No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Towards Better Brain Management: Nootropics
Abstract
The learning and memory deficits have been recognized as severe and consistent neurological disorders associated with numerous neurodegenerative states. Research in this area has gained momentum only in the recent past after the biochemical and physiological basis of these processes have been understood. A considerable alteration in the neurotransmission is a consistent finding in cognitive disorders. Therefore, many therapeutic strategies to augment the concentration of neurotransmitters in brain such as cholinergic agents, biogenic amines and neuropeptides etc. have been evaluated in cognitive deficits. CNS modulators are the type of antiamnesics that act via modulation of the neurological processes underlying memory storage. These include psychostimulants, excitatory amino acids and most important of all "nootropics". Nootropics are a heterogeneous group of compounds of diverse chemical composition and biological function that allegedly facilitate learning and memory or overcome natural or induced cognitive impairments. The literature survey incorporated in this article hallmarks the success achieved in the design and development of potential nootropic agents. Additionally, this review is an attempt towards discussing various approaches available to enhance memory, along with the classification of the known memory enhancers, authors research work towards various structural modifications carried out and the biological screening.
... Nootropics, specifically, are substances that have been classified as cognition enhancers. Nootropics can be divided into three different categories: dietary supplements, synthetic compounds, and prescription drugs (Malik et al., 2007). The primary distinctions between these categories lie in their legal regulations, the bases of their efficacy, and their safety profiles. ...
... Piracetam, one of the earliest and most widely studied nootropics, has been shown to improve memory and information processing, particularly in elderly populations and in cases of age-related decline. However, despite its long history of use, the literature suggests that its benefits may be modest or inconsistent (Malik et al., 2007). Modafinil, typically prescribed for narcolepsy, has also been investigated off-label for its cognitive-enhancing effects, including improvements in attention and executive function. ...
... Modafinil, typically prescribed for narcolepsy, has also been investigated off-label for its cognitive-enhancing effects, including improvements in attention and executive function. It is noted for its relatively low potential for abuse and side effects, making an attractive option for individuals seeking to enhance their cognitive performance without the risks associated with other stimulants (Malik & Tlustos 2022;Malik et al., 2007;Schifano et al., 2022). l-Theanine, a naturally occurring compound found in tea, is known for its anxiolytic properties and ability to enhance attention and reaction time, especially when combined with caffeine. ...
Nootropics, often referred to as “smart drugs,” are substances purported to enhance cognitive functions, particularly executive functions and memory, in healthy individuals. While primarily used by younger adults, there is growing interest in the potential of nootropics to benefit elderly, particularly in the prevention and management of cognitive decline associated with aging. This study aimed to investigate the acute cognitive enhancing effects of a single standardized dose of the dietary nootropic stack CILTEP® (Neurofuel™) in healthy elderly participants. We evaluated the cognitive benefits of a single dose of CILTEP® in 33 healthy elderly participants using a randomized, double-blind, placebo-controlled, two-way cross-over design. To assess various cognitive domains, a comprehensive test battery was employed which included tasks measuring memory performance, attention, and sensorimotor speed. The tests administered were the Verbal Learning Test, the Spatial Pattern Separation Task, the Digit Symbol Substitution Task, the Trail Making Test, the n-Back test, the Simple and Choice Reaction Time Task, and the Stroop Color-Word Task. No relevant effects attributable to acute CILTEP® treatment were observed on any cognitive measures, event-related-potentials (ERPs), or vital functions such as blood pressure and heart rate. The lack of significant cognitive enhancement in healthy elderly participants may suggest that a single acute dosing of CILTEP® is insufficient to exert measurable effects. Further studies are required to explore long-term effects, optimal dosing, and overall efficacy of the nootropic.
... Nootropics may also have neuroprotective effects reducing Aβ accumulation, synaptic dysfunctions, inflammation, apoptosis, and oxidative stress 69 . Nootropics have been demonstrated to protect against experimentally induced disruption of acquisition, retention or retrieval in animal models in either passive avoidance or similar procedures 70 . Advantages of the nootropics include absence of adverse effects usually associated with neuropsychotropic drugs, good long-term tolerability and adherence to therapy. ...
... Advantages of the nootropics include absence of adverse effects usually associated with neuropsychotropic drugs, good long-term tolerability and adherence to therapy. They improve cognitive functions 70 and have documented longterm efficacy in a variety of conditions involving decreased mental acuity from mild to moderate. ...
Objective:
The objectives of this review are to explore the neuronal pathways and cellular and molecular mechanisms involved in both healthy and impaired cognitive function and to discuss the role of nootropics, in particular, those with cholinergic activity, as promising interventions to preserve and/or improve cognitive performance in patients in the symptomatic pre-dementia stage, known as mild cognitive impairment (MCI).
Materials and methods:
Papers were retrieved by a PubMed search, using different combinations of keywords (e.g., cognitive function AND aging AND nootropics), without limitations in terms of publication date or language.
Results:
Nootropics modulate the activities of specific brain pathways involving neurotransmitters and neuromodulators that have distinct roles in the cognitive processes. The nootropic L-a-glyceryl-phosphoryl-ethanolamine (L-a GPE), by virtue of its action as a phospholipid (PL) precursor and acetylcholine (Ach) donor, targets neural stem cell aging, cholinergic depletion, oxidative stress and microglia activation, loss of entorhinal cortex neurons, and reduced hippocampal volume. Cognitive reserve levels may be linked to the resilience and adaptability of the brain to cope with age-related cognitive decline. L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action.
Conclusions:
The substantial burden of age-related cognitive decline demands effective long-term and well-tolerated interventions aimed at maximizing the span of effective functioning. The use of inappropriate medication may lower cognitive reserve, thus hastening the onset of symptomatic AD, while the use of nootropics, such as L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action.
... Stimulants, such as methylphenidate, act similarly to neurotransmitters in the brain including norepinephrine and dopamine. These drugs enhance the effects of these neurotransmitters in the brain, and this associated increase in dopamine can induce feelings of euphoria, and they also increase blood pressure and heart rate, constrict blood vessels, increase blood glucose, and dilate bronchioles [7][8][9][10]. There is strong evidence that methylphenidate, a medication prescribed to manage symptoms of attention-de cit/hyperactivity disorder (ADHD) in children and adults, is used by healthy college students to improve concentration, alertness, and academic performance [11]. ...
Background: Non-medical use of neuropharmaceuticals generates significant discussions in medical and public health circles. The main motivation for this non-medical use of neuropharmaceuticals is to enhance cognitive function in healthy individuals beyond normal human capacity. Objective: The prevalence of stimulants among Syrian Private University students and its relationship with academic achievement and psychological status.
Methods: A cross-sectional study conducted at the Syrian Private University, during the period 12/1/2023 to 7/1/2024. The students' responses, numbering 386 male and female students, were studied through an electronically distributed questionnaire.
Results: The sample consisted of 386 students. With an average age of 22.40 years. The percentage of males was 51% compared to females 49%. The financial status was average at 40%. The students of the Faculty of Human Medicine constituted the largest number of students in the sample, reaching 45%. The most common reason for using these stimulants among the students who used them was staying up late and studying during exams and projects, which was 5% of the students. The fourth year was the highest year in terms of stimulant use among the students, with a rate of 4%. The students of the Faculty of Human Medicine were the students who had the highest anxiety score, which was 1.93 compared to the students of the other faculties.
Conclusion: The percentage of stimulant use among the students in our study was 8% of the total students. The most frequent motives for using stimulant drugs were reasons related to academic activities. The results of our study differed regarding the students' knowledge of stimulants and their side effects, as only 3% of the students in our study indicated their knowledge of these drugs and their side effects.
... While this research is still emerging and the mechanisms underlying cognition are complex and multifaceted, some nootropics such as, e.g., L-theanine, caffeine, and modafinil, have shown to improve attention (Barbhaiya et al., 2008;Giesbrecht et al., 2010;Einöther et al., 2010), verbal memory (Barbhaiya et al., 2008;Illieva et al., 2015), creativity (Müller et al., 2013), and executive function (Killgore et al., 2009) in cognitively healthy individuals. Nootropics can be divided into three different categories: dietary supplements, synthetic compounds, and prescription drugs (Malik et al., 2007). Most nootropics, especially those that fall under the dietary supplement category, do not need the approval of the Food and Drug Administration (FDA) or Federal Trade Commission (FTC) and are therefore not monitored or scheduled (Howland, 2010). ...
This study investigated the acute effects of the dietary nootropic stack CILTEP®. It contains a combination of ingredients that have been individually reported to improve cognitive performance. Especially, the ingredients luteolin, which is considered a phosphodiesterase type 4 (PDE4) inhibitor, and forskolin, an adenylate cyclase stimulator, were of interest since they can increase the second messenger cAMP and thus also intracellular signaling. Numerous studies have shown that inhibition of PDE4 can improve memory in animals and humans. We examined whether acute dosing of 3 capsules of CILTEP® would improve cognitive function in healthy participants aged 30 to 40 (n = 33). We used a randomized, double-blind, placebo-controlled, two-way cross-over design. Our test battery was aimed at measuring memory performance, attention, and sensorimotor speed. The primary outcome measures were the performance on the verbal learning task and the spatial pattern separation task. Secondary outcomes included other cognitive tests, event-related potentials (ERPs), and assessment of the activity of the enzyme beta-glucuronidase and its effect on the bioavailability of luteolin, heart rate, and blood pressure. No relevant effects of acute CILTEP® treatment were found on any measure of the test battery or ERPs. Blood plasma concentrations of luteolin increased, yet about 2000 times too low to likely exert any PDE4 inhibition. CILTEP® treatment did neither affect heart rate nor blood pressure. In summary, there is no evidence that a single standardized dose of 3 capsules of CILTEP® can improve cognitive function in healthy middle-aged participants.
... 6. Serotonergics: These substances work by affecting the neurotransmitter serotonin or the components of the nervous system that use serotonin. 7. Anti-depression, Adaptogenic (Antistress) and Mood stabilization agents: Stress, depression, and depressed mood [45] . 9. Amino acids and Proteins Adult brains use amino acids, which are typically found in protein rich food, for the production of enzymes that transport molecules, structural material and neurotransmitters, along with other essential molecules. ...
... In vitro studies demonstrated oppositional activity to negative modulators of gamma-aminobutyric acid (GABA)-gated currents despite lack of binding affinity to GABA receptors. [6][7][8][9][10][11][12][13] The pharmacological activity of levetiracetam was evaluated in mice, rats, hamsters, guinea pigs and dogs. These studies revealed that levetiracetam displayed protection in various animal models of chronic epilepsy reflecting both partial and primary generalized seizures. ...
United state food and drug administration approved Levetiracetam on 30th November 1999 for the use as adjuanctive therapy in the treatment of partial onset seizures in adults with epilepsy. Therapeutic indications of Levetiracetam includes monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy. Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy, in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy, in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalised epilepsy. This article describes the pharmacological aspects of Levetiracetam that will helful to health professionals.
... Nootropic drugs have a place with the class of psychotropic operators with a particular facilitatory impact on learning and memory [18]. Memory impairment has developed as one of the main health threats in some memory disease conditions [19]. ...
One of the plants that have been used for enthno medicinal purposes in traditional civilization is Anacardium occidentale L. of the family Anacardiaceae is native to Brazil also found in tropical countries such as Malaysia and India commonly known as cashew. The purpose of this study is to determine the in-vitro and in-vivo cognitive effects of an ethanolic leaf extract of the herb Anacardium occidentale on albino rats. Orally the ethanolic extract was administered in two doses (100 mg/kg and 400 mg/kg). The Elevated Plus maze and Y-maze showed statistically significant improvement in the memory process. The estimation of acetylcholinesterase enzyme in rats brain also shows improvement in the memory process by reducing acetylcholinesterase activity. Disorders related to cognition are one of the major health problems and increasing day by day especially affecting the elder individual. There is no proper medication for the impairment of memory. The study reveals that the ethanolic extract of the leaf of Anacardium occidentale has dose-dependent memory-enhancing performance. Synthetic drugs have a lot of side effects, whereas drugs belongs to natural substances have least side effect compared to synthetic one, which has gained a lots of importance. These studies need to be documented effectively. Research findings were contributed to meet the future needs in general healthcare, research, and conservation of endangered species and may give a lead to the discovery of newer drugs.
... Среди ноотропов наибольшее распространение и популярность получил пирацетам, который согласно литературным данным практически полностью выводится из организма в нативном виде [6][7][8][9][10][11][12][13][14][15]. В отношении унифирама известно, что он выводится в нативном виде частично и имеет очень узкое окно обнаружения [16]. ...
... Among nootropics, the most widespread and popular is piracetam, which is almost completely excreted from the body in its native form according to published data [6][7][8][9][10][11][12][13][14][15]. With regard to unifiram, it is well known that it is partially excreted in its native form and has a very narrow detection window [16]. ...
The metabolism of the new nootropic drug unifiram is considered; this drug supposedly has significantly higher activity than that of piracetam, and it is under clinical trials as a means of improving memory and preventing Alzheimer's disease, attention-deficit disorder, and various forms of dementia. The structures of two potential metabolites of unifiram are proposed. Based on the interpretation of the experimental mass spectra of precursor ions and product ions, the applicability of a non-target screening methodology with the use of ultra-high performance liquid chromatography-high-resolution mass spectrometry to the detection of these compounds was demonstrated. It was established that the supposed metabolites of unifiram can be determined only with the use of enzymatic hydrolysis, while mineral hydrolysis led to the complete destruction of both the unifiram itself and the hypothetical metabolites. The use of the proposed chromatographing and mass-spectrometric detection conditions makes it possible to detect unifiram metabolites within six days after a single administration of 10 mg of the substance.
... (54) Such molecule was presented as a prototype of that new class of psychotropic drugs. (54,55,56,57) Using the properties that were attributed to piracetam, Giurgea listed the main characteristics of a nootropic drug: (a) enhancement of learning and memory; (b) greater resistance to conditions impairing learning skills (such as electroconvulsive shocks and cerebral hypoxia); (c) protection of the brain against harmful chemical or physical agents; (d) increased efficacy of control mechanisms involved in the brain tone, at a cortical and subcortical level; (e) larger flow of information between the two brain hemispheres; (f) absence of pharmacological effects typical of other psychotropic drugs, as well as a low incidence of side effects and extremely low toxicity. (55,56,58) That way, the use of piracetam was considered to treat memory loss, and mild and moderate dementia, both related to ageing. ...
By observing the processes of (bio)medicalization and pharmaceuticalization of society, this article addresses drugs that have been used by healthy individuals to increase cognitive dimensions such as alertness, memory, and concentration. The use of so-called “smart drugs” or “nootropics” has spread among young people, aided by the internet. The circulation of information about such drugs are analyzed using a Brazilian blog called “Cérebro Turbinado,” through publications available for public access between 2015 and 2017. The study adopts theoretical and methodological frameworks of the social sciences, including an anthropological perspective. Documental research was conducted on the internet, specifically with scientific dissemination materials and the material available from the aforementioned blog. The results show that the blog acts as a medium for spreading biomedical knowledge among the lay public and indicates the production of new forms of subjectivity by revealing the meanings attributed to these substances in socialization processes.
KEYWORDS:
Medicalization; Internet; Nootropic Agents; Biomedical Enhancement; Brazil
... Modern experimental psychopharmacology possesses these possibilities. Nootropics with a wide range of pharmacological effects (piracetam and mexidol, in particular) are drugs affecting learning and memory [3]. Anxiolytics are drugs that affect fear and anxiety [4]. ...
Effects of the anxiolytic diazepam and nootropics piracetam and mexidol on passive avoidance conditioning (PAC) in rats were compared in experiments using a three-compartment apparatus. The latter consisted of a central, brightly lit compartment, a noxious dark compartment in which footshock was delivered to a rat, and a safe dark compartment, where the rat was not exposed to electric shock. Footshock during the acquisition of passive avoidance response in the control animals caused an abrupt increase in the latency to escape from the central compartment during testing but did not result in preference for a safe compartment. On the basis of these data on differential effects of footshock on PAC, we suggested that learning processes, which determined the motor response delay and the safe compartment preference, had a diverse associative nature. An increase in latency is associated with the classical fear conditioning regardless of the place of electric shock exposure. In contrast to this, the safe compartment preference is associated with the formation of the memory trace about the location of the footshock exposure. The use of pharmacological substances that affect fear and memory in different ways provided additional arguments in favor of the assumption about various associative processes determining passive avoidance learning. Reduction in the level of fear using diaze-pam decreased the latency of motor response compared to the control value but did not affect the preference for a safe compartment. In contrast, the mnemotropic properties of piracetam and mexidol increased the preference for a safe compartment without increasing the latency. These differential pharmacological effects confirm that PAC is based on the fear conditioning, which causes an increase in the latency to escape from the central compartment, and on the memory of the location of shock exposure, which provides the preference for the safe compartment.
... Aniracetam is another AMPAkine created by modifying the piracetam molecule by replacing the acetamide moiety with a 4-methoxybenzoyl group [12]. Aniracetam has few side effects (e.g. ...
Understanding the effects of cognitive enhancing drugs is an important area of research. Much of the research, however, has focused on restoring memory following some sort of disruption to the brain, such as damage or injections of scopolamine. Aniracetam is a positive AMPA-receptor modulator that has shown promise for improving memory under conditions when the brain has been damaged, but its effectiveness in improving memory in neurologically healthy subjects is unclear. The aim of the present study was to examine the effects of aniracetam (100mg/kg and 200 mg/kg) on short-term memory in “neurologically healthy” pigeons. Pigeons were administered aniracetam via either intramuscular injection or orally, either 30 or 60 minutes prior to testing on a delayed matching-to-sample task. Aniracetam had no effect on the pigeons’ memory performance, nor did it affect response latency. These findings add to the growing evidence that, while effective at improving memory function in models of impaired memory, aniracetam has no effect in improving memory in healthy organisms.
... Nootropics describe a class of psychoactive drugs that both directly and selectively improve the efficiency of higher telencephalic integrated activities. Characteristic clinical effects of a nootropic include enhancements in learning acquisition and memory, whilst improving the brain's general resistance to impairing agents [4]. The current consensus is that aniracetam works through a glutamatergic mechanism of action [5], as a positive allosteric modulator on the AMPA subtype [6]. ...
The nootropic drug aniracetam is greatly limited in its application by low aqueous solubility and a poor oral bioavailability. The primary aim of this study was to design a parenteral formulation of aniracetam that can be administered intravenously. Complexation of aniracetam with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated as a strategy to enhance solubility. A phase solubility analysis was performed to quantify the extent of improvement. An 819% increase in the solubility of aniracetam was obtained, reaching 36.44 mg/mL. This marked increase enables aniracetam to exist in an aqueous solvent at levels sufficient for parenteral dosing. A stability test was then devised using a design of experiment approach. The aniracetam-HP-β-CD formulation was subjected to different relative humidity and temperature and cyclodextrin concentrations over a 12-week period. Key changes in FTIR vibrational frequencies suggest the benzene moiety of aniracetam was introduced into the hydrophobic cavity of HP-β-CD. These results are highly supportive of the formation of a predictable 1:1 molar stoichiometric inclusion complex, explaining the improvement seen in physiochemical properties of aniracetam following formulation with HP-β-CD. This novel formulation of aniracetam suitable for parenteral administration will have utility in future studies to further elucidate the pharmacokinetics of this drug.
... Levetiracetam is an active, water-soluble S-enantiomer of pyrrolidine acetamide (S)-a-ethyl-2-oxo-1-pyrrolidine acetamide. It is an (S)-enantiomer of the ethyl analog of piracetam, which is a member of the nootropic class of drugs [19][20]. Chemical formula of levetiracetam is C 8 H 14 N 2 O 2 I with a molar mass of 170.209 g/mol and it is structurally unrelated to any other antiepileptic class. ...
Background:
Neonatal seizures are the most common clinical manifestation of central nervous system (CNS) dysfunction and are associated with various neurological sequelae. There are currently no evidence-based guidelines for the management of neonatal seizures and currently used drugs such as phenobarbital, and phenytoin have limited efficacy and potential toxicities. Newer second line anticonvulsant, levetiracetam, has been used in refractory neonatal seizures despite limited data and off-label use.
Objective:
In this review, we will discuss various pharmacological properties of levetiracetam when used in neonatal population.
Methods:
A PubMed search for MEDLINE was undertaken to look for studies using the terms "Levetiracetam", AND "Neonates" as key words from year 1995 to January 2017. Relevant articles were selected and information was extracted about pharmacokinetics, pharmacodynamics and clinical uses of levetiracetam in neonates.
Results:
Levetiracetam is an active, water-soluble S-enantiomer of racemic pyrrolidine acetamide which exerts its antiepileptic action by binding to the synaptic vesicle protein within the brain. Metabolism of levetiracetam does not include the CYP P450 system and it is mainly eliminated through kidneys after rapid absorption. Also, no significant interactions with other drugs have been identified. Unlike other commonly used antiepileptic drugs, levetiracetam is not bound to plasma proteins, thereby, reducing the chances of toxicity and severe, life threatening side effects have not been reported. In fact, it has been shown to prevent neuro-degeneration after hypoxia/ischemia in rodent models of epilepsy.
Conclusion:
Levetiracetam has been emerging as a potential therapeutic option for refractory neonatal convulsions owing to its non-hepatic elimination, linear pharmacokinetics, low protein binding and better safety profile.
... The developing concern in drug-facilitated enhanced memory performance originated both from basic research sciences and from the exploration for therapeutic substitutes for memory impairments due to Alzheimer's disease (AD), aging, toxicant exposure or brain injury (Cumin, Bandle, Gamzu, & Haefely, 1982;Malik, Sangwan, Saigal, Jindal, & Piplani, 2007;Reneerkens, Rutten, Steinbusch, Blokland, & Prickaerts, 2009;Wallace, Ballard, Pouzet, Riedel, & Wettstein, 2011). However, drug specificity on memory processes has been a major issue (Heise, 1981). ...
The present paper describes the synthesis, biological evaluation and molecular simulation studies of a series of N-(4-hydroxyphenyl)-3,4,5-trimethoxybenzamide derivatives with N,N-dialkylaminoethoxy/propoxy moiety as potential memory enhancers with acetylcholinesterase inhibiting activity having IC50 in low micromolar range (4.0-16.5 μM). All the compounds showed a good degree of agreement between in vivo and in vitro results as most of these derivatives showed dose dependent increase in percent retention. Compound 10a showed significant % retention of 84.73 ± 4.51 as compared to piracetam (46.88 ± 5.42) at 3 mg kg⁻¹ and also exhibited a maximal percent inhibition of 97% at 50 μM. Molecular docking, MM-GBSA and molecular simulation studies were performed establishing a correlation between the experimental biology and in silico results. In silico results indicate that all the compounds have better docking scores and predicted binding free energies as compared to co-crystallized ligand with the best potent ligand retaining conserved hydrophobic interactions with residues of catalytic triad (HIS447), Catalytic anionic site (CAS) (TRP86, TYR337, PHE338) and peripheral anionic site (PAS) (TYR72, TYR124, TRP286 and TYR341). Root mean square deviation (RMSD=2.4 Å) and root mean square fluctuations of 10a–AChE complex during simulation proved its stable nature in binding toward acetylcholinesterase. The docked conformation of 10a and other analogs at the binding site have also been simulated with polar and non polar interactions interlining the gorge residues from PAS to catalytic triad.
... With the advancement in research in therapies relating to neurological disorders, acetylcholinestease inhibitors (AChEIs) have held upper hand in treatment of cognitive disorders and several other disorders at different stages of severity. An emergent curiosity in drug-facilitated memory performance (Malik, Sangwan, Saihgal, Jindal, & Piplani, 2007;Reneerkens, Rutten, Steinbusch, Blokland, & Prickaerts, 2009;Wallace, Ballard, Pouzet, Riedel, & Wettstein, 2011) has emerged from basic research on learning and memory as well as therapeutic hunt for neurological impairments due to Alzheimer's disease (AD), aging, and brain injury (Cumin, Bandle, Gamzu, & Haefely, 1982). Yet, specificity of these drugs on memory processes has proven tricky (Heise, 1981). ...
The present paper describes design, synthesis, and biological evaluation of a series of some 3-[3-(amino)propoxy]ben-zenamines as acetylcholinesterase inhibitors using mice as a model and piracetam as a reference drug. The structures of these compounds were confirmed by spectral analysis and compounds were tested for memory enhancing activity using elevated plus maze test and acetylcholinesterase inhibitory assay. The inhibitory range of synthesized compounds was from 8.99 to 28.31 μM. The synthesized compounds possessed higher or equivalent percent retention as compared to piracetam at 1 mg/kg with no other CNS-related activities (locomotor and muscle relaxant, analgesic and anticonvulsant activities). Compound 3-[3-(imidazolo)propoxy]benzenamine has shown significant dose-dependent (1 and 3 mg/kg) memory enhancing activity, while 3-[3-(pyrrolidino)propoxy]benzenamine also showed activity equivalent to reference drug piracetam at 1 mg/kg. Both compounds 3-[3-(pyrrolidino)propoxy]benzenamine and 3-[3-(imidazolo)propoxy]benzenamine were also found to show AChE inhibition with IC 50 value of 8.99 and 17.87 μM. The molecular docking, MM-GBSA and molecular dynamics simulation studies were performed in order to establish a relationship between the biological results. RMSD, root-mean-square fluctuations, and interaction patterns of 10a–AChE and Sck–AChE complexes proved that the binding affinity of 10a toward AChE was highly stable with the proposed binding orientations.
... Blackwood smiles, nods sympathetically and shrugs his shoulders at the same time. "Of course, the pharmaceutical industry is working on that at full speed [49]. For nootropics, so-called brain food, such as 'memory amplifiers' or 'cognitive enhancers', different targets in the brain can be imagined, such as adjusting cAMP levels or controlling the relationship between CREB-1 and CREB-2 in the hippocampus. ...
... Additionally, for P-gp, the structure-based approach is unable to distinguish out between substrate and inhibitors, so ligand-based approach gives an upper hand for distinguishing between the two. As a part of our ongoing drug discovery program based on synthetic derivatives for cancer-and memory-enhancing therapies (Piplani et al., 2012;Malik et al., 2007), in the present study, pharmacophore-based 3D-QSAR was carried out on a set of P-gp inhibitory galloyl benzamides (Pellicani et al., 2012) using Pharmacophore Alignment and Scoring Engine (PHASE) module of Schrodinger program to understand the relationship between biological activity and 3-dimensional molecular fingerprints of galloyl benzamides. ...
P-gp transporter regulates key ADME of drugs in MDR condition. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of galloyl benzamides analogs possessing P-gp inhibitory activity. Developed pharmacophore model contains two hydrogen-bond acceptors (A), one hydrophobic (H), one hydrogen-bond donor (D) and two aromatic rings (R). These are crucial molecular fingerprints which predict binding efficacy of high-affinity and low-affinity ligands to the P-gp efflux pump. These pharmacophoric features point toward key structural requirements of galloyl benzamides for potent P-gp inhibition. Furthermore, a biological correlation 3D-QSAR variants and functional fingerprints of P-gp responsible for the receptor binding were observed. Alignment of the developed model with P-gp crystal structure indicated importance of A2 and A4 H-bond acceptor sites, which are involved in the important interactions with Glu530 and His690 residues of the active site. Excellent statistical results of QSAR model such as good correlation coefficient (r
2 > 0.95), higher F value (F > 205) and excellent predictive power (Q
2 > 0.6) with low standard deviation (SD < 0.2) strongly suggest that the developed model is good for the future prediction of P-gp inhibitory activity of new galloyl benzamide analogs.
... These drugs are used to treat people with cognitive learning difficulties, neural degradation and for cases of oxygen deficit to prevent hypoxia. The main features of nootropic drugs are: [68] 1. The enhancement of learning and memory acquisition as well as resistance of learned behaviours to agents that tend to impair them. ...
In today's life of stress and strain, there is a direct need for agents having neuroprotective and neuropharmacological activity enhancing learning and memory function of the brain. Stress is also known to interfere with cognitive functions, tending to retard the memory anagram rather than the acquisition of learning. Cognition enhancers, often referred to as nootropics, can be defined as drugs able to facilitate attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with age and age-related pathologies. By definition, this class of drugs improves declining of cognitive functions but does not change the rate of progression of neurodegeneration. In course of time, numbers of neurotransmitters and signaling molecules have been identified which have been considered as therapeutic targets. Conventional as well as newer molecules have been tried against these targets. Moreover, ongoing research progress have validated some of the newer targets such as nicotinic receptors, PDE4, 5HT6, ACE inhibitors, beta-amyloid manipulations, calcium channel blockers, Aluminium chelation therapy which can be of therapeutic importance. In this review, some conventional as well as newer strategies have been discussed.
... Currently, first world people are increasingly using various kinds of nootropic enhancers in order to increase 'normal neurocognitive function' (Farah et al. 2004, Malik et al. 2007, Lanni et al. 2008, Saniotis 2009. The use of nootropics to enhance cognition is referred to as 'cosmetic neurology' (Chatterjee 2006). ...
Since prehistory, the genus Homo has used technologies in order to enhance fitness. With the growth of bio-technologies, western medicine is improving the structure and function of the human body beyond its natural state. Bio-technological improvements in the next 50 yr promise further increases in human life span and performance. Notwithstanding the ethical argument encouraging transhumanist technologies, present human societies have yet to come to grips with the possibility of such a future world. This article will discuss future nootropic enhancers and human-animal gene splicing as possible enhancement technologies in relation to their ethical and social implications.
... 3. Improving neuron function. 4. Preventing free radical and oxidative damage to brain cells. ...
Nootropics also referred to as smart drugs, memory enhancers, neuro enhancers, cognitive enhancers, and intelligence enhancers, are drugs, supplements, nutraceuticals, and functional foods that purportedly improve mental functions such as cognition, memory, intelligence, motivation, attention, and concentration. Nootropics are thought to work by altering the availability of the brain's supply of neurochemicals (neurotransmitters, enzymes, and hormones), by improving the brain's oxygen supply, or by stimulating nerve growth. Drugs considered cognitive enhancers include dietary products and supplements, racetams, stimulants, dopaminergics, cholinergics, GABA blockers, glutamate activators, serotonergics and hormones, etc. however not all are healthy or safe to use but they can still have mental benefits. The safest types of cognitive enhancers constist of herbal drugs and are available in supplement form, which mostly contain vitamins, fatty acids, antioxidants, amino acids, minerals, etc and other herbal ingredients. Vitamins are involved in brain development and in adult brain function. Omega-3 influences both communication between cells and cell function. Antioxidants help to retain the mental abilities longer, keep the brain younger and protect it from oxidative damage. Amino acids help to produce the catecholamines and create alertness. Hormones increase neurogenesis and improve both memory encoding and recall. Iron helps create hemoglobin, which transports oxygen to the brain. Creatinine protects ATP during transport. Lipoic acid improves oxygen usage and antioxidant recycling, improving memory and Germanium increases oxygen supply to the brain. Herbs and herbal products which have been found useful in improving cognitive ability include Bacopa monniera, Ginkgo biloba, Siberian ginseng, Rhodiola rosea, Brahmi rasayana, , Lycoris radiata, Sutherlandia frutescens, Mucuna pruriens, Butea frondosa, St John's Wort, Arecholine, Royl Jelly, Caffeine, Curcumin and so on. The mechanism of action is different for different drugs. These drugs are used primarily to treat people with cognitive difficulties as in Alzheimer's disease, Parkinson's disease and Attention-deficit hyperactivity disorder (ADHD).
... Levetiracetam is an (S)-enantiomer of the ethyl analog of piracetam, in the class of nootropic drugs which are considered to be "pharmacologically safe" (2,3). It is structurally unrelated to any other antiepileptic class and has a novel mechanism of action. ...
Status epilepticus and acute repetitive seizures still pose a management challenge despite the recent advances in the field of epilepsy. Parenteral formulations of old anticonvulsants are still a cornerstone in acute seizure management and are approved by the FDA. Intravenous levetiracetam (IV LEV), a second generation anticonvulsant, is approved by the FDA as an adjunctive treatment in patients 16 years or older when oral administration is not available. Data have shown that it has a unique mechanism of action, linear pharmacokinetics and no known drug interactions with other anticonvulsants. In this paper, we will review the current literature about the pharmacology and pharmacokinetics of IV LEV and the safety profile of this new anticonvulsant in acute seizure management of both adults and children.
... Cognition enhancers (Malik et al., 2007) improve the declining cognitive functions but do not change the rate of progression of neurodegeneration (Hirai, 2000;Parnetti et al., 1997). The most comprehensive and integrated approach towards the discovery of memory and cognition facilitating drugs has been based on the functions of central cholinergic system (Marta et al., 1988). ...
The present research was designed to describe the synthesis of a series of some 1-naphthol derivatives with their antiamnesic activity using mice as the animal model and piracetam as the reference drug. All the synthesized compounds were characterized by spectroscopic techniques, elemental analysis and were screened for their efficacy as cognition enhancers by elevated plus maze test and acetylcholinestrase inhibitory assay. Compound 7a was found to be the most potent in reversing the amnesia and in inhibiting the acetylcholinesterase.
... Cognition enhancers (Malik et al., 2007) improve the declining cognitive functions but do not change the rate of progression of neurodegeneration (Hirai, 2000;Parnetti et al., 1997). The most comprehensive and integrated approach towards the discovery of memory and cognition facilitating drugs has been based on the functions of central cholinergic system (Marta et al., 1988). ...
The present paper describes the design and synthesis of a series of some 2-naphthyloxy derivatives with their antiamnesic activity using mice as the animal model and piracetam as the reference drug. All the synthesized compounds were characterized by spectroscopic techniques and were screened for their efficacy as cognition enhancers by elevated plus maze test and acetylcholinestrase inhibitory assay. Molecular modeling and docking studies of the selected compounds into the crystal structure of acetylcholinestrase complexed with functional ligand succinylcholine using GRAMM software was performed in order to predict the affinity and orientation of the synthesized derivatives at the active site. The binding energy of ligands was calculated using ArgusLab software. The docking score and hydrogen bonds formed with surrounding amino acids show the good agreement with predicted binding affinities obtained by molecular docking studies, as verified by acetylcholinestrase activity.
The use of natural substance-based supplements and treatments for mental wellness is increasingly gaining attention. Southeast Asia, with its rich heritage of medicinal practices and cultural reliance on natural remedies, presents a unique opportunity to explore such interventions. Delightex is actively collaborating with research partners in Southeast Asia to investigate natural substances that may enhance mental well-being and create enriching experiences. Memory, defined as the capacity to record, retain and recall sensory stimuli, events and information, is a fundamental aspect of mental health. Memory loss and Alzheimer’s Disease (AD) are significant and growing concerns worldwide, particularly due to aging populations. Nootropics are generally well tolerated and typically mild. However, occasional complications can still occur. Hence, it is important to explore more natural alternatives for memory enhancement or treatment of memory loss. In this review, following an initial comprehensive literature search on mental well-being, we focused on memory improvement, identified and summarized 57 natural substances from 31 families with potential memory-enhancing effects. This review highlights their traditional use in Southeast Asia and examines the scientific evidence supporting their efficacy in enhancing memory and potential as nootropics alternatives.
Nootropics are compounds that enhance cognitive performance and have been highlighted as a medium-term human augmentation technology that could support soldier performance. Given the differing ethical, safety and legal considerations associated with the pharmaceutical subset of nootropics, this analysis focuses on dietary supplementation which may enhance cognition during training and operations. Numerous supplements have been investigated as possible nootropics; however, research is often not context specific or of high quality, leading to questions regarding efficacy. There are many other complex cofactors that may affect the efficacy of any dietary nootropic supplement which is designed to improve cognition, such as external stressors (eg, sleep deprivation, high physical workloads), task specifics (eg, cognitive processes required) and other psychological constructs (eg, placebo/nocebo effect). Moreover, military population considerations, such as prior nutritional knowledge and current supplement consumption (eg, caffeine), along with other issues such as supplement contamination, should be evaluated when considering dietary nootropic use within military populations. However, given the increasing requirement for cognitive capabilities by military personnel to complete role-related tasks, dietary nootropics could be highly beneficial in specific contexts. While current evidence is broadly weak, nutritional nootropic supplements may be of most use to the military end user during periods of high military specific stress. Currently, caffeine and L-tyrosine are the leading nootropic supplement candidates within the military context. Future military-specific research on nootropics should be of high quality and use externally valid methodologies to maximise the translation of research to practice.
Nootropics are substances that enhance cognition through various mechanisms. Nootropics include various substances, ranging from derivatives of neurotransmitters to naturally occurring plants. They are used therapeutically for certain psychological disorders including Alzheimer’s dementia and mild cognitive impairment. More recently, healthy individuals have been shown to consume nootropics to enhance mental processes above baseline levels. Nootropic modes of action vary, but the most supported mechanisms include increased acetylcholine levels in synapses, increased levels of monoamine oxidases, long-term potentiation through neural modulation of glutamate receptors, and decreased adenosine levels. However, numerous side effects can occur when taking nootropics, including insomnia, dependence, nausea, and anxiety. Nootropics also need to be considered when physicians prescribe them, as some individuals who request these drugs are perfectly healthy. In addition, the effects of nootropics are often misportrayed in popular media, leading individuals to think that these substances will give them a drastic increase in their cognitive ability.
More than 65% of the elderly population globally suffers from dementia. The term “smart drug” refers to any drug substance that positively impacts mental skills. Nootropics are agents that are used for boosting the performance of the brain and to increase one's concentration. These are also called cognitive enhancers as these can enhance memory, creativity, awareness, and attention. Natural sources, as well as synthetic approaches, both, are being employed by researchers worldwide for developing smart drugs. Smart drugs are intended to enhance academic, social, as well as career performance. These drugs work by boosting the oxygen supply and nutrition to the brain and are useful for treating various neurodegenerative disorders. Several mechanistic pharmacological approaches have been explored for the development of smart drugs and enhancement of brain activity, the most prominent ones being glutamatergic, dopaminergic, serotonergic, and cholinergic pathways. This chapter reviews the various approaches for developing synthetic smart drugs and their applications and limitations.
Café e chá são as bebidas mais consumidas no mundo depois da água, variando o padrão de consumo diante a cultura de cada país. Estudos demostram o uso da cafeína em pacientes adultos com depressão relacionada a sua genética e ao uso de fármacos. Esta revisão teve como objetivo avaliar o uso da cafeína na terapia nutricional de pacientes com depressão, caracterizar a influência e suas respostas metabólicas além de abordar estratégias nutricionais para melhora do quadro clínico na depressão. Tendo em vista que o número de casos da depressão cresce a cada dia, torna-se um problema na saúde pública relevante para a nutrição. Estudos abordam que a ingestão de alguns alimentos pode contribuir com a diminuição dos sintomas da depressão e proteção da função neuronal, além disso, fatores ambientais podem interferir trazendo prejuízos a saúde. Esta revisão abordou uma bibliografia que incluam artigos científicos e teses relacionados a depressão, cafeína, doenças neurológicas, citocromo p450 e metabolização fármaco-nutriente. Eles foram selecionados de acordo com critérios de inclusão e exclusão, utilizados bancos de dados com relevância científica, Pubmed, Scielo, publicados nos idiomas inglês, português e espanhol, por meio dos descritores em Ciência a Saúde (DeCS): antidepressivo, café, depressão, nootrópicos e terapia nutricional. Com essa revisão, foi verificado quais os benefícios e malefícios do consumo de alimentos que apresentam teores de cafeína, juntamente com a terapia medicamentosa de pacientes com depressão e sua influência na melhora cognitiva e neuroproteção, na prevenção de doenças neurodegenerativas e no bem-estar destes indivíduos.
Nootropics, also known as “smart drugs” are a diverse group of medicinal substances whose action improves human thinking, learning, and memory, especially in cases where these functions are impaired. This review provides an up-to-date overview of the potential effectiveness and importance of nootropics. Based on their nature and their effects, this heterogeneous group of drugs has been divided into four subgroups: classical nootropic compounds, substances increasing brain metabolism, cholinergic, and plants and their extracts with nootropic effects. Each subgroup of nootropics contains several main representatives, and for each one, its uses, indications, experimental treatments, dosage, and possible side effects and contraindications are discussed. For the nootropic plant extracts, there is also a brief description of each plant representative, its occurrence, history, and chemical composition of the medicinal part. Lastly, specific recommendations regarding the use of nootropics by both ill and healthy individuals are summarized.
Background
: Adaptogens are generally referred to the substances, mostly found in plants, which non-specifically increase resilience and chances of survival by activation of signaling pathways in affected cells.
Purpose
: This literature review was conducted to summarize the investigation, until March 2021, on selected adaptogenic plants and plant-derived substances.
Study Design
: Electronic databases were searched (up to March 2021) for in vitro and animal studies, as well as clinical trials. Moreover, all modes of action connected with the adaptogenic effects of plants and phytochemicals were collected.
Methods
: The search of relevant studies was performed within electronic databases including Scopus, Science Direct, PubMed, and Cochrane library. The most important keywords were adaptogen, plant, phytochemical, and plant-derived.
Results
: The most investigated medicinal herbs for their adaptogenic activity are Eleutherococcus senticosus, Panax ginseng, Withania somnifera, Schisandra chinensis, and Rhodiola spp., salidroside, ginsenosides, andrographolide, methyl jasmonate, cucurbitacin R, dichotosin, and dichotosininare are phytochemicals that have shown a considerable adaptogenic activity. Phytochemicals that have been demonstrated adaptogenic properties mainly belong to flavonoids, terpenoids, and phenylpropanoid glycosides.
Conclusion
: It is concluded that the main modes of action of the selected adaptogenic plants are stress modulatory, antioxidant, anti-fatigue, and physical endurance enhancement. Other properties were nootropic, immunomodulatory, cardiovascular, and radioprotective activities.
Multiple studies have been conducted, many within the last 3-5 years, to develop a deeper understanding into how certain chemical substances enhance and improve certain aspects of our performance, both mental and physical. The successful synthesis, isolation and purification of such human performance enhancing substances have led to breakthroughs not only in the treatment of debilitating diseases such as Alzheimer’s and Parkinson’s disease, but also have a significant impact on endurance training. While the chief use of such performance enhancing agents is in the treatment of diseases like anaemia, depression, attention deficit and neurodegenerative disorders, such substances are also misused and sometimes abused in sport. This review highlights 6 major substances used as performance enhancers, namely, creatine, racetams, melatonin, caffeine, cholinergics and EPO. The six substances enhance different features of human performance. The chemistry of these substances, their chemical biology, methods of synthesis and latest data obtained from various clinical trials are discussed.
Nootropics also called as smart drug, memory enhancers, neuron enhancers, cognitive enhancers and intelligent enhancers are drugs, supplements, neutraceuticals and functional foods that provide one or more aspects of mental function. Specific effect can include improvement to working memory motivation or attention. Nootropics drugs are able to promote, enhance and protect cognitive functions. As cognition is the typically human higher activity of brain, nootropic concept looked quite appealing for scores of people dreaming to enjoy better and longer lasting mental activity and for drug maker keen to produce such enviable products. There are large number of drugs which can be used as nootropic agents and help to enhance memory of people. Nootropics offer lot of benefits for cognitive aptitude and brain health. Nootropics used for the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease, dementia and cognitive symptoms of schizophrenia.
Alzheimer’s disease (AD), a progressive neurodegenerative disorder is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine via inhibiting acetylcholinesterase (AChE). The present study involves identification of newer AChE inhibitors by dual approach of e-pharmacophore and structure based virtual screening of Asinex library. Robustness of docking protocol was validated by enrichment calculation with ROC value 0.71 and BEDROC value 0.028. Among eleven selected hits, ZINC72338524 with best MM-GBSA dG binding shows optimal range of CNS properties and ligand-AChE complex stability. Further, molecular dynamics study revealed its molecular interactions with Trp86, Phe338 and Tyr341 amino acid residues of catalytic anionic site and Tyr124, Ser125 and Trp286 amino acid residues of peripheral anionic site. Physicochemical properties and ADMET risk prediction indicates their potential in druggability and safety.
Now a day's use of herbal products has been increasing greatly in developing countries. There are various natural products which are used as therapeutic in the treatment for diverse purposes such as loss of memory. Memory is necessary aspect for the human beings. It stores the information temporary or permanently which helps in learning and modify it according to our own need. Loss of memory occurs due to aging or alzheimer's disease. So, there are number of herbal drugs which have cognitive enhancing property due to its chemical constituents. The drugs which are used to enhance memory are called as nootropic drugs. This review article shows memory enhancing property of commonly used plants. The plants which are used for treatment of loss of memory are known as nootropic plants and their constituents are known as smart drugs. These drugs enhance the memory, increase blood circulation and increase acetylcholine level in brain.
The present research was designed to describe the synthesis of a series of some 1-naphthol derivatives with their antiamnesic
activity using mice as the animal model and piracetam as the reference drug. All the synthesized compounds were characterized
by spectroscopic techniques, elemental analysis and were screened for their efficacy as cognition enhancers by elevated plus
maze test and acetylcholinestrase inhibitory assay. Compound 7a was found to be the most potent in reversing the amnesia and in inhibiting the acetylcholinesterase.
Cognitive enhancers are drugs, supplements, nutraceuticals and functional foods that are purported to improve mental functions such as cognition, memory, intelligence, motivation, attention and concentration. Drugs considered cognitive enhancers include dietary products and supplements, racetams, stimulants, dopaminergics, cholinergics, GABA blockers, glutamate activators, serotonergics and hormones, etc. Not all of them are healthy or safe to use but they can still have mental benefits. The safest types of cognitive enhancers are made up of natural ingredients and are available in supplement form, which mostly contain vitamins, fatty acids, antioxidants, amino acids, minerals, etc and herbal ingredients. Vitamins make neurotransmitters and maintain the nervous system by helping to metabolize fatty acids. Omega-3 influences both communication between cells and cell function. Antioxidants help to retain the mental abilities longer, keep the brain younger and protect it from oxidative damage. Amino acids help to produce the catecholamines and create alertness. Hormones increase neurogenesis and improve both memory encoding and recall. Iron helps create hemoglobin, which transports oxygen to the brain. Creatinine protects ATP during transport. Lipoic acid improves oxygen usage and antioxidant recycling, improving memory and Germanium increases oxygen supply to the brain. Herbs and herbal products which have been found useful in improving cognitive ability include Ginkgo biloba, Rhodiola rosea, Siberian ginseng, Brahmi rasayana, Bacopa monniera, Lycoris radiata, Sutherlandia frutescens, Mucuna pruriens, Butea frondosa, St John’s Wort, Arecholine, Grape seed extract, Caffeine, Curcumin and many more. Most of them act through receptors while some of them alter the availability of neurotransmitters in the brain. In general, cognitive enhancers are used primarily to treat people with cognitive difficulties such as Alzheimer’s disease, Parkinson’s disease and Attention-deficit hyperactivity disorder.
Piracetam, the prototype of the so-called nootropic drugs’ is used since many years in different countries to treat cognitive impairment in aging and dementia. Findings that piracetam enhances fluidity of brain mitochondrial membranes led to the hypothesis that piracetam might improve mitochondrial function, e.g., might enhance ATP synthesis. This assumption has recently been supported by a number of observations showing enhanced mitochondrial membrane potential, enhanced ATP production, and reduced sensitivity for apoptosis in a variety of cell and animal models for aging and Alzheimer disease. As a specific consequence, substantial evidence for elevated neuronal plasticity as a specific effect of piracetam has emerged. Taken together, this new findings can explain many of the therapeutic effects of piracetam on cognition in aging and dementia as well as different situations of brain dysfunctions.
The advent of adult neurogenesis and neural stem cell (NSC) research opens new avenues and opportunities for treating neurological diseases and disorders, particularly for the discovery and development of novel drugs. Adult neurogenesis is modulated by a broad range of stimuli, physio- and pathological processes, trophic factors/cytokines and drugs, particularly drugs used for treating neurological diseases and disorders. Hence, adult neurogenesis is the target of drugs used for treating neurological diseases and disorders, such as Alzheimer's disease and depression, and the activities of neurological drugs may be mediated by adult NSCs. Although the contribution and mechanism of adult neurogenesis and newly generated neuronal cells of the adult brain in the activities of neurological drugs remain to be determined, new research is geared toward discovering and developing novel drugs that target specifically adult neurogenesis and the NSCs of the adult brain. Neurogenic drugs may reverse or compensate deficits and impairments associated with neurological diseases and disorders, particularly those associated with the hippocampus. They may have a potential for regenerative medicine and for the treatment of brain tumors. However, limitations in established models and protocols currently used in the drug discovery and development process of these drugs may hinder their potency and specificity. Here, we reviewed and discussed recent patents on neurogenic drugs and compounds, particularly nootropic agents and apigenin and related compounds.
Brain-machine interfaces (BMIs) are mostly investigated as a means to provide paralyzed people with new communication channels with the external world. However, the communication between brain and artificial devices also offers a unique opportunity to study the dynamical properties of neural systems. This review focuses on bidirectional interfaces, which operate in two ways by translating neural signals into input commands for the device and the output of the device into neural stimuli. We discuss how bidirectional BMIs help investigating neural information processing and how neural dynamics may participate in the control of external devices. In this respect, a bidirectional BMI can be regarded as a fancy combination of neural recording and stimulation apparatus, connected via an artificial body. The artificial body can be designed in virtually infinite ways in order to observe different aspects of neural dynamics and to approximate desired control policies.
Unlabelled:
The Food and Drug Administration (FDA), Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute for Drug Abuse (NIDA) report that no sound scientific studies support the medicinal use of cannabis. Despite this lack of scientific validation, many patients routinely use "medical marijuana," and in many cases this use is for pain related to nerve injury. We conducted a double-blinded, placebo-controlled, crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain. Thirty-eight patients with central and peripheral neuropathic pain underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis. In addition to the primary outcome of pain intensity, secondary outcome measures included evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance. A mixed linear model demonstrated an analgesic response to smoking cannabis. No effect on evoked pain was seen. Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly with memory, at higher doses.
Perspective:
This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain, and may be an alternative for patients who do not respond to, or cannot tolerate, other drugs. However, the use of marijuana as medicine may be limited by its method of administration (smoking) and modest acute cognitive effects, particularly at higher doses.
The present research was designed to synthesize some 2-naphthyloxy derivatives of N,N-substituted acetamides employing the secondary amino moiety and insertion of-OCH2-group between the aromatic ring and the side chain.2-Naphthol was condensed with methylchloroacetate followed by fusion with different amines to give target compounds 3a-3f. The compounds synthesized after pharmacological investigations have been found to possess significant antiamnesic activity when compared with piracetam. Compounds 3b, 3d, 3f showed dose dependent antiamnesic effect with 3b being most potent. Further, neuropsychopharmacological studies (hypnotic, anti-convulsant, antianxiety, locomotor, muscle relaxant, antidepressant and antiamnesic activities) on 3b confirmed its memory enhancing potential which was comparable to piracetam, a known nootropic agent.
As the mean age of the general population increases, so does the need for reliable drugs for improving cognitive-memory disturbances in the elderly. Nootropic agents have been shown to improve memory and learning processes in animals and to be useful in patients with several types of senile or traumatic dementia. Pramiracetam, one of the newest nootropics to be launched, has exhibited good efficacy in both animal models of memory or learning impairment and patients with senile and presenile cognitive impairment, including dementia of the Alzheimer type. The exact mechanism of action of this drug has not been fully established, but clinical data on good efficacy, favorable pharmacokinetic properties and advantageous safety even on prolonged treatment make it a reasonable choice for treating attention and memory alterations in elderly patients with degenerative or vascular brain diseases.
Fipexide, a cognition activator, has been studied from the toxicopharmacological standpoint. Acute, subacute and chronic toxicity studies showed effects at only 37-300 times the human dose in acute studies and at 13-20 times this dose in chronic studies. There were no relevant pathological changes. Embryotoxic or teratogenic effects were absent up to 200-500 mg/kg. CNS pharmacology indicated actions compatible with dopaminergic mechanisms, without amphetamine-like activity. Unwanted actions on organs and systems were not observed; only intestinal transit might be moderately inhibited by fipexide. Human pharmacokinetics indicated rapid intestinal absorption, a terminal t(1/2) of 6.5 h and 16% urinary excretion within 12 h. Oral fipexide appears suitable for the management of those disorders which require activation of cognitive brain mechanisms.
Memory dysfunctions have been reviewed from preclinical and clinical perspectives. No effective therapy exists for primary degenerative dementia (PDD, Alzheimer's disease), mild (or minimal) memory impairment (benign senescent forgetfulness), or for multi-infarct dementia (MID). PDD remains the focus of most clinical research on cognitive disorders, but the pseudo-dementias, korsakoff's syndrome, geriatric depression, and attentional deficit disorder are beginning to receive appropriate attention. Possible causes of PDD include genetic predisposition, altered proteins, infectious agents, toxins, blood-flow disorders, neurotransmitter abnormalities, and multiple factors. This chapter discusses the various hypothesis related to explanations for memory deficit in PDD, the cholinergic system—muscarinic agonists, cholinesterase inhibitors, cholinergic releasing agents, cholinergic precursors, drugs minaprine, scopolamine, muscarinic receptors, analogues of arecoline, biogenic amines, neuropeptides, nootropics, and other agents. The varying effects of drugs on the different cognitive disorders have been considered. There is respective study on the structure activity relationships proposed for piracetam analogues that affect spontaneous locomotor activity, ECS-induced retrograde amnesia, and survival under hypoxic conditions.
BR-16A, a herbal preparation, attenuates amnestic deficits induced by electroconvulsive shocks (ECS) in rats. In a study designed to test the cognition-protecting limits of BR-16A, adult, male, Wistar rats (n = 28), preselected for slow learning on the Hebb Williams complex maze, received 6 once-daily ECS. Before (1 week), during (6 days) and after (1 week) the ECS course, the rats received (p.o) either BR-16A (200 mg/kg/day) or vehicle alone. Post-ECS, learning was assessed over 7 days on the complex maze. Rats receiving BR-16A performed significantly better than controls in both speed and magnitude of learning. The present experiment hence found no floor effect for BR-16A-mediated attenuation of ECS-induced anterograde amnesia.
The cholinergic hypothesis has provided the first rational approach in the treatment of Alzheimer's disease. Among the various therapeutic approaches investigated to enhance cholinergic transmission, acetylcholinesterase (AChE) inhibition is presently the most successful method to ameliorate cholinergic deficit and lead to symptomatic improvement. Tacrine (Cognex®), an AChE inhibitor, was the first drug approved by the FDA for the clinical treatment of senile dementia of the Alzheimer type. A second, E-2020 (donepezil hydrochloride, Aricept®), was just recently approved, while SDZ-ENA-713 (Exelon®) is pending approval. At present there is a large amount of information concerning the crystallographic structure of the AChE inhibitor complex and computer aided molecular modelling methods are intensively used to study the inhibitory mechanism of these compounds. The methods used to evaluate the pharmacological and clinical efficacy are reviewed, as well as the clinical results for tacrine hydrochloride, eptastigmine tartrate, donepezil hydrochloride and SDZ-ENA-713.
The conformational properties of the nootropic agent Tenilsetam (3-(2-thienyl)-2-piperazinone) have been assessed in the solid, liquid and isolated state by X-ray diffraction, NMR spectroscopy (H-1, C-13) and quantum chemical calculations (MO semiquantitative PM-3 method), respectively. The thienyl and 2-piperazinone rings are nearly perpendicular in the crystal. The 6-membered ring adopts a very distorted chair conformation with the thienyl at C(6) in equatorial position. Bond angles and distances agree with their standard values. The high-field H-1 and C-13 NMR spectra were run in CDCl3 solution. The results of the spectral analysis indicate that the 2-piperazinone ring in solution undergoes fast interconversion between the half-chair and the twist-boat forms. Theoretical calculations produced 2 almost equi-energetic conformational minima, both corresponding to the 2 relative possible perpendicular arrangements of the rings. The relative minimum is in fairly good agreement with the conformation in the crystal.
Changes in intracellular free calcium concentration ([Ca2+]i ) play a crucial role in cellular physiology. A number of cell surface receptors and channels are known to regulate [Ca2+]i through different molecular mechanisms. Therefore, the functional and pharmacologic properties of many of these cell surface receptors and ion channels can be studied effectively by measuring changes in [Ca2+]i in intact cells. For drug discovery efforts, several ion channel and receptor systems have been targeted that play different roles in neuronal physiology and pathophysiology. These molecular targets include voltage- and ligand-gated ion channels: the human neuronal voltage-gated calcium channels (VGCCs), ligand-gated nicotinic acetylcholine receptor channels (NAChRs), ionotropic N-methyl-D-aspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- and kainate-type excitatory amino acid receptor (EAA) channels. All of these channels mediate elevation of [Ca2+]i via Ca2+ influx from the extracellular medium upon depolarization or activation by agonist. This chapter describes the experimental methods with particular emphasis on the validation of the assay for human VGCCs, NAChRs, and NMDA receptors.
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.
George Heise surveys the experimental research with animals on three groups of compounds — cholinergics, nootropics, and neuromodulators — that facilitate memory and cognition in animals, with emphasis on the adequacy and logic of ‘animal models’ of normal or deficient human performance that underlie the research. Although there are compounds that dramatically improve performance in animals, the beneficial effects of these compounds on human memory or cognitive performance, while sometimes statistically significant, have been small and of questionable clinical relevance. No clearly effective ‘reference’ compound has as yet been discovered. He makes suggestions for redirecting the animal research towards more effective models.
HEK293 cells were stably transfected with the cDNAs encoding full-length human neuronal nicotinic acetylcholine receptor (nAChR) subunit combinations α3β2 or α4β2. [3H]-(±)Epibatidine ([3H]-(±)EPI) bound to membranes from A3B2 (α3β2) and A4B2.2 (α4β2) cells with Kd values of 7.5 and 33.4 pM and Bmax values of 497 and 1564 fmol/mg protein, respectively.Concentration-dependent increases in intracellular free Ca2+ concentration were elicited by nAChR agonists with a rank order of potency of EPI>1,1-dimethyl-4-phenylpiperazinium (DMPP)>nicotine (NIC)=suberyldicholine (SUB)>cytisine (CYT)=acetylcholine (ACh) for A3B2 cells and EPI>CYT=SUB=NIC=DMPP>ACh for A4B2.2 cells. Antagonists of nAChRs blocked NIC-induced responses with a rank order of potency of d-tubocurarine (d-Tubo)=mecamylamine (MEC)>dihydro-β-erythroidine (DHβE) in A3B2 cells and MEC=DHβE>d-Tubo in A4B2.2 cells.Whole-cell patch clamp recordings indicate that the decay rate of macroscopic ACh-induced currents is faster in A3B2 than in A4B2.2 cells and that A3B2 cells are less sensitive to ACh than A4B2.2 cells. ACh currents elicited in α3β2 and α4β2 human nAChRs are maximally potentiated at 20 and 2 mM external Ca2+, respectively.Our results indicate that stably expressed α3β2 and α4β2 human nAChRs are pharmacologically and functionally distinct.
The present study was initiated to examine the effect of pramiracetam sulfate [N-[2-[bis(1-methylethyl)amino]ethyl]-2 oxo-1-pyrrolidineacetamide sulfate (1:1)] (PR), a new cognition-activator agent, on various neurochemical parameters in order to gain some insight into the mechanism of action of this agent. PR (100 mg/kg i.p.) did not alter the concentration of norepinephrine, dopamine (DA), serotonin (5-HT), 5-hydroxyindoleacetic, and homovanillic acid in various brain areas. The agent also did not alter d-methamphetamine-induced changes in monoamine metabolism nor prolactin concentration in rat serum. PR did not exhibit any affinity in vitro for dopaminergic, adrenergic, serotoninergic, GABAergic, muscarinic, adenosine (IC50 > 10 μM), and benzodiazepine receptors (IC50 > 1 μM) binding sites. It may be concluded that the mechanism of action of pramiracetam does not appear to be due to a direct action upon DA and 5-HT neurotransmitter systems or various brain receptors. PR (44 and 88 mg/kg i.p.) caused a significant increase in the rate of sodium-dependent high-affinity choline uptake (HACU) into rat hippocampal synptosomes in vitro. This was specific as no effect was observed in cerebral cortex and corpus striatum. These results would seem to indicate that PR is accelerating hippocampal acetylcholine turnover and thus septal-hippocampal cholinergic neuronal impulse flow. This effect could be at least partially responsible for the enhancement of cognition processes observed for this agent.
The term “nootropic” refers to compounds that act on cognitive functions. These drugs should facilitate learning and memory and prevent impairment of cognitive functions induced by diseases and brain insults. In animal models of impaired cognitive functions, the effects of several nootropic substances were investigated. Learning and retention in passive avoidance, and positive reinforcement paradigms were disrupted by hypoxia, cerebral ischemia and amnesia-inducing agents. Piracetam and several other novel nootropic compounds were shown to improve performance in these animal models. These results indicate that experimentally induced cognitive dysfunction in animals can be attenuated with drug treatment.
Upon reductive cyclization cyano esters 2, 3, and 9 yielded piperidones and perhydropyrrolo[3,4-c]pyridine lactams, generally as a mixture of diasteromeric cis-trans forms. X-ray crystallographic analyses were carried out on bicyclic dilactam derivatives 6 and 10, and a cis configuration at the ring junction was determined in both cases. A series of neuropsychopharmacological tests performed on the title compounds indicated that they are generally nontoxic even at high doses (up to 1000 mg/kg ip). The cognition activating properties of lactams 4, 5, 6, and 10 were evaluated in enhancing retention for passive avoidance learning in rats without and after electroconvulsive shock (ECS); compounds 5 and 10 were found to be more potent than piracetam in the amnesia-reversal testing.
Due to the complex mechanism of cation transport by neuronal nicotinic acetylcholine receptors (nAChR), potential ligands of these receptors must be characterized with respect to functional activity and corresponding subtype selectivity. Conventional radioactive binding assays have been established in high throughput screening (HTS) formats for rapid assessment of ligand subtype selectivity; however, the current radiometric methods of functionally profiling these ligands are not suitable for HTS formats. In this article, a high throughput, cell-based assay is described which exploits the Ca2+ transport activity of nAChRs as a method of functional assessment. By coupling the use of Fluo-3, a Ca2+-chelating fluorescent dye, with a fluorescence imaging plate reader (FLIPR), the movement of Ca2+ by nAChRs can be observed. Fluorescence changes can be measured simultaneously over an entire 96-well plate, allowing six to eight concentrations of six ligands to be examined in duplicate on each plate within minutes. In the data presented, 36 nAChR ligands were functionally profiled in IMR-32 cells, a model of ganglionic nAChR subtypes. The calculated potency values (pEC50 values) from this fluorescence assay compare well with those determined by 86Rb+-efflux and demonstrate a correlation coefficient of 0.91 between the two methods. Thus, the functional profile of novel nAChR ligands can rapidly be assessed by monitoring the flux of calcium upon activation of these ligand gated ion channels (LGICs). Moreover, this HTS assay can be easily adapted for any cell line expressing receptors involved directly or indirectly with the influx of calcium into the cytosol, including similar LGICs and G-protein coupled receptors. Drug Dev. Res. 44:14–20, 1998. © 1998 Wiley-Liss, Inc.
Nerve growth factor plays an important role in the survival and maintenance of cholinergic neurons in the central neuronal system. In senile dementia of the Alzheimer type, learning and memory are impaired by the loss of neurons in the magnocellular cholinergic neuronal system. It is, therefore, of interest to investigate the role of nerve growth factor in senile dementia of the Alzheimer type. We now found that 6-(4-hydroxybutyl)-2,3,5-trimethyl-1,4-benzoquinone (TMQ) stimulates nerve growth factor synthesis in mouse astroglial cells and that the compound has improving effects on memory and choline acetyltransferase activity in basal forebrain-lesioned rats, an amnesia animal model. TMQ ameliorated amnesia in the water maze and passive avoidance tasks. The compound not only restored the reduced choline acetyltransferase activity in the parietal cerebral cortex, but also increased nerve growth factor content and choline acetyltransferase activity in the hippocampus, although it did not change either of these parameters in any brain region in intact rats. These results suggest that the compound activates cholinergic neurons only in the damaged brain and, further, indicate that nerve growth factor stimulators could be used in clinical trials for the treatment of senile dementia of the Alzheimer type.
The effects of N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)-acetamide (DM-9384, nefiracetam), a cyclic derivative of GABA, were investigated in the carbon monoxide (CO)-induced amnesia model in the mice using the passive avoidance task. Memory deficiency occurred when mice were exposed to CO before memory was completely consolidated after training (acute amnesia), at 7 days before training and 7 days after training (delayed amnesia). DM-9384 prolonged the step-down latency in mice with CO-induced amnesia. Scopolamine blocked the anti-amnesic effect of DM-9384 on delayed amnesia that had been induced by pre- or post-training exposure to CO. Bicuculline had a tendency to antagonize the anti-amnesic effect of DM-9384, but this tendency was not significant. Under these conditions, no significant change in the activity of choline acetyltransferase and glutamic acid decarboxylase was observed in the frontal cortex, striatum and hippocampus. These results suggest that DM-9384 potentiates cholinergic neuronal function and that it may modify acquisition and/or consolidation of memory.
1. In recent years It has been established that patients with AD have a relatively specific loss of cerebral cortical and hippocampal chollnergic nerve terminals. This may be a reflection of degeneration of cholinergic neurons originating In the nucleus basalls of Meynert and septum Which project to the cortex and hippocampus, respectively.2. In view of the long-standing association of chollnergic mechanisms with cognitive processes and the recognition of selective chollnergic deficits in AD, therapeutic attempts to enhance CNS chollnergic function have been undertaken In patients with AD.3. While only limited success with this strategy has been achieved to date, the use of TRH may offer a novel, yet rational, approach to treating AD. This assumption is predicated on the extensive literature documenting unique, facilltatory interactions of this peptide with chollnergic neurons throughout the neuraxis.4. Furthermore, the same rationale may account for the recently reported therapeutic benefit of TRH in patients with amyotrophic lateral sclerosis, which like AD, is a disease whose symptoms are manifested through a progressive degeneration of a subpopulation of CNS cholinergic neurons.
Methyllycaconitine (MLA), a norditerpenoid alkaloid isolated from Delphinium seeds, is one of the most potent non-proteinacious ligands that is selective for αbungarotoxin-sensitive neuronal nicotinic acetylcholine receptors (nAChR). [3H]MLA bound to rat brain membranes with high affinity (Kd=1.86±0.31 nM) with a good ratio of specific to non-specific binding. The binding of [3H]MLA was characterised by rapid association (t=2.3 min) and dissociation (t=12.6 min) kinetics. The radioligand binding displayed nicotinic pharmacology, consistent with an interaction with αbungarotoxin-sensitive nAChR. The snake α-toxins, αbungarotoxin and αcobratoxin, displaced [3H]MLA with high affinity (Ki=1.8±0.5 and 5.5±0.9 nM, respectively), whereas nicotine was less potent (Ki=6.1±1.1 μM). The distribution of [3H]MLA binding sites in crudely dissected rat brain regions was identical to that of [125I]αbungarotoxin binding sites, with a high binding site density in hippocampus and hypothalamus, but low density in striatum and cerebellum. [3H]MLA also labelled a sub-population of binding sites which are not sensitive to the snake αtoxins, but which did not differ significantly from the major population with respect to their other pharmacological properties or regional distribution. [3H]MLA, therefore, is a novel radiolabel for characterising α7-type nAChR. A good signal to noise ratio and rapid binding kinetics provide advantages over the use of radiolabelled αbungarotoxin for rapid and accurate equilibrium binding assays.
The present study examined the relative importance of α- and β-adrenoceptors in the memory modulatory effects of epinephrine. Posttraining epinephrine administration enhancef retention performance of a one-trial inhibitory avoidance respone. Further pretraning injections of a variety of adrenoceptor antagonists, including selective α1-,α2, β1- and /or β2-adrenoceptor antagonists, attenuated the retention enhancing effects of posttraining epinephrine. These results suggest that α- and β-adrenoceptors of both subtypes are involved in the memory-modulating effects of epinephrine.
Long-term potentiation (LTP) has for a long time captured the imagination of neuroscientists as a model with which to probe the cellular mechanisms of learning and memory in the mammalian brain. In this article we describe the recent evidence that has revealed the pivotal role of NMDA receptors in the induction of LTP, and discuss the possible mechanisms involved in the maintenance of the potentiated state.
1.1. Nootropic drugs were proposed as a class of psychoactive drugs that selectively improve efficiency of higher telencephalic integrative activities.2.2. The main features of the nootropic profile consist of: (a) enhancement of learning acquisition; (b) resistance to impairing agents; (c) facilitation of interhemispheric transfer of information; (d) enhanced resistance to brain “aggressions”; (e) increased tonic, cortico-subcortical “control”; and (f) absence of usual pharmacological effects of neuro psychotropic drugs.3.3. The animal experimental results are thoroughly corroborated by the data obtained in clinical pharmacology and pharmacotherapeutics supporting the concept that nootropic activity is based on a functional telencephalic selectivity.4.4. The basic mechanism of action at molecular and cellular levels of nootropic drugs is not yet known. Some recent data emphasized a possible role for cerebral ATP.
C1300 mouse neuroblastoma cells gradually accumulate lipofuscin-like pigment when they are maintained in culture. Pigment was demonstrated by positive straining for acid phosphatase and with periodic acid-Schiff stain. Pigment was formation in cells was reduced by exposure of the cells to lower doses of dihydroergotoxine mesylate which also induced neurite formation and increased protein synthesis. Since lipofuscin appears to originate as a result of wear and tear within the cells, the drug probably exerts its beneficial effects by reducing the rate of intracellular wear and tear associated with aging.
Brain monoamine concentrations were determined post mortem in 19 patients with dementia of Alzheimer type. Samples were taken from 10 parts of the brain and compared with an age-matched control group.
There were lower mean concentrations of dopamine in the demented group of patients in seven regions of the brain, and two of these were at a significant level. There were also significantly lower concentrations of homovanillic acid in the nucleus caudatus and in the putamen. The means of the concentrations of noradrenaline were also lower, and in the putamen and the cortex gyrus frontalis significant differences were observed. The 5-hydroxytryptamine concentrations were slightly lower in the demented group but the differences did not reach significance. The degree of intellectual deterioration was negatively correlated with the noradrenaline concentrations in the hypothalamus and the cortex gyrus cinguli.
Nootropyl (Piracetam) a drug reported to facilitate learning in animals was tested for its effect on man by administering it to normal volunteers. The subjects were given 3x4 capsules at 400 mg per day, in a double blind study. Each subject learned series of words presented as stimuli upon a memory drum. No effects were observed after 7 days but after 14 days verbal learning had significantly increased.
Using voltage- and current-clamp methods the effects of nebracetam 4-aminomethyl-1-benzylpyrrolidine-2-one hemifumarate, WEB 1881 FU, CAS 118607-07-1), a new agent with nootropic property, on the nicotinic (nAChRs) and muscarinic acetylcholine receptors (mAChRs) were studied, which were expressed in Xenopus oocytes by injecting E. electricus mRNA and rat brain mRNA, respectively. Simultaneous application of nebracetam (0.03-2 mmol/l) with acetylcholine (ACh) (0.01-1 mmol/l) inhibited the ACh-responses of both nAChRs and mAChRs, whereas preapplication of these concentrations of nebracetam for 30 s to 1 min potentiated such inhibition. A simple competitive inhibition model for the effects of both drugs simultaneously applied yielded the inhibition constant, K1 of 0.419 and 0.212 mmol/l for nAChRs and mAChRs, respectively, indicating that the action on mAChRs is a little more potent than on nAChRs. Nebracetam induced a concentration-dependent slight increase in inward currents on mAChRs but not on nAChRs. It is suggested that the direct effects of nebracetam on nAChRs and mAChRS, which were induced only by a rather high concentration, as compared with the clinically expected plasma level, may be a contributing factor to the clinical effectiveness of the drug only if there is some critical change in the sensitivity to the drug.
BR-16A (Mentat 50-500 mg/kg) improved acquisition and retention of a passive avoidance task in a step-down paradigm in mice. BR-16A (50-500 mg/kg) reversed scopolamine (0.3 mg/kg)-induced disruption of acquisition and retention. BR 16-A (50 and 100 mg/kg) attenuated amnesia produced by the acute treatment with electroconvulsive shock (ECS), immediately after training. Chronic treatment with ECS, for 6 successive days at 24 h interval, disrupted memory consolidation on the 7th day. Daily administration of BR-16A (50 and 100 mg/kg) for 6 days significantly improved memory consolidation in mice receiving chronic ECS treatment. BR-16A (20-500 mg/kg), administered on the 7th day, also attenuated the disruption of memory consolidation produced by chronic treatment with ECS. On elevated plus-maze, BR-16A (50 and 100 mg/kg) reversed scopolamine (0.3 mg/kg)-induced delay in transfer latency on the 1st day. The above data suggests a nootropic effect of BR-16A in naive and amnesic mice.
We have studied the interaction of the reversible acetylcholine esterase inhibitor (-)physostigmine (D-eserine) with the nicotinic acetylcholine receptor (nAChR) from Torpedo marmorata electric tissue by means of ligand-induced ion flux into nAChR-rich membrane vesicles and of equilibrium binding. We find that (-) physostigmine induces cation flux (and also binds to the receptor) even in the presence of saturating concentrations of antagonists of acetylcholine, such as D-tubocurarine, alpha-bungarotoxin or antibody WF6. The direct action on the acetylcholine receptor is not affected by removal of the methylcarbamate function from the drug and thus is not due to carbamylation of the receptor. Antibodies FK1 and benzoquinonium antagonize channel activation (and binding) of eserine, suggesting that the eserine binding site(s) is separate from, but adjacent to, the acetylcholine binding site at the receptor. In addition to the channel activating site(s) with an affinity of binding in the 50 microM range, there exists a further class of low-affinity (Kd approximately mM) sites from which eserine acts as a direct blocker of the acetylcholine-activated channel. Our results suggest the existence of a second pathway of activation of the nAChR channel.
The angiotensin converting enzyme (ACE) inhibitors captopril and enalapril and the nootropic piracetam reduced the amnesiogenic effects of cerebral electroshock treatment in mice. These compounds also directly improved passive-avoidance learning if administered before the learning trial. When given immediately after the learning trial, captopril and piracetam were active, but not enalapril. Captopril, but neither enalapril nor piracetam, facilitated memory retrieval after a 2-month retention interval. Unlike those of piracetam, the memory-improving effects of captopril and enalapril are not established by aldosterone-receptor blockade, suggesting that the two types of drug act via different mechanisms of action.
Functional recovery from motor hypoactivity of rats with 6-OHDA lesions in the nucleus accumbens is accelerated by intra-accumbal or subcutaneous treatment with the ACTH-(4-9) analog ORG 2766. The spontaneous recovery period of 3 weeks is shortened to 7 days by daily treatment with this peptide during the first 6 days after the lesion. The 6-OHDA lesion induced a decrease of about 30-40% in the levels of dopamine, HVA and DOPAC as well as in the uptake of [3H]dopamine in nucleus accumbens tissue in vitro. Treatment with ORG 2766 during the first 6 days following the lesion did not affect the lesion-induced changes in these biochemical parameters. Binding studies with [3H]haloperidol in nucleus accumbens tissue of placebo or ORG 2766-treated sham-lesioned rats revealed a linear Scatchard plot 7 days after the sham lesion. In tissue of placebo-treated 6-OHDA lesioned animals a similar linear Scatchard plot was found but in tissue of ORG 2766-treated 6-OHDA-lesioned rats the Scatchard plot was curvilinear in shape indicating two types of binding sites. In the 6-OHDA-lesioned rats treated with ORG 2766 the behavioral response upon apomorphine challenge was enhanced suggesting the existence of functional supersensitivity of the DA system. Similar changes in Scatchard plots and apomorphine-induced behavioral changes have been previously reported after spontaneous recovery. The present study indicates that ORG 2766 accelerates the process of functional recovery from impaired motor behavior of rats with 6-OHDA lesions in the nucleus accumbens, which may be due to development of denervation supersensitivity.
In neurons, alpha-bungarotoxin is often associated with nicotinic receptor but does not always block the acetylcholine operated channel. In a human neuroblastoma cell line, IMR 32, we have demonstrated a large number of alpha-Bungarotoxin binding sites (2640 per cell in non differentiated cells and 4660 per cell in differentiated cells) in presence of 0 to 4 Acetylcholine activated-channels per cell. This neuronal cell line promises to be an useful model for the study of structure and function of the alpha-Bungarotoxin binding site not related to the nicotinic receptor.
An isotopic rubidium ion efflux assay has been developed for the functional characterization of nicotinic acetylcholine receptors on cultured neurons. This assay first involves the intracellular sequestration of isotopic potassium ion analog by the ouabain-sensitive action of a sodium-potassium ATPase. Subsequently, the release of isotopic rubidium ion through nicotinic acetylcholine receptor-coupled monovalent cation channels is activated by application of nicotinic agonists. Specificity of receptor-mediated efflux is demonstrated by its sensitivity to blockade by nicotinic, but not muscarinic, antagonists. The time course of agonist-mediated efflux, within the temporal limitations of the assay, indicates a slow inactivation of receptor function on prolonged exposure to agonist. Dose-response profiles (i) have characteristic shapes for different nicotinic agonists, (ii) are described by three operationally defined parameters, and (iii) reflect different affinities of agonists for binding sites that control receptor activation and functional inhibition. The rubidium ion efflux assay provides fewer hazards but greater sensitivity and resolution than isotopic sodium or rubidium ion influx assays for functional nicotinic receptors.
In experiments on male Wistar rats trained on active avoidance (shuttle-box) and passive avoidance (step-through) tasks, we found that (-) nipecotic acid, the inhibitor of GABA reuptake, and muscimol, a GABAA-receptor agonist, applied after training either improved or had no effect on retention, depending on the dose used. Angiotensin II (ATII) at a dose of 0.1 microgram/kg injected intracerebroventricularly (i.c.v.) after training facilitated retention. Combinations of ATII and (-) nipecotic acid or muscimol potentiated the memory effects of ATII and GABAergic drugs, respectively. Blockade of GABA receptors (GABAA) by bicuculline or picrotoxin abolished the effects of GABAergic agonists on ATII. It is suggested that GABAergic transmission participates in the consolidation and formation of memory traces and in the retention-facilitating mechanism of action of ATII.
The effects of Hoe 065 (n-octyl 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo [3.3.0]octane-3-carboxylate maleate salt) were studied on the performance of mice and rats in different learning tasks. Hoe 065 prevented the disruption of memory induced by scopolamine administered before training. The results indicate that Hoe 065 improves cognitive function in different tasks.
The effect of the anticonvulsant and neuroprotective agent (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK-801) has been studied on synaptic events in the CA1 region of rat hippocampal slices. MK-801 blocked selectively the N-methyl-D-aspartate receptor-mediated component of synaptic transmission, which can be recorded in response to single shock stimulation of the Schaffer collateral-commissural pathway in the absence of added Mg2+ to the perfusate. MK-801 also prevented the induction of long term potentiation, which is normally produced in this pathway by high frequency stimulation in the presence of Mg2+.
Human studies of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) have shown age-related changes in serum levels of these two sex hormone precursors. The levels of both DHEA and DHEA-S are characterized by monotonic decreases after puberty in females and after 20-24 yr of age in males. Further studies have shown that DHEA and DHEA-S levels are significantly low or close to minimal at ages when the incidence of senile dementia of Alzheimer's type (SDAT) begins to increase. We propose that DHEA and DHEA-S play a significant role in normal function of neuronal cells and that supplementation with them may prevent neuronal loss and/or damage. In the present study, using methods of immunocytochemistry, autoradiography, and scanning electron microscopy, we show that a supplement of as little as 10(-8) M DHEA or DHEA-S greatly increases neuronal survival and differentiation and reduces astroglial proliferation rates in mouse brain cells in cultures. These results suggest that correcting the DHEA and the DHEA-S deficit may prevent and/or improve the SDAT condition in humans.
Fourteen children with Attention Deficit Disorder with Hyperactivity (ADD + H) were administered the psychostimulant methylphenidate in a double-blind, placebo-controlled, crossover study. Subjects were evaluated on a well-validated measure of verbal memory and learning with an experimental design comprised of four conditions: placebo and active drug at three doses. Positive memory effects were found in the drug conditions. Significant dose-response relationships were found, indicating enhanced learning from placebo to low to medium to high dose. However, there was a differential drug effect on the memory task; methylphenidate selectively enhanced storage and retrieval mechanisms without affecting immediate acquisition.
A food supplement, namely DMAE, that facilitates the induction of lucid dreams is discussed. Included is a brief consideration of the therapeutic potential of such dreams.
The synthesis of a series of physostigmine analogs, in which the methylcarbamyl group has been substituted with monoalkylcarbamyl, dimethyl- and diethylcarbamyl groups, is reported. These compounds were prepared with the aim of investigating their possible therapeutic effects in the treatment of Alzheimer's type dementia. The new analogs of physostigmine are inhibitors of acetylcholinesterase from Electroforus electricus, with a value of the reactivation constant, k3 smaller than the one of physostigmine. The percentage of anticholinesterase activity in vitro and in vivo, the acute toxicity and some behavioural effects were also evaluated for selected derivatives. The reactivation constant, in vitro, supports the view that the derivatives described would be more suitable for therapeutic use than physostigmine.
The pharmacological mechanism of action of the piracetam-like nootropics is still obscure. Their unique feature is that they exert distinct effects on memory, but show hardly any biochemical activity and are practically devoid of toxic effects. Our results indicate that the memory-enhancing action of these substances is dependent on the presence of the adrenals, suggesting that their central effects might be mediated by peripheral mechanisms.