Vol 40, No 2 (2023)

The concept of nootropics was introduced into pharmacology in the early 1970s by Corneliu Giurgea, a Belgian pharmacologist of Romanian origin, based on the study of 2-oxo-1-pyrrolidine derivatives, which later became known as racetams. The paper substantiates the position that the emergence of modern ideas about nootropics and similar compounds (psychoenergizers, antihypoxants, actoprotectors) in a certain sense was preceded by the concept of adaptogens by N.V. Lazarev (1953–1958), whose theoretical development went towards concretization of certain provisions of this concept. The formation of the problem of nootropics, their place in modern pharmacology, the origins and prospects for the development of the concept, the search for new pharmacological agents with nootropic properties are considered. Nootropic activity is analyzed from the standpoint of the mechanisms of action of racetams, neuropeptides, GABA derivatives, benzimidadols.

The 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.

Neurodevelopmental Disorders (NDD) are characterized by disturbances of the formation of cognitive functions, communication skills, behavior characteristics and / or motor skills, which are caused by abnormalities in the course of the processes of neuroontogenesis. Factors of the etiology and pathogenesis of NDD include genetic mechanisms, early damage to the developing brain, and adverse external influences. Most forms of NDD manifest themselves in the early stages of development and before the child begins school eduction. The most common NDD, with which medical doctors of various specialties constantly meet, include speech development disorders and attention deficit hyperactivity disorder (ADHD). Since disorders of neuroplasticity processes are considered among the mechanisms of the NDD pathogenesis, their therapy should be aimed at restoring and stimulating the neuroplasticity potential. Manifestations of NDD, undergoing age-related evolution, significantly disrupt normal life and have an adverse effect on various functional areas not only in children, but also in adolescents and adults. The increase in symptoms in patients with NDD at one age or another is not due to the progressive nature of cerebral changes, but to increased difficulties of adaptation with increasing loads, including educational, social, professional ones. Therefore, in most cases, they require many years of complex management and the use of pharmacotherapy, the prospects of which are primarily associated with nootropic drugs. The data of new studies on the effectiveness of nootropics in developmental dysphasia and ADHD are discussed, and possible mechanisms of the nootropics influence on neuroplasticity processes are considered.

The effects of the nootropic peptides selank (300 mg/kg), noopept (1 mg/kg), and semax (0.6 mg/kg) after subchronic intraperitoneal (i.p.) and intranasal (i.n.) administration on the binding of [3H]-MDL105,51 to NMDA glycine site in BALB/c and C57Bl/6 mice brain were examined. It was found that in C57Bl/6 mice in comparison with BALB/c the number of glycine binding sites (B_max) at baseline was 15% higher in the cortex and 47% lower in the hippocampus. In the cortex i.n. administration of selank, noopept, and semax resulted in 18, 19, and 66% decrease in the number of glycine binding sites in BALB/c mice, and in 53, 49, and 66% in C57Bl/6 mice, respectively. In the hippocampus i.n. administration of selank, noopept, and semax resulted in 15, 63, and 95% increase in the number of glycine binding sites in BALB/c mice, respectively, while in C57Bl/6 mice all three peptides were not effective. In the cortex i.p. administration of selank and semax decreased glycine binding sites by 24 and 40% in the cortex and by 11 and 19% in the hippocampus in BALB/c mice, while in C57Bl/6 mice the reduction was 15% and 47% in the cortex and 45 and 24% in the hippocampus, respectively. Noopept did not affect the binding. These patterns observed in the cortex after i.n. and i.p. administration appear to be common to the both mice strains suggesting an engagement of the cortical NMDA glycine site in action(s) that underlie some common pharmacological effects of the selected peptides. Whereas the specific effect of selank, noopept, and semax after i.n. administration in the BALB/c hippocampi may be associated with the mechanisms of nootropic and anxiolytic activities of these peptides manifested in that mice strain.

In our previous experiments, it was found that the nootropic drugs piracetam (200 mg/kg/day, intraperitoneally), pantogam (100), pantogam active (200), phenibut (70), semax (0.6), as well as a new derivative of racetam GIZh-290 (3) and the comparison drug atomoxetine (3.0) as a result of subchronic administration, attention stability to new objects is restored in the “closed enriched cross maze” test, showing selectivity of the effect in relation to a subpopulation of CD-1 mice with an initially low attention index (ED-Low). In this study, the effect of nootropics on metabotropic glutamate receptors (mGluRII) in the prefrontal cortex of these mice was studied using the receptor binding of a specific radioligand [G-³H]LY354740. It was found that the density (B_max) of mGluII receptors in the brains of subpopulation with the ED-Low phenotype was 11–25% lower than in subpopulation with the ED-High phenotype. None of the drugs had an effect on these receptors in the subpopulation with the ED-High phenotype, whereas phenibut, semax and GIZh-290 showed efficacy with respect to the ED-Low phenotype, increasing B_max values by 60, 19 and 22%, respectively. Thus, it was shown for the first time that mGluRII are involved in the pathogenesis of attention impairment, and the ability of phenibut, semax and GIZh-290 (2,6-dimethylanilide (2-oxo-4-phenylpyrrolidine-1-yl) acetate to selectively normalize the reduced density of these receptors indicates the prospects of their use in as a drugs for the treatment of attention deficit disorder.

Our recent researches demonstrate shifts in brain activity of rats, both at behavioral and biochemical levels, induced by one of modeled impacts of interplanetary spaceflight, i.e. space radiation. Thus emerges a question, whether such shifts occur in molecular underlying processes of brain function. We have investigated the gene expression for proteins of SNARE (soluble NSF attachment receptor), responsible for fusion of transport vesicles with terminal membranes. Our result is an evidence of changes in some SNARE elements after irradiation and an indirect evidence of a link between nature of such changes and animal nervous system typology. Thus, in order, impairments of brain activity after model irradiation compared to such of an interplanetary flight are observed at every level of nervous system structure.