Cholinesterase Inhibitorsmentioning

confidence: 97%

“…Depending on the region, human brain AChE activity is 1.5 (temporal and parietal cortex) to 60 (caudate nucleus)-fold higher than BuChE activity (36,(48)(49)(50)(51)(52)(53).…”

Section: Effects Of Cholinesterase Inhibitors On Cortical Neuro Transmentioning

confidence: 97%

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From Molecular Structure to Alzheimer Therapy.

Giacobini

1997

Jpn.J.Pharmacol

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ABSTRACT-Clinical trials in the USA, Japan and Europe have confirmed the hypothesis that a steady state increase of acetylcholine resulting from cholinesterase inhibition in the brain results in an improve ment of cognitive function in mild to moderate Alzheimer disease (AD) patients. During the last decade, a systematic effort to develop a pharmacological treatment for AD has resulted in two drugs being registered for the first time in the USA and Europe for this specific indication. Both are cholinesterase inhibitors (ChEI). Based on these first positive results, several second generation ChEI are being developed. An ad ditional effect of certain ChEI is to maintain cognitive function at a constant level during a 6 months to one year period of treatment as compared to placebo. It is possible that the drug effect is one of slowing down cognitive deterioration. Comparison of clinical effects of 5 ChEI demonstrates a rather similar magnitude of improvement. For some drugs, this may represent a limit, while for others it may be possible to increase the benefit further. To maximize and prolong positive drug effects, it is important to start early and adjust the dosage during the treatment. Other strategies may involve combinations with other cholinergic drugs such as muscarinic or nicotinic agonists. A second important class of drugs which is being developed is that of muscarinic ml agonists. However, their clinical use is still limited by side effects. The increased knowledge and recognition of the beta-amyloid molecule as a central focus of AD pathology has strongly stimulated research with the hope of finding ways of influencing its processing and deposition. At this point, no product in this line of development has reached clinical trial level. Other pharmacological approaches are related to preventive and neuroprotective interventions (estrogens, anti-oxidants and anti-inflammatories). In conclusion, given the relatively short time of research in this field, results are encouraging.

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Section: Molecular Design Of New Cholinesterase Inhibitorssupporting

confidence: 92%

Section: Molecular Design Of New Cholinesterase Inhibitorsmentioning

confidence: 97%

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From Molecular Structure to Alzheimer Therapy.

Giacobini

1997

Jpn.J.Pharmacol

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“…The finding likely represents the activation of G-proteins by different muscarinic M receptors which could be differently regulated and expressed during aging. Non-selective decreases of the in vitro muscarinic receptor density (Rinne 1987;Giacobini et al 1989;Giacobini 1990;Nordberg et al 1992) and in vivo (PET) binding potential (Dewey et al 1990;Lee et al 1996) have been reported with increasing age in human brain cortex. Since muscarinic M receptors are coupled to pertussis toxin-sensitive (G ␣i/o ) and pertussis toxin-insensitive (G ␣q/11 ) G-proteins, further studies with selective agonists are needed to assess the biochemical and functional regulation of the different M receptor subtypes during the process of aging.…”

Section: Discussionmentioning

confidence: 99%

Effects of Age, Postmortem Delay and Storage Time on Receptor-mediated Activation of G-proteins in Human Brain

González-Maeso

2002

Neuropsychopharmacology

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“…Nicotinic receptor deficits have been shown to be key in the cognitive impairments of Alzheimer's disease (Nordberg and Winblad, 1986;Shimohama et al, 1986;Whitehouse et al, 1988;Giacobini et al, 1989;London et al, 1989;Kellar and Wonnacott, 1990;Rinne et al, 1991;Perry et al, 1995) and schizophrenia (Durany et al, 2000;Leonard et al, 2000). Nicotine delivered through means other than smoking such as transdermal patches may prove to be a safe and effective treatment for cognitive impairment seen in Alzheimer's disease, schizophrenia and attention deficit hyperactivity disorder (ADHD) and other types of cognitive dysfunction (Wilson et al, 1995;Levin et al, 1996b;Levin et al, 1996d;Newhouse et al, 1997;White and Levin, 1999).…”

Section: Introductionmentioning

confidence: 99%

Nicotinic receptor subtypes and cognitive function

2002

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ABSTRACT:Nicotinic receptor systems are involved in a wide variety of behavioral functions including cognitive function. Nicotinic medications may provide beneficial treatment for cognitive dysfunction such as Alzheimer's disease, schizophrenia, and attention deficit hyperactivity disorder (ADHD). Nicotine has been shown to improve attentional performance in all of these disorders. Better efficacy with fewer side effects might be achieved with novel nicotinic ligands selective for particular nicotinic subtypes. To develop these novel selective nicotinic ligands it is important to use animal models to determine the critical neurobehavioral bases for nicotinic involvement in cognitive function. Nicotineinduced cognitive improvement in rats is most consistently seen in working memory tasks. We have found that both acute and chronic nicotine administration significantly improves working memory performance of rats in the radial-arm maze. The pharmacologic and anatomic mechanisms for this effect have been examined in our laboratory in a series of local drug infusion studies. Both ␣4␤2 and ␣7 nicotinic receptors in the ventral hippocampus and basolateral amygdala are involved in working memory function. Working memory impairments were caused by local infusion of either ␣4␤2 or ␣7 antagonists. Ventral hippocampal ␣4␤2 blockade-induced working memory deficits are reversed by chronic systemic nicotine treatment, while ventral hippocampal ␣7 blockade-induced working memory deficits were not found to be reversed by the same nicotine regimen. Interestingly, ␣4␤2 and ␣7 induced deficits were not found to be additive in either the ventral hippocampus or the basolateral amygdala. In fact, in the amygdala, ␣7 antagonist cotreatment actually reversed the working memory impairment caused by ␣4␤2 antagonist administration. These studies of the neural nicotinic mechanisms underlying cognitive function are key for opening avenues for development of safe and effective nicotinic treatments for cognitive dysfunction.

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Chapter 33 The cholinergic receptor system of the human brain: neurochemical and pharmacological aspects in aging and Alzheimer

Cited by 50 publications

References 29 publications

From Molecular Structure to Alzheimer Therapy.

From Molecular Structure to Alzheimer Therapy.

Effects of Age, Postmortem Delay and Storage Time on Receptor-mediated Activation of G-proteins in Human Brain

Nicotinic receptor subtypes and cognitive function

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