Abstract—This review provides information about the features of cognitive dysfunctions that occur in various diseases and conditions, and data on the history of the creation and characteristic features of nootropics. The review presents the mechanisms of action and the spectrum of pharmacological effects of nootropic drugs from various groups: drugs that affect brain metabolism, neurotransmitter systems (cholinergic, glutamatergic, GABAergic, and others), cerebral vasodilators, neuropeptides and their analogues, antioxidants, membrane protectors, and others. The free radical and mitochondrial concepts of aging and the possibility of using nootropics for the correction of cognitive impairments arising from aging, dementia, and other neurodegenerative diseases are considered.
One of the most important functions of the central nervous system, along with other higher functions of the brain (intelligence, praxis, gnosis, speech, etc.), is memory, which fixes, stores, and uses information; memory impairment is one of the most common manifestations of various diseases. Memory includes short-term memory, which has a limited volume, long-term memory, and the process of memory trace consolidation, in which structural intraneuronal changes occur that ensure long-term preservation of a memory trace .
Memory impairment is an obligatory symptom of dementias of various origins (vascular, atrophic, traumatic, postencephalic, intoxication, etc.); dementia is defined as a diffuse impairment of higher brain functions, primarily memory, acquired as a result of an organic brain disease leading to significant difficulties in everyday life [1–3]. The prevalence of dementia among the population is very significant, especially in the elderly: from 5 to 10% of people over 65 years of age have dementia . Amnesia is the main clinical manifestation of Korsakov’s syndrome in patients with chronic alcoholism, while other higher brain functions (intelligence, praxis, gnosis, and speech) are usually not changed in these patients . Alzheimer’s disease is characterized by pronounced mnestic disorders, in which increased forgetfulness of current events is an early sign of the disease, and then other cognitive impairments appear: apracto-agnostic syndrome, speech disorders such as amnestic or sensory aphasia, and advanced stages of memory impairment characterized by a combination of fixation, anterograde and retrograde amnesia [2–4]. In Alzheimer’s disease, in contrast to memory impairments in Korsakov’s syndrome, all types of long-term memory suffer: episodic, semantic, procedural, and involuntary, and the volume and time of keeping a trace in working memory are reduced.
Cognitive deficits are also observed in other neurodegenerative diseases: Parkinson’s disease, multiple sclerosis, Huntington’s chorea, as well as in children with pathologies such as oligophrenia, autism, and attention deficit hyperactivity disorder [1, 5]. Memory loss can be observed in patients with various neurological, mental and somatic diseases: cerebrovascular accidents, including strokes, pulmonary, hepatic and renal insufficiency, traumatic brain injury, brain oncology, asthenic syndrome, and epilepsy. Cognitive impairments accompany prolonged hypoglycemia, are detected in hypothyroidism, vitamin B12 and folic acid deficiency and in various intoxications, including medicines: central anticholinergics, tricyclic antidepressants, neuroleptics, benzodiazepine drugs with long-term use at high doses, narcotic analgesics, and others.
Disruption of cognitive functions starting from a slight, unsharp deterioration in concentration and assimilation of new information: names, numbers, things, and retrieval of old information from memory, accompanies aging and most often occurs in the age range from 40 to 65 years and is considered as a normal, non-pathological, age memory impairment [1, 6, 7]. The weakening of memory during normal aging correlates with impaired brain metabolism and cerebral circulation. Memory impairment can be observed in healthy people in stressful situations, with overwork caused by excessive physical and mental stress, hormonal disorders, or vitamin deficiency.
For the treatment of various cognitive impairments in clinical and outpatient practice, nootropic drugs are used (in the English literature they are also called smart drugs or cognitive enhancers), which is one of the largest groups of drugs. Nootropics can be defined as a group of neurotropic drugs that have the ability to improve memory, restore impaired cognitive function of the brain, improve learning and information reproduction, stimulate active wakefulness and increase the body’s resistance to adverse or extreme factors [8–12]. The concept of nootropic action also includes the effect on impaired higher cortical functions: the level of judgments, critical analysis, improvement of cortical control of subcortical activity, thinking, speech, attention, increased level of wakefulness, clarity of consciousness. According to the WHO definition, the group of nootropic drugs includes “drugs that can have a direct activating effect on learning processes, improve memory and mental activity, and also increase the brain’s resistance to aggressive influences.”
The term “nootropics” (from Greek “noos,” mind, thinking; “tropes,” direction) was proposed by Belgian scientists K. Giurgea and V. Scondia (UCB) to refer to a new class of drugs that positively affect cognitive and integrative brain functions [8–10]. These researchers, while searching for new hypnosedative drugs, showed that the compound UCB-6215: 2‑oxo-1-pyrrolidone-acetamide (cyclized GABA), later called piracetam, improves transcollosal evoked potentials in the experiment, and patients experience an improvement in memory without expected hypnosedative effect. Piracetam (Nootropil) is the first drug from the group of nootropics, which has been resynthesized in many countries of the world under different trade names. According to the spectrum of pharmacological effects, nootropics differ significantly from other psychotropic drugs. It is no coincidence that the second chapter of the first book on nootropics Nootropil, published by UCB in 1980, was originally called “What nootropil is not,” which presented data on the lack of effects of nootropil according to tests for evaluating known psychotropic drugs from different groups.
The main effect of nootropic drugs is the actual nootropic effect, that is, the impact on learning and memory processes, on impaired higher cortical functions, and mental retardation. Along with this, the range of pharmacological effects of various nootropics may include: psychostimulating effect, that is, the influence on intellectual and motor retardation, apathy, and mental inertia; anti-asthenic effect, that is, the influence on mental and physical asthenia, lethargy, weakness, and exhaustion; adaptogenic effect, that is, increased tolerance to various extreme exogenous factors; anxiolytic effect, that is, influence on emotional lability, irritability, and anxiety; antihypoxic, neuroprotective action, the ability to improve cerebral circulation, and some other effects [9–16]. One feature of the action of many nootropic drugs is their ability to facilitate interhemispheric transcallosal transmission to the CNS, which improves both interhemispheric and intrahemispheric information transfer [10, 12].
Nootropic drugs have low toxicity, minor side effects, as a rule, and do not cause speech and motor excitement, anxiety, the development of addiction, or depletion of the body’s functional capabilities; they combine well with drugs from other groups. Contraindications to the use of certain nootropics, taking the patient’s condition into account, are: acute renal failure, diabetes mellitus, neuroinfections, epilepsy, and mental agitation; nootropic therapy is not recommended for persistent and significant impairment of mental activity and intelligence.
The group of nootropic drugs is extremely diverse both in terms of chemical structure and mechanisms of action. Various classifications of substances with nootropic effects are described. For example, Kumar et al. (2016) distinguishes seven groups of drugs with nootropic action: racetams, ampakines, cholinergic substances, B vitamins and their synthetic analogues, substances of natural origin, peptides, and Smart substances , whereas Malík, M., Tlustoš, P. (2022) classify substances with a nootropic effect into four groups: classic nootropic drugs, substances that increase brain metabolism, cholinergic nootropics, and plants and their extracts .
The classification of the heterogeneous group of nootropics proposed in this review is a variant (with clarifications and additions) of the classification of nootropics that we developed earlier [11, 12] and is based on the concept of the predominant component of the drug’s mechanism of action. It should be borne in mind that individual nootropic drugs are polytargeted and realize their effect through the inclusion of several components of the mechanism of action.
CLASSIFICATION OF SUBSTANCES WITH NOOTROPIC AND NEUROPROTECTIVE ACTION
(1) Pyrrolidone nootropic drugs (racetams) with a predominant effect on brain metabolism: piracetam, oxiracetam, aniracetam, pramiracetam, etiracetam, dipracetam, rolziracetam, nebracetam, nefiracetam, fenotropil (phenylpiracetam), etc.
(2) Substances affecting the cholinergic system.
2.1. Substances that cause increased synthesis of acetylcholine and its release: choline chloride, lecithin, phosphatidylcholine, dimethylaminoethanol (deanol), meclofenoxate, centrophenoxine, pyritinol, acetyl-L-carnitine, citicholine, etc.
2.2. Acetylcholinesterase inhibitors: physostigmine, tacrine, amyridine, donepezil, rivastigmine, galantamine, metrifonate, etc.
(3) Substances that affect the system of excitatory amino acids: glutamic acid, memantine, glycine, milacemide, nooglutil, ampasse, etc.
(4) Substances affecting the GABA system: gammalon, pantogam, picamilon, digam, phenibut, sodium, lithium, calcium oxybutyrate, etc.
(5) Neuropeptides and their analogues: ACTH, somatostatin, vasopressin, angiotensin-II, thyroliberin, neuropeptide Y, substance P and their fragments and analogues, cerebrolysin, cortexin, semax, noopept (a peptide analogue of piracetam), etc.
(6) Vasoactive, neuroprotective drugs: nicergoline, vincamine, vinpocetine, nimodipine, cinnarizine, flunarizine, etc.
(7) Antioxidants, antihypoxants, membrane modulators: mexidol, dibunol, ubiquinone, pyritinol, aterovit, alpha-tocopherol, emoxipin, selenium, etc.
(8) Vitamins, their analogues, neurosteroids, melatonin, and substances of plant origin: vitamins E, B6, B12, nicotinamide, foliates, thiamine, alpha-lipoic acid, folic acid, orotic acid, succinic acid, ginkgo biloba, tanakan, ginseng, lemongrass, etc.
Taking the predominant clinical effect into account, nootropic drugs can be divided into drugs with a dominant effect on mnestic functions: pyrrolidone nootropics, drugs that affect the cholinergic system, substances that affect the glutamatergic system, neuropeptides and their analogues, and drugs that combine a pronounced neuroprotective effect with a nootropic effect: vasodilators, calcium antagonists, antioxidants, membrane protectors, and substances that affect the GABA system.
Additionally, we can indicate:
Substances that affect the process of neurodegeneration in Alzheimer’s disease: substances that reduce the synthesis and affect the aggregation, deaggregation, and deposition of beta-amyloid and clean amyloid plaques, chelating metals, substances that reduce hyperphosphorylation of the tau protein and blockade of tau aggregation, increase the level of chaperones, anti-inflammatory drugs, statins, etc.
Drugs used to treat Attention Deficit Hyperactivity Disorder (ADHD): methylphenidate, atomoxetine, modaphenyl, phenibut, fenotropil, etc.
Combined drugs: phezam (piracetam and cinnarizine), vintotropil (piracetam and vinpocetine), orocetam (piracetam and orotic acid), diapiram (piracetam and diazepam), neuronal (piracetam and succinic acid, riboxin, nicotinamide, riboflavin mononucleotide, and pyridoxine), instenol (hexabidine, etamivan, and etafillin), cytoflavin (succinic acid, riboxin, nicotinamide, and riboflavin mononucleotide), etc.
Below are the characteristics of the most widely used nootropics in Russia, with an analysis of the spectra of their pharmacological activity and mechanisms of action.
Nootropics of the pyrrolidone series. According to experimental and clinical data, the main effects of piracetam and most of its analogues are nootropic, antihypoxic, and anxiolytic; the mechanism for the implementation of these effects is multicomponent, but, first of all, is associated with the effect on metabolic processes and cerebral circulation [10, 11, 17–19]. It has been shown that piracetam increases the synthesis of phospholipids, activates adenylate cyclase, increases the level of ATP, enhances the utilization of glucose in the brain, increases the permeability of cell and mitochondrial membranes for Krebs cycle mediators, and increases the synthesis of cytochrome b5 [20–22]. Piracetam has an antioxidant effect , increases the density of cholinergic receptors [24, 25], and interacts with some neuropeptides (substance P, vasopressin, and adrenocorticotropic hormone) . It has been established that piracetam activates the AMPA subtype of glutamate receptors with no effect on the NMDA receptors of neurons, which leads to an increase in the release of calcium from the cell [26, 27]. Piracetam improves microcirculation in ischemic areas of the brain, inhibits the aggregation of activated platelets, and has a protective effect during extreme effects on the brain caused by hypoxia, intoxication, and electric shock [11, 19, 28, 29].
Phenylpiracetam, a phenyl analogue of piracetam (trade names: phenotropil, carphedon, and phenylpiracetam), was developed at the Institute of Biomedical Problems as a new generation psychostimulant that can increase the mental and physical performance of astronauts at various stages of space flights. It was experimentally established that phenylpiracetam improves learning and memory, has an antiamnesic effect, activates operant behavior, has anxiolytic, antiasthenic, and anticonvulsant effects, weakens the sedative effect of benzodiazepines, increases resistance to cold, and improves sleep [29–31]. In a model of cerebral ischemia, phenylpiracetam improves cognitive functions, reduces manifestations of neurological deficit, and is superior in effectiveness to piracetam [32, 33]. It has been shown that phenylpiracetam does not bind to GABA-A, GABA-B and dopamine receptors, or 5-HT2 serotonin receptor, but is a synaptic transmission modulator and binds to α4β2 nicotinic acetylcholine receptors in the cerebral cortex (IC50 = 5.86 μm) [34, 35].
Nootropics with a cholinergic mechanism of action. Phosphatidylcholine (lecithin) is one of the main lipid components of cell membranes, and choline released from lecithin is a precursor of acetylcholine synthesis . It has been shown that the administration of phosphatidylcholine to mice (under conditions of a dementia model) or to patients with cognitive dysfunctions and dementia increases the concentration of acetylcholine in the brain and improves memory [37–39]. Acetyl-L-carnitine is a source of acetylcholine precursors and has a distinct nootropic effect . Deanol (dimethylaminoethanol, DMAE) is a precursor of choline and also has a pronounced antioxidant effect [18, 41]. In the experiment, deanol improves learning and memory and reduces amnesia caused by scopolamine [42, 43]. Deanol is the second structural component of meclofenoxate, which, like deanol, increases the level of choline in the brain, has an antioxidant effect, improves memory, decreases the levels of pro-inflammatory mediators, and reduces neuronal damage during cerebral ischemia [18, 44]. Pyritinol (consists of two molecules of vitamin B6 bonded with a disulfide bridge) improves learning and memory, including in old animals and humans, increases the activity of choline acetyltransferase, which contributes to the accumulation of choline in cholinergic neurons, increases the level of acetylcholine in the brain, and has an antioxidant effect [45–48].
Nootropics with a GABAergic mechanism of action. Pantogam (D-isomer of homopantothenic acid) and pantogam active (racetam hopantenic/D-, L-hopantenic acid) is the original domestic nootropic drugs, whose spectrum of pharmacological effects, in addition to the nootropic effect, includes neuroprotective, antihypoxic, anticonvulsant, anxiolytic, antiasthenic, and vegetostabilizing effects [49–51]. Pantgam and pantogam active have been shown to improve learning and memory processes, to have antiamnesic and antihypoxic effects, and to relieve seizures caused by pentylenetetrazole and bemegride [52, 53]. The mechanism of action of the drugs is determined by the presence of GABA in its structure and is associated primarily with a direct effect on the GABA-B receptor and an improvement in GABA metabolism . Pantogam increases the resistance of the brain to hypoxia and the effects of toxic substances, and stimulates anabolic processes in neurons. Pantogam and pantogam active are widely used in clinical practice, including in children from the first days of life.
Neuropeptides and their analogues. Semax, developed on the basis of a fragment of adrenocorticotropic hormone, that is, ACTH(4–10), at the Institute of Molecular Genetics of the Russian Academy of Sciences and at the Department of Human and Animal Physiology of the Department of Biology, Moscow State University, is one of the first domestic drugs of a peptide nature [55, 56]. It was experimentally shown that Semax stimulates learning processes, reduces amnesia caused by various influences, normalizes cerebral circulation, and has antihypoxic and anxiolytic effects [56–59]. Semax reduces the level of glutamate excitotoxicity and oxidative stress, increases the conjugation of oxidation and phosphorylation in mitochondria, which, under conditions of oxygen deficiency, maintains a high level of ATP formation, and increases the content of neurotrophic factors in the brain tissue [55–57, 60]. In practical medicine, Semax has shown efficacy in the treatment of ischemic stroke, chronic cerebrovascular diseases, traumatic brain injury, Huntington’s chorea, various forms of intellectual-mnestic and astheno-neurotic disorders, migraine, and trigeminal neuralgia [61, 62].
Noopept (ethyl ester of N-phenylacetyl-L-prolylglycine) is a nonpeptide prototype of piracetam, synthesized and studied at the Zakusov Research Institute of Pharmacology. Experimental studies show that noopept has nootropic and antihypoxic properties and is superior in activity to piracetam . The nootropic effect of the drug may be associated with the formation of cycloprolylglycine during its metabolism, which is similar in structure to the endogenous cyclic dipeptide with antiamnestic activity. The study of the primary interactions of noopept with more than 100 known receptor formations, performed by CEREP (France), did not lead to the expected identification of primary targets . It has been shown that noopept has an anticholinergic effect , enhances the expression of neurotrophins NGF and BDNF , and selectively increases the DNA-binding activity of HIF-1 (hypoxia-inducing factor). These data, taking the functional significance of the genes activated by this transcription factor into account, allow us to consider the positive effect of HIF-1 as the primary mechanism of action of noopept .
Vasoactive, neuroprotective drugs. Nicergoline (an ergot alkaloid) has a nootropic and neuroprotective effect, improves cholinergic neurotransmission , protects neurons from β-amyloid toxicity , is an α1-adrenergic receptor antagonist , inhibits platelet aggregation, increases oxygen and glucose utilization, and has antioxidant properties . Vinpocetine is a semi-synthetic derivative of the alkaloid vincamine, which is found in Vinca minor (periwinkle) and has a nootropic and neuroprotective effect. Vinpocetine is a voltage-dependent sodium channel blocker [71, 72], a selective inhibitor of Ca2+/calmodulin-dependent cyclic nucleotide phosphodiesterase type 1, increases the level of ATP in the brain, inhibits platelet aggregation, reduces blood viscosity, increases cerebral blood flow along with glucose and oxygen consumption in brain tissues [73–76].
Antioxidants, antihypoxants, and membrane protectors can improve learning and memory processes, including in diseases accompanied by neurodegeneration. It has been shown that the nootropic centrophenoxin is first cleaved into parachlorophenoxyacetic acid and dimethylaminoethanol (DMAE), which is incorporated into the cell membrane of nerve cells in the form of phosphatidyl DMAE, remains there for a long period of time and is a strong inhibitor of OH free radicals . Under pathological conditions (aging or stress), it increases membrane fluidity, protects membrane lipids from the action of free radicals, reduces the concentration of intracellular K+ and increases the water content in the cell, i.e. reduces the shifts caused by pathology . Mexidol (2-ethyl-6-methyl-3-oxypyridine succinate) synthesized at the Zakusov Research Institute of Pharmacology also has membranotropic, antioxidant, and antihypoxic properties; the spectrum of its pharmacological activity includes nootropic, neuroprotective, anxiolytic, antidepressant, anticonvulsant, antialcoholic, and some other effects [78–81]. The experiment showed that mexidol has a pronounced antiamnestic effect in severe amnesia tests caused by maximum electric shock or deprivation of paradoxical sleep phase, is not inferior in efficiency in these tests to nootropics centrophenoxin and cleregil, and is superior in both antiamnesic activity and effectiveness to piracetam: the mexidol dose that has an antiamnestic effect is 2 times lower, and the effect is higher than that of piracetam [78, 79, 82, 83].
Mexidol, both in experiments and in the clinic, has a pronounced neuroprotective effect, including in ischemic and hemorrhagic strokes; it improves cerebral circulation. Experiments have shown that mexidol in rats with hemorrhagic stroke improves impaired learning and memory processes, increases the survival rate of animals, and reduces the manifestations of neurological deficits, which is accompanied by normalization of the concentrations of TBA-active products in the blood and homogenates of the cerebral cortex of rats and indicates the participation of antioxidant mechanisms in the nootropic and neuroprotective effects of mexidol .
In clinical practice, mexidol has shown efficacy in the treatment of mild and moderate cognitive impairment observed in patients by physicians in wide therapeutic practice , in the treatment of cognitive impairment in patients with cerebrovascular diseases, including stroke [86–89], with pre-dementia cognitive disorders [90, 91], as well as in the complex therapy of Alzheimer’s disease , Parkinson’s disease [93–96], and multiple sclerosis [97, 98].
It has been established that substances with antioxidant and antihypoxic activity (alpha-tocopherol, melatonin, chelating agents, ascorbic acid, mexidol, cysteine hydrochloride, succinic acid, and some others) can not only improve cognitive functions but also increase the lifespan of laboratory animals [99–104].
Nootropics are widely used for cognitive impairment that occurs with aging and neurodegenerative diseases that often accompany aging.
Modern concepts of aging consider oxidative stress, with the formation of reactive oxygen species (ROS), and mitochondrial dysfunction as key causes of subsequent cell death [104–109]. According to the free radical theory of aging, the imbalance of oxidant and antioxidant systems that occurs during aging leads to the generation of ROS, primarily in the mitochondria of cells, which causes damage to various macromolecules and structures: DNA, chromatin, proteins, lipids, membranes, and collagen, and disrupts the regulation of the intracellular level calcium, etc., which leads to oxidative stress triggering the apoptosis cascade that leads to programmed cell death and contributes to the onset of age-related pathological processes and neurodegenerative diseases [104, 106, 107,110–113].
According to the mitochondrial theory, aging is based on progressive dysfunction of mitochondria in various tissues of the body: mitochondria change their structure, the rate of electron transport decreases, the energy-producing function is limited, the balance of oxidant and antioxidant systems is disturbed, mitochondrial DNA mutations occur, which serves as the basis for the development of neurodegenerative processes and the formation of age-related pathology, including memory impairment [104–105, 114–116]. Age-related disorders of mitochondrial respiration and a high frequency of mutations in mtDNA are detected not only with aging but also in individuals with neurodegenerative diseases (Alzheimer’s and Parkinson’s diseases, dementia, Huntington’s chorea, as well as myopathies of skeletal and cardiac muscles, movement disorders, etc.) [116, 117].
Thus, in disorders, including cognitive ones, arising from aging and neurodegenerative diseases, the use of drugs that have nootropic, antioxidant, and antihypoxic effects and positively affect mitochondrial dysfunction is justified. One of these drugs is 2-ethyl-6-methyl-3-hydroxypyridine succinate (Mexidol). It has been shown that in old animals, a long-term course (two courses of 2 months) of mexidol restores cognitive and motor-neurological deficits and increases life expectancy [118, 119].
The nootropic and neuroprotective action of mexidol, including in aging and neurodegenerative diseases, is determined by its basic polytarget mechanism of action. Mexidol has an antihypoxic effect, the ability to improve the energy status of the cell and restore processes in the Krebs cycle [120, 121], suppress ascorbate-dependent (nonenzymatic) and NADPH2-dependent lipid peroxidation [80, 83, 122], increase the activity of Se-dependent glutathione peroxidase, decrease the activity of inducible NO-synthase and bind the superoxide anion radical, and reduce glutamate excitotoxicity . The ability of 2-ethyl-6-methyl-3-oxypyridine to increase the content of phosphatidylserine, phosphatidylinositol, and sphingomyelin in the synaptosomal membranes of the brain has been shown [83, 124], which has a significant effect on memory processes, since it is known that Ca2+,K+-ATPase activity depends on an increase in the content of phosphatidylserine, and an increase in the content of phosphatidylinositol leads to an increase in the affinity of the acetylcholine receptor for acetylcholine. Thus, the nootropic action of mexidol occurs via antioxidant and membrane-modulating mechanisms, leading to structural and functional changes in the biomembrane and to optimizing the functioning of acetylcholine receptors, which are of paramount importance for improving synaptic transmission and memory processes.
Recent data indicates the ability of mexidol to induce cerebral mitochondriogenesis and eliminate mitochondrial dysfunction in both young and old rats . It has been shown that after the course administration of mexidol in the cerebral cortex of rats, a dose-dependent induction of the succinate receptor SUCNR1 and proteins-markers of mitochondrial biogenesis was observed: the transcriptional co-activator PGC-1α, transcription factors (NRF1, TFAM), catalytic subunits of respiratory enzymes (NDUFV2, SDHA, cyt b, and COX2), and ATP synthase (ATP5A) . Activation of the succinate receptor causes effects that overcome energy imbalance and causes activation of erythropoiesis and angiogenesis, stimulation of cardiac activity, etc. [126, 127]. Mitochondrial biogenesis and the succinate receptor are considered as important pathogenetically substantiated targets in the study of aging and neurodegenerative diseases and the search for drugs with neuroprotective and nootropic effects [128–131].
Thus, the effects of mexidol in cognitive dysfunctions, including those arising from aging and neurodegenerative diseases, are determined by the both fragments of its structure, each of which affects the key pathogenetic links in the process of neurodegeneration: 2-ethyl-6-methyl-3-hydroxypyridine has an antioxidant and membrane-protective action, and succinate, first of all, restores disorders in mitochondrial dysfunction.
The use of mexidol proved to be effective in the treatment of cognitive impairments, motor-motor disorders, dizziness, asthenia, anxiety in older patients with chronic cerebral pathology [132, 133], including vascular encephalopathy , as well as in elderly patients with cardiovascular pathology and arterial hypertension [135, 136].
Thus, the group of nootropic drugs is extremely diverse, both in terms of chemical structure and the spectrum of pharmacological effects and mechanisms of action. Various nootropics, in addition to the actual nootropic (influence on learning and memory) action, can have psychostimulating, antiasthenic, anxiolytic, and adaptogenic effects, neuroprotective and antihypoxic action and can also improve cerebral circulation and exert some other effects.
Based on the analysis of currently available data on the action of individual drugs, the following main components of the mechanism of nootropic effect can be distinguished: influence on neurotransmitter systems: cholinergic and glutamatergic systems, as well as GABA, dopaminergic, adrenergic and serotonergic systems; increased brain bioenergetics (activation of adenylate cyclase, increased synthesis of ATP and cAMP); antioxidant action (inhibition of the formation of free radicals and peroxidation); membrane-stabilizing action: regulation of the synthesis of phospholipids and proteins in nerve cells, stabilization of the structure of cell membranes; influence on cerebral mitochondriogenesis and mitochondrial dysfunction; activation of plasticity processes in the central nervous system (increased synthesis of RNA, DNA, and proteins–improved formation of informational macromolecules; improved microcirculation (dilation of cerebral vessels, reduced platelet aggregation, etc.); increased resistance to oxygen deficiency, increased glucose intake through neuronal membranes and its improved utilization; influence on ion channels (calcium, sodium, etc.); influence on metal chelators; influence on nerve growth factors; influence on monoclonal antibodies interacting with beta-amyloid and tau protein and some other components of the mechanism.
Nootropic drugs are among the most widely used drugs, both in outpatient and clinical practice. The main indications for the use of nootropics are dementia of various origins: vascular, atrophic, postencephalic, post-infectious, memory impairment during aging, stroke, traumatic brain injury, and vegetative-vascular dystonia. Nootropics are used for Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and in children for Down’s disease, autism, attention deficit disorder, and mental retardation. Nootropics are used in complex therapy for atherosclerosis and hypertension, for various intoxications (drugs, alcoholism, drug addiction, and others), for coma of various etiologies, for brain tumors, neuroinfections, asthenia, neurosis, depression, schizophrenia, epilepsy, and other diseases. Nootropics are used by healthy people to improve mental performance during periods of increased stress.
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The work was carried out within the framework of the EGISU NIOKR No. 122020100281-9 of the State assignment to Zakusov Research Institute of Pharmacology.
Conflict of interests. The authors declare that they have no conflicts of interest.
Corresponding author; address: ul. Baltiiskaya 8, Moscow, 125315 Russia; phone: +7-499-601-21-53; e-mail: email@example.com.
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Voronina, T.A. Cognitive Impairment and Nootropic Drugs: Mechanism of Action and Spectrum of Effects. Neurochem. J. 17, 180–188 (2023). https://doi.org/10.1134/S1819712423020198