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PubMedDate not supplied

Pharmacology of WEB 1881-FU, a central cholinergic agent, which enhances cognition and cerebral metabolism.

The pharmacological effects of the novel compound WEB 1881 FU (4-amino-methyl-1-benzyl-pyrrolidine-2-one-fumarate) were investigated. The tests performed indicate that the compound has cytoprotective as well as metabolism and cognition enhancing and central cholinomimetic properties. The nootropic effects in all tests were more pronounced than those of piracetam, while the central cholinomimetic effects were generally weaker than those of directly acting cholinomimetic agents. However, the typical peripheral cholinergic side effects were not observed. From the results we believe that the stimulating effect of WEB 1881 FU upon the central cholinergic system is modulatory rather than direct. The combination of nootropic and cholinomimetic properties appears favorable for treatment of brain dysfunction in the elderly. Side effects are less serious than with other known cholinomimetics.

Adenine Nucleotides↗

PubMed2006

Ampakines and the threefold path to cognitive enhancement.

Ampakines are the first peripherally administered drugs that increase excitatory monosynaptic responses in the brain. Because of this effect, the compounds improve communication in complex networks, potently facilitate long-term potentiation (LTP) and induce the expression of neurotrophic factors. Ampakines are effective in animal models of neuropsychiatric disorders and have produced positive results in a small number of human studies. Neurobiological considerations and modeling studies suggest that the drugs, in addition to their effects on disturbed behavior, will alter the encoding and organization of information in normal brains. Results from physiological and behavioral studies accord with this prediction. Building on these findings, this article considers how the threefold effects of ampakines will modify, and enhance, cognition.

Animals↗

PubMed2004

Testosterone's analgesic, anxiolytic, and cognitive-enhancing effects may be due in part to actions of its 5alpha-reduced metabolites in the hippocampus.

Although testosterone (T) may decrease anxiety and enhance cognitive performance, its mechanisms are not well understood. The authors hypothesized that if T's effects are mediated in part through actions of its 5alpha-reduced, nonaromatizable metabolite dihydrotestosterone (DHT) and/or its 3alpha-hydroxysteroid dehydrogenase reduced metabolite 3alpha-androstanediol (3alpha-diol) in the hippocampus, then T, DHT, and 3alpha-diol administration should produce similar behavioral effects concomitant with elevating T metabolites in the hippocampus. Gonadectomized male rats administered T, DHT, or 3alpha-diol via Silastic capsules or intrahippocampal infusions had greater analgesia (tail flick, paw lick), less anxiety behavior (plus-maze, open field, defensive freezing), and better learning (inhibitory avoidance) compared with vehicle control rats. Only 3alpha-diol levels in the hippocampus were consistently elevated in conjunction with these behavioral effects.

3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)↗

PubMed2002

Antioxidant property of Celastrus paniculatus willd.: a possible mechanism in enhancing cognition.

In the present study aqueous, methanolic, chloroform and petroleum ether extracts of seeds of Celastrus paniculatus were investigated for their effect on cognitive functions in rats. Male Wistar rats weighing 200-250 g each were used to study effect on learning and memory through use of the shuttle-box, step-through, step-down and elevated plus maze paradigms. Only the aqueous seed extract (200 mg/kg body wt. for 14 days) showed an improvement in learning and memory in both the shuttle-box and step-through paradigms. Therefore, further experiments were conducted using the aqueous extract at 100, 200 and 300 mg/kg body wt. doses in different paradigms of cognition. All three doses of the aqueous extract increased the number of avoidances in the shuttle-box and step-through latency the in step-through apparatus, but no significant difference was observed between the doses tested. In the step-down apparatus, the 200- and 300-mg/kg body wt. doses of aqueous extract showed a significant increase in step-down latency, whereas no significant difference was observed in the elevated-plus-maze paradigm between drug-treated and vehicle-treated groups. Since the behavioral impairments are associated with oxidative stress, we investigated the effect of the aqueous extract on oxidative stress parameters. Among the three doses tested, only 200 and 300 mg/kg body wt. stimulated a significant decrease in the brain levels of malondialdehyde, with simultaneous significant increases in levels of glutathione and catalase. The present findings indicate that the aqueous extract of Celastrus paniculatus seed has cognitive-enhancing properties and an antioxidant effect might be involved.

Animals↗

PubMed2004

Cognition-enhancing drugs.

New drugs that enhance cognition in cognitively healthy individuals present difficult public policy challenges. While their use is not inherently unethical, steps must be taken to ensure that they are safe, that they are widely available to promote equality of opportunity, and that individuals are free to decide whether or not to use them.

Adult↗

PubMed1997

The "kynurenate test", a biochemical assay for putative cognition enhancers.

Some putative cognition enhancers (oxiracetam, aniracetam and D-cycloserine) were previously shown to prevent the kynurenic acid antagonism of the N-methyl-D-aspartate (NMDA)-evoked norepinephrine (NE) release in rat hippocampal slices. This functional in vitro assay was further characterized in the present work. D-Serine, a glutamate coagonist at the NMDA receptor glycine site, concentration-dependently (EC50 approximately 0.1 microM) prevented the kynurenate (100 microM) block of the NMDA (100 microM)-evoked [3H]NE release. L-Serine was ineffective up to 10 microM. The gamma-aminobutyric acidB (GABA[B]) receptor antagonist CGP 36742, reported to improve cognitive performance, potently prevented the kynurenate antagonism. The activity of CGP 36742 (1 microM) appeared to be unaffected by 10 microM (-)-baclofen, a GABA(B) receptor agonist; furthermore, CGP 52432, a GABA(B) antagonist more potent than CGP 36742, but reportedly devoid of nootropic properties, was inactive in the "kynurenate test." The novel putative cognition enhancer CR2249, but not its enantiomer CR2361, also potently prevented the kynurenate antagonism. In contrast, linopirdine, nicotine and tacrine were inactive. In rat hippocampal synaptosomes glycine and D-cycloserine enhanced the NMDA-evoked [3H]NE release, whereas oxiracetam and CR2249 did not. These four compounds were all similarly effective in preventing kynurenate antagonism, both in slices and in synaptosomes. The NMDA potentiation caused by glycine (0.1-100 microM) was not affected by 100 microM oxiracetam, which suggested that drugs active in the "kynurenate test" may bind to sites different from the glycine site of the NMDA receptor. To conclude, the "kynurenate test" is an in vitro assay useful in the identification and characterization of putative cognition enhancers acting via NMDA receptors.

Animals↗

PubMed1989

An hypothesis on the role of glucose in the mechanism of action of cognitive enhancers.

This review presents evidence that some cognition enhancing drugs produce their beneficial effects on learning and memory by increasing the availability of glucose for uptake and utilization into the brain. The hypothesis further suggests that many cognition enhancing drugs act through a peripheral mechanism rather than directly on the brain. The general hypothesis is supported by four independent and converging pieces of evidence: 1) Some cognition enhancing drugs may not cross the blood-brain barrier, but can still facilitate memory; 2) Some cognition enhancing drugs are effective only when injected peripherally, but not when injected directly into the brain; 3) Many cognition enhancing drugs are not effective after adrenalectomy; 4) Cognitive function is correlated with glucose regulation in aged animals and humans. These four lines of research have implications for the role of glucose in the action of specific cognitive enhancers.

Cognition↗

PubMed2004

Cognitive enhancement therapy for schizophrenia: effects of a 2-year randomized trial on cognition and behavior.

BACKGROUND: Deficits in social cognition and neurocognition are believed to underlie schizophrenia disability. Attempts at rehabilitation have had circumscribed effects on cognition, without concurrent improvement in broad aspects of behavior and adjustment. OBJECTIVE: To determine the differential effects of cognitive enhancement therapy (a recovery-phase intervention) on cognition and behavior compared with state-of-the-art enriched supportive therapy. DESIGN: A 2-year, randomized controlled trial with neuropsychological and behavioral assessments completed at baseline and at 12 and 24 months. SETTING: An outpatient research clinic housed in a medical center's comprehensive care service for patients with severe mental illness. PATIENTS: A total of 121 symptomatically stable, non-substance-abusing but cognitively disabled and chronically ill patients with schizophrenia or schizoaffective disorder. INTERVENTIONS: Cognitive enhancement therapy is a multidimensional, developmental approach that integrates computer-assisted training in neurocognition with social cognitive group exercises. Enriched supportive therapy fosters illness management through applied coping strategies and education. MAIN OUTCOME MEASURES: Six highly reliable summary measures--Processing Speed, Neurocognition, Cognitive Style, Social Cognition, Social Adjustment and Symptoms--were tested using analysis of covariance and linear trend analysis. RESULTS: At 12 months, robust cognitive enhancement therapy effects were observed on the Neurocognition and Processing Speed composites (P<.003), with marginal effects observed on the behavioral composites. By 24 months, differential cognitive enhancement therapy effects were again observed for the 2 neuropsychological composites and for Cognitive Style (P=.001), Social Cognition (P=.001), and Social Adjustment (P=.01). As expected, no differences were observed on the residual Symptoms composite. Effects were unrelated to the type of antipsychotic medication received. Enriched supportive therapy also demonstrated statistically significant within-group effect sizes, suggesting that supportive psychotherapy can also have positive, although more modest, effects on cognitive deficits. CONCLUSION: Many cognitive deficits and related behaviors of patients with stable schizophrenia are improved when sufficient exposure to relevant rehabilitation is provided.

Adult↗

PubMed2006

[Ethical aspects of pharmacological cognition enhancement and the use of psychostimulants by children and young persons].

DEFINITION OF THE PROBLEM: Pharmacological cognition enhancement aims at an improvement of cognitive activity and performance in healthy people by means of appropriate drugs. Ethical implications of this kind of cognition enhancement stand in need of reflection. ARGUMENTS: For a number of reasons, the distinction between treatment and enhancement is fuzzy with regard to Attention Deficit Hyperactivity Disorder (ADHD). In consideration of the growing number methylphenidate prescriptions, one question addressed in this article is whether or not psychostimulants are used not only for therapy but also for cognitive enhancement by children and young people. The possibility of a "grey zone" between treatment and enhancement seems to open the field for medicalization of social and pedagogical problems as well as for "hidden enhancement." In clinical practice, the use of stimulants is associated with certain ethical problems concerning diagnosis, treatment and prevention of ADHD. Some of these problems are associated with the possibility of cognition enhancement. In order to evaluate ethical problems of pharmacological cognition enhancement, short-term and long-term consequences of stimulant use need to be taken into account. This refers to the level of transmitter balance in the learning process, to the level of individual learning strategies as well as to the level of interaction. This raises the question (1) of how well adapted the means of enhancement are with regard to the end of a comprehensive education and socialization, and (2) whether there are justifiable limits to the standardization of behavior and knowledge. (3) Moreover, stipulating an autonomous decision as a minimum prerequisite for legitimate cognition enhancement seems inadequate in the case of children and young persons. CONCLUSION: Considering the evidence and the many open questions associated with pharmacological cognition enhancement for children and young persons, it is concluded that it is indeed a morally problematic technique.

Adolescent↗

PubMedDate not supplied

Choosing a target for cognitive enhancers.

The development of drugs to improve cognitive functions (cognitive enhancers) has been hampered by the failure to define pharmacologic targets. The justifications for the development of cognitive enhancers for medicine, the pharmaceutical industry, and society are outlined. The procedures required for the development of these drugs and their therapeutic objectives are discussed. It is concluded that a better definition of the direct targets of cognitive enhancers can guarantee cost and time savings for the industry and produce a therapeutically effective agent.

Animals↗

PubMed2026

Dissociable neural mechanisms of cognitive enhancement through transcranial stimulation and behavioral training.

BACKGROUND: Transcranial direct current stimulation (tDCS) and adaptive working memory (WM) training are promising cognitive enhancement approaches; however, their neural mechanisms and potential synergies remain poorly understood. OBJECTIVE: We directly compared how tDCS and WM training modulate neural oscillations during WM performance and examined whether combining both interventions produces additive effects. METHODS: We randomized 112 healthy adults into four groups: control (sham tDCS + non-adaptive 1-back), tDCS-only (active tDCS + non-adaptive 1-back), training-only (sham tDCS + adaptive n-back training), or combined (active tDCS + adaptive training). Participants underwent five daily intervention sessions. We recorded high-density EEG during transfer n-back tasks at baseline, post-intervention, and one-week follow-up. RESULTS: All active interventions improved WM performance relative to the control group, with the combined group showing the largest gains (n-back accuracy: +15.6% vs. + 10.1% tDCS-only, +9.7% training-only, +0.7% control; all p < 0.001). Critically, tDCS selectively increased gamma-band (30-50 Hz) power in the frontal and parietal regions (cluster p = 0.018, d > 1.0), whereas WM training enhanced frontal theta-band (4-8 Hz) power and theta-gamma phase-amplitude coupling (both cluster p < 0.012, d > 0.85). The combined group exhibited both neural signatures. Brain-behavior correlations revealed dissociable relationships: gamma increases predicted n-back accuracy improvements (r = 0.61, p < 0.001), whereas theta enhancements correlated with operation span gains (r = 0.58, p = 0.002). CONCLUSIONS: tDCS and WM training enhance cognition through distinct yet complementary neural mechanisms: tDCS via gamma-mediated cortical excitability and WM training via theta-mediated cognitive control. These findings provide neurophysiological evidence for multimodal enhancement strategies that target parallel pathways within WM networks.

Humans↗

PubMed1999

Practice principles of cognitive enhancement therapy for schizophrenia.

Cognitive Enhancement Therapy (CET) is a developmental approach to the rehabilitation of schizophrenia patients that attempts to facilitate an abstracting and "gistful" social cognition as a compensatory alternative to the more demanding and controlled cognitive strategies that often characterize schizophrenia as well as much of its treatment. Selected cognitive processes that developmentally underlie the capacity to acquire adult social cognition have been operationalized in the form of relevant interactive software and social group exercises. Treatment methods address the impairments, disabilities, and social handicaps associated with cognitive styles that appear to underlie the positive, negative, and disorganized symptom domains of schizophrenia. Style-related failures in secondary rather than primary socialization, particularly social cognitive deficits in context appraisal and perspective taking, are targeted goals. Illustrative examples of the techniques used to address social and nonsocial cognitive deficits are provided, together with encouraging preliminary observations regarding the efficacy of CET.

Adult↗

PubMed2003

Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders.

RATIONALE: Current treatments for schizophrenia adequately treat the positive symptoms of schizophrenia but only modestly improve cognitive deficits. This review provides evidence for and against the use of selective 5-HT receptor drugs as cognition enhancing agents for schizophrenia and other disorders. METHODS: Pre-clinical and clinical literature concerned with the role of the serotonergic system in cognition and memory as it relates to schizophrenia is reviewed. Individual 5-HT receptor subtypes for which selective drugs are available that are likely to improve cognition are reviewed. Recommendations for clinical testing are proposed. RESULTS AND CONCLUSIONS: Four 5-HT receptor systems (5-HT(1A), 5-HT(2A), 5-HT(4), 5-HT(6)) are highlighted as suitable targets for enhancing cognition and memory. Because many clinically available antipsychotic drugs already target 5-HT(1A), 5-HT(2A) and 5-HT(6) receptors, design of clinical trials will need to take into account the serotonergic pharmacology of concurrently administered antipsychotic medications. 5-HT(1A) partial agonists and 5-HT(2A) antagonists have shown modest effectiveness in improving cognition in schizophrenia. 5-HT(6)-selective compounds for cognition enhancement are in late-stage clinical trials, while 5-HT(4) compounds have not yet been tested in humans for cognition enhancement. RECOMMENDATIONS: For stand-alone therapy for enhancing cognition, 5-HT(1A) partial agonists, 5-HT(2A) antagonists, 5-HT(4) partial agonists and 5-HT(6) antagonists are all likely to induce at least modest improvement in cognition in schizophrenia. If "add-on therapy" is contemplated, antipsychotic drugs with weak affinities for serotonin receptors should be used to avoid confounds. It is likely that serotonergic drugs will soon be available as cognition enhancing medications for disorders other than schizophrenia (e.g. dementia).

Animals↗

PubMed1991

Clinical issues of cognitive enhancers in Alzheimer disease.

Cognitive enhancers is a provocative and vague label for drugs used to treat dementia of the Alzheimer type. Several issues have to be carefully considered in order to perform reliable clinical trials with such compounds. The lack of an animal model appropriately matching the human pathology, the difficulty in finding worldwide criteria for clinical diagnosis and determining which patients are eligible and how they are best tested, methods of treatment, and interpreting results are undoubtedly the major problems to be solved. A review of the literature points out that the "day-after" approach of treatment (once severe neuropathological damage has been established) is no longer feasible, or has limited advantages. A different pharmacological approach, based on preventive measures during the first stages of the neurodegeneration, seems mandatory.

Alzheimer Disease↗

PubMed1995

General pharmacology of the putative cognition enhancer linopirdine.

The putative cognition enhancer linopirdine (3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one, CAS 105431-72-9) is supposed to act by enhancing the release of neurotransmitters, especially acetylcholine. The present study assessed the effects of a single administration of this compound on the central nervous system in eight different rat and mouse models (CNS general pharmacology). In each test performed, linopirdine was administered subcutaneously in doses of 3, 10, and 30 mg/kg. The compound did not affect traction ability and nociceptive responsiveness nor did it induce catalepsy. Linopirdine impaired motor coordination in the balance rod test. The compound showed a distinct proconvulsive action in the pentylenetetrazole threshold dose test and induced in the highest dose tested (30 mg/kg) lethal seizures in some mice. It increased the duration of hexobarbital-induced anaesthesia in mice. Rats treated with linopirdine showed ptosis, salivation, slight sedation, paw beating and slight hypothermia. These results support the hypothesis that linopirdine acts by elevating the release of different neurotransmitters such as acetylcholine and dopamine. The compound has a low potential to produce side effects at pharmacodynamic active doses.

Animals↗

PubMed2004

Design of new cognition enhancers: from computer prediction to synthesis and biological evaluation.

To discover new cognition enhancers, a set of virtually designed synthesizable compounds from different chemical series was investigated using two computer-aided approaches. One of the approaches is prediction of biological activity spectra for substances (PASS) and the second is prediction of toxicity, mutagenicity, and carcinogenicity (DEREK). To increase the probability of finding new chemical entities, we investigated a heterogeneous set of highly diverse chemicals including different types of heterocycles: five-membered (thiophenes, thiazoles, imidazoles, oxazoles, pyrroles), six-membered (pyridines, pyrimidines), seven-membered (diazepines, triazepines), fused five+six-membered heterocycles (indoles, benzothiazoles, purines, indolizines, neutral, mesoionic, and cationic azolopyridines). A database including 5494 structures of compounds was created. On the basis of the PASS and DEREK prediction results, eight compounds with the highest probability of cognition-enhancing effect were selected. The cognition-enhancing activity testing showed that all of the selected compounds had a pronounced antiamnesic effect and were found to reduce significantly scopolamine-induced amnesia of passive avoidance reflex (PAR). The action of compounds at doses of 1 and 10 mg/kg caused a statistically significant increase in latent time of reflex and in the number of animals, which did not enter the dark chamber when testing the PAR. Therefore, on the basis of computer prediction, new cognition-enhancing agents were discovered within the chemical series, in which this activity was not known previously.

Amnesia↗

PubMed2006

Preclinical research into cognition enhancers.

The preclinical development of drugs to treat the cognitive symptoms of neuropsychiatric and neurological disorders is a formidable challenge. Evidence from a wide range of preclinical behavioral and neuropharmacological tests has formed the basis for predicting drug-induced cognition enhancement in normal volunteers and in patients with cognitive impairments. However, the limited validity of preclinical predictions of this enhancement in humans indicates that conventional screening for "broadly active" compounds represents a below-optimal research strategy. This article conceptualizes the evidence needed to improve the predictive validity of preclinical research designed to discover and characterize cognition enhancers. We suggest that the investigation of reciprocal relationships among molecular, cellular, behavioral and cognitive processes modulated by candidate drugs represents the core of such research. By contrast, the usefulness of simple and high-throughput screening tests for the detection of cognition enhancers might be restricted to advanced drug-finding programs that are guided by evidence of the modulation of neurocognitive relationships by cognition enhancers and that are informed by iterative preclinical-clinical cross-validation of research approaches. We stress the need for basic biopsychological research approaches in preclinical programs to find and characterize drugs to treat cognitive disorders.

Animals↗

PubMed1989

Cognitive enhancers: potential strategies and experimental results.

1. Cognitive impairments follow natural processes such as aging, diseases, exposure to neurotoxins, and traumatic injury. In all of these instances, the brain possesses some capability for recovery. 2. A cognitive enhancer is any compound that will help this recovery occur more rapidly, or increase the final level of performance. 3. This chapter describes the types of strategies that can be used to develop a cognitive enhancer with emphasis on studies of the cholinergic system.

Animals↗