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Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

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Cognitive enhancers (nootropics) are drugs to treat cognition deficits in patients suffering from Alzheimer's disease, schizophrenia, stroke, attention deficit hyperactivity disorder, or aging. Cognition refers to a capacity for information processing, applying knowledge, and changing preferences. It involves memory, attention, executive functions, perception, language, and psychomotor functions. The term nootropics was coined in 1972 when memory enhancing properties of piracetam were observed in clinical trials. In the meantime, hundreds of drugs have been evaluated in clinical trials or in preclinical experiments. To classify the compounds, a concept is proposed assigning drugs to 18 categories according to their mechanism(s) of action, in particular drugs interacting with receptors, enzymes, ion channels, nerve growth factors, re-uptake transporters, antioxidants, metal chelators, and disease-modifying drugs meaning small molecules, vaccines, and monoclonal antibodies interacting with amyloid-β and tau. For drugs, whose mechanism of action is not known, they are either classified according to structure, e.g., peptides, or their origin, e.g., natural products. The review covers the evolution of research in this field over the last 25 years.
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... Recent evidence indicates that cognitive enhancers, such as nootropics, are increasingly used to improve or maintain brain health (e.g., cognitive performance, psychosocial and emotional status, etc.) (1,2). Cognition refers to the capacity for information processing, applying knowledge, and changing preferences (2). ...
... Recent evidence indicates that cognitive enhancers, such as nootropics, are increasingly used to improve or maintain brain health (e.g., cognitive performance, psychosocial and emotional status, etc.) (1,2). Cognition refers to the capacity for information processing, applying knowledge, and changing preferences (2). Cognitive performance is composed of the intermingling of different processes such as memory, attention, executive functions, creativity, and intelligence cognitive functions (3). ...
... This cognitive performance is dependent on an interplay between the genotype and lifestyle factors, including cognitive activity, physical activity, sleep habits, and diet (4,5). The primary use of nootropics has been focused on the treatment of cognitive deficits, commonly associated with neurodegenerative disorders or aging (1,2). However, nootropics are being currently used among healthy individuals and athletes with the aim to enhance their performance. ...
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Aim To study the acute effect of a dietary multi-ingredient nootropic on cognitive performance in young healthy adults. We also analyzed the influence of the dietary multi-ingredient nootropic on emotional state, heart rate (HR), and heart rate variability (HRV). Methods This is a randomized, triple-blinded, placebo-controlled, crossover trial. In total, 26 young healthy adults (50% women; 24.9 ± 3.3 years old) ingested 10 g of a dietary multi-ingredient nootropic [Evo-Gamers ® ; Harrison Sport Nutrition (HSN), Granada, Spain] or placebo (maltodextrin) in a randomized order ( clinicaltrials.gov No. NCT04790188). After 30 min of the ingestion, participants performed a battery of cognitive performance tests to measure the processing speed, inhibitory control, working memory, cognitive flexibility, creativity, and verbal fluency. The emotional status was assessed through questionnaires, and HR and HRV were measured using a heart rate monitor. Results In comparison with placebo, the acute ingestion of the nootropic showed a significantly better response time in several cognitive tests (i.e., processing speed, inhibitory control, spatial working memory, and cognitive flexibility, all P < 0.05 and effect size range of 0.4–0.6). It also displayed a higher accuracy in the processing speed, the inhibitory control, and cognitive flexibility tests (all P < 0.05; effect size ranged from 0.4 to 0.6). Furthermore, the nootropic showed a higher creativity and positive emotions and lower sadness-depression emotions, whereas HR and HRV remained similar between placebo vs. nootropic conditions. However, there were no differences between the nootropic and placebo in verbal fluency, motivation, or anxiety (all P > 0.05). Conclusion An acute ingestion of a dietary multi-ingredient nootropic enhances cognitive performance in comparison with placebo without negatively influencing HR or HRV in young healthy adults.
... Froestl et al. [14][15][16] proposed a classification of 1705 molecules as nootropic agents, with a high proportion (42%) of them being putative β-amyloid aggregation inhibitors that were tested for the treatment of dementia and/or molecules whose development was discontinued in phase II or III clinical trials. ...
... psychostimulants, excitatory amino acids [EAAs]), and miscellaneous (i.e. nutrients and nutraceuticals, corticosteroids, antioxidants, etc.) [15]. Finally, those CEs whose mechanism of action is unknown are classified either according to their chemical structure (e.g. ...
... peptides) or their source (e.g. herbal products) [15]. ...
... Froestl et al. [14][15][16] proposed a classification of 1705 molecules as nootropic agents, with a high proportion (42%) of them being putative β-amyloid aggregation inhibitors that were tested for the treatment of dementia and/or molecules whose development was discontinued in phase II or III clinical trials. ...
... psychostimulants, excitatory amino acids [EAAs]), and miscellaneous (i.e. nutrients and nutraceuticals, corticosteroids, antioxidants, etc.) [15]. Finally, those CEs whose mechanism of action is unknown are classified either according to their chemical structure (e.g. ...
... peptides) or their source (e.g. herbal products) [15]. ...
Article
'Smart drugs' (also known as 'nootropics' and 'cognitive enhancers' [CEs]) are being used by healthy subjects (i.e. students and workers) typically to improve memory, attention, learning, executive functions and vigilance, hence the reference to a 'pharmaceutical cognitive doping behaviour'. While the efficacy of known CEs in individuals with memory or learning deficits is well known, their effect on non-impaired brains is still to be fully assessed. This paper aims to provide an overview on the prevalence of use; putative neuroenhancement benefits and possible harms relating to the intake of the most popular CEs (e.g. amphetamine-type stimulants, methylphenidate, donepezil, selegiline, modafinil, piracetam, benzodiazepine inverse agonists, and unifiram analogues) in healthy individuals. CEs are generally perceived by the users as effective, with related enthusiastic anecdotal reports; however, their efficacy in healthy individuals is uncertain and any reported improvement temporary. Conversely, since most CEs are stimulants, the related modulation of central noradrenaline, glutamate, and dopamine levels may lead to cardiovascular, neurological and psychopathological complications. Furthermore, use of CEs can be associated with paradoxical short- and long-term cognitive decline; decreased potential for plastic learning; and addictive behaviour. Finally, the non-medical use of any potent psychotropic raises serious ethical and legal issues, with nootropics having the potential to become a major public health concern. Further studies investigating CE-associated social, psychological, and biological outcomes are urgently needed to allow firm conclusions to be drawn on the appropriateness of CE use in healthy individuals.
... Hypoxanthine caffeine is an antagonist of all four adenosine receptor subtypes, with the highest affinity towards the A2AAR (Ki(human) = 9.5-23.4 mM) [7,8], which is thought to mediate its psychostimulant and nootropic effects [9]. ...
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The cerebral expression of the A2A adenosine receptor (A2AAR) is altered in neurodegenera-tive diseases such as Parkinson's (PD) and Huntington's (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A2AAR-specific antagonist radiotracer [ 18 F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone-treated mice, and conducted dynamic PET studies with healthy pigs. We performed analysis of mouse brain time-activity curves to calculate the mean residence time (MRT) by non-compartmental analysis , and the binding potential (BPND) of [ 18 F]FLUDA using the simplified reference tissue model (SRTM). For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume (VT) at baseline and under blocking conditions with tozadenant. The MRT of [ 18 F]FLUDA in the striatum of mice was decreased by 30% after treatment with the A2AAR antagonist istradefylline. Mouse results showed the highest BPND (3.9 to 5.9) in the striatum. SRTM analysis showed a 20% lower A2AAR availability in the rotenone-treated mice compared to the control-aged group. Tozadenant treatment significantly decreased the VT (14.6 vs. 8.5 mL · g −1) and BPND values (1.3 vs. 0.3) in pig striatum. This study confirms the target specificity and a high BPND of [ 18 F]FLUDA in the striatum. We conclude that [ 18 F]FLUDA is a suitable tool for the non-invasive quantitation of altered A2AAR expression in neurodegenerative diseases such as PD and HD, by PET. Citation: Gündel, D.; Toussaint, M.; Lai, T.H.; Deuther-Conrad, W.; Cumming, P.; Schröder, S.; Teodoro, R.; Moldovan, R.-P.; Pan-Montojo, F.; Sattler, B.; et al. Quantitation of the A2A Adenosine Receptor Density in The Striatum of Mice and Pigs with [ 18 F]FLUDA by Positron Emission Tomography. Pharmaceuticals 2022, 15, 516. https://
... Positive allosteric modulators (PAM) improve short-term memory in humans by slowing down the deactivation of AMPA receptors [30], which makes them beneficial for the treatment of depression and other disorders and diseases of CNS [26,31,32]. The structures of known PAM of AMPA-receptors are quite diverse: racetams, a γ-lactam fragment, various benzamide type ampakines, sulfo-derivatives, etc. [33]. The test compound contains several structural descriptors found in molecules of known PAM (Figure 7a). ...
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We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound 1) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound 1, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound 1 is capable of crossing the blood–brain barrier in intact and ischemic animals. Compound 1 improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions.
... They improved impaired cognitive functions in man and animal models. Their systematics, depending on the mechanism of action, was proposed by Froestl et al. (2012). Nootropics influence brain neurotransmission (dopaminergic, glutamatergic/cholinergic, and serotonergic systems) and receptors essential for cognitive functioning. ...
Article
Background Cognitive deficits represent an urgent biomedical problem, and are commonly reduced by nootropic drugs. Animal models, including both rodents and zebrafish, offer a valuable tool for studying cognitive phenotypes and screening novel nootropics. Beta-alanine and its derivatives have recently been proposed to exert nootropic activity. Aims This study aimed to characterize putative nootropic profile of a novel β-alanine analogue, 1,3-diaminopropane (MB-005), in adult zebrafish. Methods Nootropic profile of MB-005 was assessed in adult zebrafish in the novel tank and conditioned place aversion (CPA) tests acutely, and in cued-learning plus-maze (PMT) tests chronically. Results/Outcomes MB-005 did not alter zebrafish anxiety-like behavior or monoamine neurochemistry acutely, improved short-term memory in the CPA test, but impaired cognitive performance in both CPA and PMT tests chronically. Conclusions/Interpretation This study reveals high sensitivity of zebrafish cognitive phenotypes to MB-005, suggesting it as a potential novel cognitive enhancer acutely, but raises concerns over its cognitive (and, possibly, other) side-effects chronically.
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Marijuana is the most widely used illicit drug in the Western hemisphere and affects physiological processes and cognition. Clear deficits are observed in working memory (WM) 36 that involve the temporary storage and online manipulation of information to solve complex tasks. Marijuana-induced WM deficits have been ascribed to the primary psychoactive compound in marijuana,  9-tetrahydrocannabinol, which acts at CB1 cannabinoid receptors (CB1r). Recent work emphasized the role of CB1r and cholinergic interaction across this cognitive domain without formal anatomical demonstration. We generated mice with a conditional deletion of CB1r on cholinergic neuron terminals, and WM was evaluated in operant chambers. Control of physiological variables (temperature, nociception, neuromuscular function) was also performed, and additional motor, motivation, time estimation behaviors, and effort-based decision-making. Discrete WM enhancement measured in a novel Delay-Non-Matching-To-Position task was evidenced that incorporates early acquisition during randomized delays (mixed procedure), and remarkably, improved performance when these (2s, 47 8s, 16s, 20s) were kept constant (same procedure) across a testing block of trials. We reported sustained motivation in an exponential progressive ratio schedule whilst locomotor activity did not differ between genotypes in the rotarod and open field. However, timing behavior was modified as indicated by higher discriminated motor responses for the shortest interval in conditional deleted mice in the Fixed-Interval task (10s, 30s). We reported no effect on effort-based decision-making. Our work outlines presynaptic CB1r-cholinergic neuron function(s), and the hippocampus, neocortex, and amygdala brain regions as critical loci through known basal forebrain efferent projections possibly involved in WM and motivation in marijuana intoxication.
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Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by loss of memory and cognitive impairment via dysfunction of the cholinergic nervous system. In cholinergic dysfunction, it is well known that impaired cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) signaling are major pathological markers and are some of the strategies for the development of AD therapy. Therefore, this study is aimed at evaluating whether a mixture comprising Ginkgo biloba L. leaf (GL) and Hericium erinaceus (Bull.) Pers. (HE) fruit extract (GH mixture) alleviated cognitive impairment induced in a scopolamine-induced model. It was discovered that GH reduced neuronal apoptosis and promoted neuronal survival by activating BDNF signaling in an in vitro assay. In addition, the GH (p.o. 240 mg/kg) oral administration group significantly restored the cognitive deficits of the scopolamine-induced mouse group (i.p. 1.2 mg/kg) in the behavior tests such as Y-maze and novel object recognition task (NORT) tests. This mixture also considerably enhanced cholinergic system function in the mouse brain. Furthermore, GH markedly upregulated the expressed levels of extracellular signal-regulated kinase (ERK), CREB, and BDNF protein levels. These results demonstrated that GH strongly exerted a neuroprotective effect on the scopolamine-induced mouse model, suggesting that an optimized mixture of GL and HE could be used as a good material for developing functional foods to aid in the prevention of neurodegenerative diseases, including AD.
Article
Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. Ginkgo biloba was the most relevant nootropic regarding perceptual and motor functions. Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research.
Article
Question In community-dwelling patients with moderate-to-severe Alzheimer disease, what are the benefits of continuing donepezil and/or initiating memantine treatment? Methods Design: Randomized, 2 x 2 factorial, placebo-controlled trial (Donepezil and Memantine in Moderate to Severe Alzheimer's Disease [DOMINO] study). Current Controlled Trials ISRCTN49545035. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, outcome assessors, and {trialists}†). Follow-up period: 30 weeks. Follow-up at 1 year was < 80% (results not reported in this abstract). Setting: {14 clinical centers in the UK.}† Patients: 295 community-dwelling residents (mean age 77 y, 65% women) who had probable or possible moderate or severe Alzheimer disease, had been prescribed donepezil for ≥ 3 continuous months at a dose of 10 mg for ≥ 6 previous weeks, and scored 5 to 13 on the Standardized Mini-Mental State Examination (SSMSE). Eligible patients had caregivers who lived with them or visited them daily, and their clinicians were considering changing their drug treatments. Exclusion criteria included severe or unstable medical conditions and use of memantine. Intervention: Continuation of donepezil with placebo memantine (n = 73), continuation of donepezil plus memantine (n = 73), discontinuation of donepezil plus placebo memantine (n = 73), or discontinuation of donepezil plus memantine (n = 76). Memantine was initiated in week 1 at a dose of 5 mg and increased weekly by 5-mg increments to a dose of 20 mg in week 4. Outcomes: Cognitive (SMMSE) and functional (Bristol Activities of Daily Living Scale [BADLS]) scores. Patient follow-up: 83% (intention-to-treat analysis). Main results The main results are in the Table. Groups did not differ for serious adverse events or death (P = 0.77). Conclusions In community-dwelling patients with moderate-to-severe Alzheimer disease, continued donepezil improved cognitive functioning and activities of daily living at 30 weeks. Memantine improved cognitive functioning at 30 weeks.
Article
Over the past decade, considerable effort was focused on the development of muscarinic and nicotinic agonists for the treatment of Alzheimer's disease. The rationale for developing muscarinic agonists was based on the role of acetylcholine in learning and memory function and the consistent neurochemical finding that cholinergic neurons degenerated in Alzheimer's patients. Thus far, the clinical utility of muscarinic agonists remains unproven, yet recent studies suggest that muscarinic agonists might be useful in treating not only memory deficits, but also psychiatric disturbances and some of the underlying causes of Alzheimer's disease, such as the deposition of Abeta. In addition, nicotinic receptors may play a role in cognitive function and help regulate the toxicity of amyloid precursor protein. Ultimately, cholinergic agonists may prove useful in the treatment of Alzheimer's disease.
Article
Memantine (Ebixa®, Axura®, Namenda®, Akatinol®) is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic overstimulation of the NMDA receptor. Memantine is approved in the US and the EU for the treatment of patients with moderate to severe dementia of the Alzheimer’s type. In well designed clinical trials, oral memantine, as monotherapy or in addition to a stable dose of acetylcholinesterase inhibitors, was well tolerated during the treatment of mild to severe Alzheimer’s disease for up to 52 weeks. Memantine generally modified the progressive symptomatic decline in global status, cognition, function and behaviour exhibited by patients with moderate to severe Alzheimer’s disease in four 12- to 28-week trials. In patients with mild to moderate Alzheimer’s disease, data from three 24-week trials are equivocal, although meta-analyses indicate beneficial effects on global status and cognition. Memantine is an effective pharmacotherapeutic agent, and currently the only approved option, for the treatment of moderate to severe Alzheimer’s disease. Pharmacological Properties Memantine is an uncompetitive antagonist that blocks the NMDA channel with higher affinity, but less voltage-dependency, than magnesium. It moderately inhibits excitatory activity while preserving learning behaviours in vivo when compared with more potent NMDA receptor channel blockers. During pathological activation of the NMDA receptor, memantine blocks excessive calcium entry through the channel and is neuroprotective in in vitro and in vivo models. Oral memantine is completely absorbed with an absolute bioavailability of ≈100%. Steady-state plasma concentrations, achieved after about 2 weeks of memantine 20 mg/day, range from 70 to 150 gmg/L, while the steady-state area under the plasma concentration-time curve from time 0 to 24 hours is ≈1800 gmg · h/L after 4 weeks of treatment. Memantine is excreted in urine mostly as unchanged parent drug with the remainder being metabolised by glucuronidation, hydroxylation and N-oxidation to form NMDA-inactive metabolites. Memantine and its metabolites are primarily eliminated by the kidneys with a terminal elimination half-life of 60–100 hours. Total renal clearance in healthy volunteers is 170 mL/min/1.73m2. Therapeutic Efficacy The efficasy of memantine 20 mg/day has been examined in seven randomised, double-blind, placebo-controlled, multicentre trials of 12–28 weeks’ duration in patients with mild to severe Alzheimer’s disease. In two of four trials in patients with moderate to severe Alzheimer’s disease, intent-to-treat analyses indicated that global status was significantly better with memantine than with placebo, either as monotherapy or in addition to a stable dose of donepezil. In a third trial, while global status did not differ significantly based on intent-to-treat analysis, observed-case analysis favoured memantine over placebo. However, preliminary data from a fourth trial indicate numerical differences between memantine and placebo treatment groups that were not significant. In patients with moderate to severe Alzheimer’s disease, memantine or donepezil plus memantine also maintained superior cognitive performance and function with respect to placebo or placebo plus donepezil in two of the three trials in which they were assessed, and superior behaviour in two of the four trials. In one published trial in patients with mild to moderate Alzheimer’s disease, memantine monotherapy significantly attenuated the decline in global status and cognition observed in placebo recipients; however, in preliminary data from another monotherapy trial, significantly greater effects with memantine seen at 12 and 18 weeks were lost at trial end, apparently as a result of an improvement in global status and cognition in placebo recipients in the last weeks of the trial. Initial results of a third study in this patient population, with memantine or placebo added to a stable dose of an acetylcholinesterase inhibitor, indicate a numerical difference that was not significant. Meta-analyses indicate significant effects of memantine on global status, cognition and function in patients with mild to severe Alzheimer’s disease, and on global status, cognition, function and behaviour in patients with moderate to severe Alzheimer’s disease. Tolerability Memantine was generally well tolerated with a good safety profile during clinical trials, most adverse events being of mild or moderate severity. Adverse events were reported by 70% of patients receiving either memantine or placebo, but most were not considered drug related. In pooled analyses, memantine was associated with a higher incidence of dizziness, headache, constipation and somnolence than placebo. Serious adverse events occurred in 12.7% of memantine and 13.8% of placebo recipients.
Article
Memantine (Ebixa®, Namenda™, Axura®) is an uncompetitive NMDA receptor antagonist used in the management of patients with moderate-to-severe Alzheimer’s disease. It is currently the only drug approved for use in these more advanced stages of the disease. Significant reductions in functional and cognitive decline have been demonstrated with memantine relative to placebo in randomised, double-blind trials in this patient population. Clinical trial and postmarketing surveillance data indicate that the drug is generally well tolerated. Two fully published modelled cost-effectiveness analyses of memantine in moderate-to-severe Alzheimer’s disease have been conducted in the UK and Finland, in which patient progression was simulated through health states related to dependency, residential setting and cognitive function. Although the specific costs included in the analyses varied, as did the study perspective and geographical location, results of the base-case analyses consistently showed that memantine was dominant over no pharmacological treatment. In the UK and Finnish analyses, memantine increased the duration of independence by 1.3 and 4.1 months, respectively, and the time to institutionalisation by 0.8 and 1 month. Mean total per-patient costs were reduced by £1963 over 2 years (2003 costs) in the UK analysis and by €1687 over 5 years (2001 costs) in the Finnish analysis. Memantine was also associated with a small gain in quality-adjusted life expectancy in the UK model. In sensitivity analyses, memantine remained dominant for almost all plausible changes to key variables. Memantine reduced total societal costs by $US1090 per patient per month (1999 costs) compared with no pharmacological treatment over 28 weeks in a resource utilisation and cost analysis conducted alongside a pivotal US trial in patients with moderate-to-severe Alzheimer’s disease. Results were primarily driven by reductions in total caregiver costs, which included the opportunity cost of time spent in caregiving tasks, and in direct nonmedical costs, which included the cost of care in a nursing home or similar institution. In conclusion, in patients with moderate-to-severe Alzheimer’s disease, memantine is associated with significant reductions in functional and cognitive decline compared with no pharmacological treatment. Available pharmacoeconomic data from Europe and the US, despite some inherent limitations, support the use of memantine as a cost-effective treatment in this patient population, although definitive conclusions are not feasible because of limited data.
Article
Memantine (Axura(R), Merz Pharmaceuticals GmbH; Ebixa(R), H. Lundbeck A/S, Namenda(TM), Forest Laboratories, Inc.) is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with low to moderate affinity for the (+)MK-801 binding site. It is characterized as a voltage-sensitive open-channel NMDA receptor blocker that antagonizes NMDA receptor-mediated inward currents in vitro with an IC(50) of 1-3 muM. In animal models,memantine displays both neuroprotective (antiexcitotoxic) and cognition-enhancing properties at therapeutically relevant concentrations. The strong voltage dependency and rapid blocking/unblocking kinetics of memantine are thought to be the basis for its excellent clinical tolerability. Recently completed clinical studies demonstrate positive effects of memantine in Alzheimer's disease both as a monotherapy and in patients receiving continuous donepezil treatment. Memantine treatment also has demonstrated significant improvement of cognitive performance in patients suffering from vascular dementia. Furthermore, the safety and tolerability of memantine in clinical trials has been excellent, with the incidence of premature withdrawals due to adverse events no greater than placebo and overall low frequencies of total adverse events. In 2002, memantine was approved by the European Medicines Agency (EMEA) for the treatment of moderately severe to severe Alzheimer's disease. More recently, memantine was approved in the US for the treatment of moderate to severe Alzheimer's disease (October 2003). Here, we review the most recent pharmacological and clinical data in dementia patients that has emerged from the systematic evaluation of memantine.
Article
It is widely recognized that cognitive dysfunction is among the most debilitating symptoms of many neuropsychiatric disorders, including Alzheimer's disease and schizophrenia. Accordingly, there is a critical need for new drugs with procognitive activity. Recently, the role of the neurotransmitter serotonin (5-HT) and its receptor subtypes in cognition has emerged, and as a result, the focus on 5-HT receptor subtypes as targets for memory enhancement has increased. Among the 5-HT subtypes, the 5-HT6 receptor may be a particularly attractive target given its almost exclusive localization in the brain and its expression in both limbic areas and other brain regions known to be critical to cognition. Novel ligands with selective affinity for 5-HT 6 receptors would be predicted to have a low incidence of peripheral side effects and to potentially address both cognitive and noncognitive symptoms (e.g., anxiety, depression) of neuropsychiatric disorders. To date, several preclinical studies of 5-HT6 antagonists in rodent models have indeed provided evidence of cognitive enhancement (especially in aged and pharmacologically impaired rats), as well as anxiolytic and antidepressant effects. Accordingly, several 5-HT6 antagonists are currently in clinical trials for the treatment of neuropsychiatric disorders. The purpose of this review is to provide a brief overview of the 5-HT6-related pharmacological approaches designed to enhance memory function. Copyright © 2009 Prous Science, S.A.U. or its licensors. All rights reserved.
Article
In replyWe thank Dr Sakurai for his insightful comments. The observation that pioglitazone was associated with improvement in clinical and biomarker outcomes in patients with AD and diabetes mellitus reinforces the potential value of this line of therapeutics.1 There is increased risk for AD among patients with diabetes.2 Taken together, these observations suggest additional means of enriching samples for future trials of PPARγ agonists and other insulin-sensitizing agents beyond the typical APOE genotyping. We also concur that these agents are likely to be most useful in prevention, rather than response to, symptomatically expressed AD. Therefore, trials of patients with mild cognitive impairment (or biomarker evidence of incipient AD) and relative insulin resistance might have the highest likelihood of detecting clinical efficacy for insulin-sensitizing drugs as antidementia agents.
Article
TPA023 and α5IA are structurally related compounds that selectively modulate certain GABAA receptor subtypes. Hence, TPA023 has weak partial agonist efficacy at the α2 and α3 subtypes whereas α5IA has inverse agonist efficacy at the α5 subtype. These efficacy characteristics translate into novel pharmacological profiles in preclinical species with TPA023 being a nonsedating anxiolytic in rats and primates whereas α5IA enhanced cognition in rats but was devoid of the proconvulsant or kindling liabilities associated with nonselective inverse agonists. In vitro and in vivo metabolic studies showed that TPA023 was metabolized via CYP3A4-mediated t-butyl hydroxylation and N-deethylation whereas α5IA was metabolized to produce the hydroxymethyl isoxazole, the latter of which was highly insoluble and caused renal toxicity in preclinical species. In humans, TPA023 had a half-life in the region of 6-7 h whereas the half-life of α5IA was 2-2.5 h. TPA023 was clearly differentiated from the nonselective agonist lorazepam in terms of saccadic eye movement and unlike lorazepam, it did not impair either postural stability, as judged by body sway, or cognition. The occurrence of the hydroxymethyl isoxazole metabolite of α5IA in human urine precluded the use of α5IA in prolonged dosing studies. Nevertheless, α5IA was evaluated in an alcohol-induced cognitive impairment model in healthy normal volunteers and was found to reverse the memory-impairing effects of alcohol. To date, however, no efficacy data for either TPA023 or α5IA in patient populations has been reported, although at the very least, the preclinical and limited clinical data with TPA023 and α5IA validate the approach of targeting specific GABAA receptors through subtype-selective efficacy.
Article
It was discovered recently that alcuronium and strychnine (which is a precursor of alcuronium) allosterically increase the affinity of cardiac muscarinic receptors for the antagonist, N-methylscopolamine. We have now investigated the effects of l-eburnamonine and vincamine, which are both closely related to strychnine. In experiments on rat heart atria, l-eburnamonine was found to increase the binding of [3H]N-methylscopolamine with Ehlert's cooperativity coefficient α = 0.35, which indicates that the strength of its allosteric action is close to that of alcuronium and strychnine (α = 0.31 and 0.44, respectively). However, the affinity of l-eburnamonine for the cardiac muscarinic receptors is lower than the affinities of alcuronium and strychnine (KAR = 22.6 μM, 0.15 μM, and 3.4 μM, respectively). In spite of its extremely close similarity to l-eburnamonine, vincamine has a negative allosteric effect on the binding of [3H]N-methylscopolamine (α = 4.1; KAR = 22.8 μM). It is likely that a systematic investigation of the allosteric effects of the analogues of strychnine will not only yield new allosteric effectors on muscarinic receptors, but also clarify the structural features responsible for the direction (positive or negative) of their allosteric effect.
Article
Our recent developments have yielded a novel phytoestrogenic formulation, referred to as the phyto-β-SERM formulation, which exhibits an 83-fold binding selectivity for the estrogen receptor subtype β (ERβ) over ERα. Earlier studies indicate that the phyto-β-SERM formulation is neuroprotective and promotes estrogenic mechanisms in the brain while devoid of feminizing activity in the periphery. Further investigation in a mouse model of human menopause indicates that chronic exposure to the phyto-β-SERM formulation at a clinically relevant dosage prevents/alleviates menopause-related climacteric symptoms. This study assessed the efficacy, in an early intervention paradigm, of the phyto-β-SERM formulation in the regulation of early stages of physical and neurological changes associated with Alzheimer's disease (AD) in a female triple transgenic mouse model of AD. Results demonstrated that, when initiated prior to the appearance of AD pathology, a 9-month dietary supplementation with the phyto-β-SERM formulation promoted physical health, prolonged survival, improved spatial recognition memory, and attenuated amyloid-β deposition and plaque formation in the brains of treated AD mice. In comparison, dietary supplementation of a commercial soy extract preparation showed no effect on cognitive measures, although it appeared to have a positive impact on amyloid pathology. In overall agreement with the behavioral and histological outcomes, results from a gene expression profiling analysis offered insights on the underlying molecular mechanisms associated with the two dietary treatments. In particular, the data suggests that there may be a crosstalk between ERβ and glycogen synthase kinase 3 signaling pathways that could play a role in conferring ERβ-mediated neuroprotection against AD. Taken together, these results support the therapeutic potential of the phyto-β-SERM formulation for prevention and/or early intervention of AD, and warrants further investigations in human studies.