Derivative Of Gamma-aminobutyric Acid Research Articles

Advances in the chemoenzymatic synthesis of gamma-aminobutyric acid derivatives

Gamma-aminobutyric acid (GABA) derivatives are a class of effective inhibitory neurotransmitters for treating neurodegenerative diseases, with an immense market demand. Chemical methods are currently the main synthetic strategies for GABA derivatives, facing challenges such as complex processes, low yields, low atom economy, and environmental burden. In recent years, chemoenzymatic synthesis of GABA derivatives has garnered increasing attention because of the high atom economy, high yields, and environmental friendliness. This article reviews the latest advances in the chemical synthesis and chemoenzymatic synthesis of GABA derivatives. Furthermore, it introduces the progress in the industrial synthesis of representative GABA derivatives such as gabapentin, pregabalin, and brivaracetam and prospects the future development of GABA derivatives.

Epinephrine, Pregabalin, and Crizotinib as Three Medicines with Polish Implications over Three Last Centuries and in View of Three Different Drug Discovery Approaches.

The discovery of epinephrine (adrenaline) and its subsequent implications in medicine owes significant contributions to Cybulski across different centuries, who, in 1894, was pivotal in identifying the adrenal medulla's role in blood pressure regulation and naming the active substance "nadnerczyna", known today as adrenaline. His work demonstrated the adrenal glands' critical function in the body's regulatory mechanisms beyond the nervous system. Cybulski's groundbreaking research laid foundational knowledge for future endocrinological studies and pharmaceutical advancements. In the late 20th century, Andruszkiewicz collaborated with Silverman at Northwestern University to develop pregabalin, the active ingredient in Lyrica. Their innovative synthesis of gamma-aminobutyric acid derivatives led to a significant advancement in treating epilepsy, neuropathic pain, and fibromyalgia. Andruszkiewicz's expertise in organic chemistry and enzymology was crucial in this collaborative effort, resulting in the successful development and commercialization of Lyrica. Additionally, Mroczkowski's leadership at Pfizer contributed to the development of crizotinib, a notable anaplastic lymphoma kinase and proto-oncogene 1 tyrosine-protein kinase inhibitor used to treat specific types of non-small cell lung cancer. Her work exemplifies the continuing influence of Polish researchers in pioneering drug discovery and advancing therapeutic treatments over the past three centuries. These contributions highlight Poland's significant role in global pharmaceutical innovations and medical research.

Phenibut: A drug with one too many "buts".

Phenibut is a gamma aminobutyric acid derivative with activity at γ-aminobutyric acid (GABA)B, A and β-phenethylamine receptors. It was developed as a drug in the former Soviet Union to overcome anxiety and improve cognitive function in military personnel. In the last decade, it has made inroads into the European and U.S. markets, being marketed for purported nootropic properties. Here, we summarize the current knowledge on phenibut, its toxicology, pharmacology, adverse health effects, and patterns of use. Publications in peer-reviewed journals were searched in PubMed, Web of Science, and Google Scholar databases. Available literature points to adverse side effects associated with intoxication, withdrawal, and addiction to phenibut. Some of these effects can be life-threatening, requiring hospitalization and therapeutic interventions. Supportive efforts are often complicated by a lack of knowledge regarding phenibut's toxicology and pharmacology. Ingestion of phenibut was often associated with concomitant use of other substances of abuse. As control over its online marketing seems unrealistic, current efforts need to be focused on the addition of phenibut to current drug screening tests and the development of generally accepted treatment strategies for phenibut-associated toxicities.

Trolox, Ferulic, Sinapic, and Cinnamic Acid Derivatives of Proline and GABA with Antioxidant and/or Anti-Inflammatory Properties.

Degenerative conditions, such as neurodegenerative disorders (Alzheimer's disease (AD), Parkinson's disease (PD)) and cardiovascular diseases, are complex, multifactorial disorders whose pathophysiology has not been fully elucidated yet. As a result, the available treatment options cannot eliminate these diseases radically, but only alleviate the symptoms. Both inflammatory processes and oxidation are key factors in the development and evolution of neurodegeneration, while acetylcholinesterase inhibitors are the most used therapeutic options against AD. In this work, following the multi-targeting compound approach, we designed and synthesized a series of proline and gamma-aminobutyric acid (GABA) amides with various acidic moieties that possess an antioxidant and/or anti-inflammatory potency. Proline is the pharmacophore of nootropic drugs (e.g., piracetam) used for memory improvement, while GABA is the main inhibitory neurotransmitter in the central nervous system. The designed molecules were subjected to a preliminary screening of their bioactivity in antioxidant and anti-inflammatory assays, as well as against acetylcholinesterase. Most of the synthesized compounds could inhibit lipid peroxidation (IC50 as low as 8 μΜ) and oxidative protein glycation (inhibition of up to 48%) and reduce the 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH). In addition, all of the compounds were moderate inhibitors of lipoxygenase (LOX) (up to 46% at 100 μΜ) and could decrease carrageenan-induced paw edema in rats by up to 55%. Finally, some of the compounds were moderate acetylcholinesterase inhibitors (IC50 as low as 219 μΜ). The results confirmed the design rationale, indicating that the compounds could be further optimized as multi-targeting molecules directed against degenerative conditions.

N-SALICYLOYL AMIDES AND THEIR SALTS: SYNTHESIS, BIOLOGICAL ACTIVITY AND TOXICITY

The Schotten-Baumann reaction was used to synthesize N-salicyloyl derivatives of Morpholine, Glycine and gamma-aminobutyric acid in the process between salicyloyl chloride with morpholine, glycine or gamma-aminobutyric acid with high yield. Sodium and lithium salts of the salicylamides were synthesized by the reaction of an amide with sodium ethylate or lithium hydroxide in inert solvent. The synthesized compounds were charachterized by 1H nuclear magnetic resonance spectra and elemental analysis. Purity was checked by thin layer chromatography. Quantitative analysis of metal ions was done by potentiometry. To select the most promising compounds exhibiting psychotropic (Pa > 0.8) and antiviral (Pa about 0.5) activities, computer analysis was carried out through the PASS program. In the present study, psychotropic (the open-field exploratory test, the forced swim test, the elevated plus-maze test, the passive avoidance test), analgesic (current vocalization threshold) activities and acute toxicity were evaluated. The results of psychotropic activity revealed that amides possess significant psychotropic activity and low acute toxicity. Disodium salicylurate showed a significant antiamnesic action. The results suggested a significant antidepressant activity and antiamnesic action for dilithium salicylurate and sodium salt of salycyloyl morphlide, a psychostimulant action for lithium salt of salicyloyl morphlide. Lithium gamma-(N-salycylamino)butyrate demonstrated psychostimulant and antiamnesic activities. Our present investigation demonstrated that all compounds are very safe for consumption with high LD50 value. All obtained compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex viruses 1 and 2, vaccinia virus, vesicular stomatitis virus, HIV-1 and HIV-2. These compounds were evaluated against human cervix carcinoma cells (HeLa) and CEM T-lymphocytes as well as murine leukemia cells (L1210). The antiviral activity studies depicted that none of the tested compounds were active against DNA or RNA viruses.

Experimental Substantiation of the Use of Phenibut Combinations with Salicylic, Nicotinic, and Glutamic Acids in Cerebral Ischemia.

One of the possible ways to increase the effectiveness of drugs based on gamma-aminobutyric acid derivatives is to introduce biologically active acids into their structure. In this regard, the compositions of phenibut with organic acids, which have a more pronounced psychotropic activity, low toxicity, and good tolerability, are of interest. The purpose of this study is to experimentally substantiate the use of phenibut combinations with organic acids in various forms of cerebral ischemia. The study was performed on 1210 male Wistar rats weighing 180-220g each. The cerebroprotective activities of phenibut combinations with salicylic acid (2:1, doses of 15, 30, and 45mg/kg), nicotinic acid (2:1, doses of 25, 50, and 75mg/kg), and glutamic acid (2:1, doses of 25, 50, and 75mg/kg) have been studied. The study involved a single prophylactic administration of phenibut combinations with organic acids and a 7days course of the combination treatment administered at doses that proved the most effective according to the results of a single prophylactic administration. The rate of local cerebral blood flow and the vasodilating function of cerebral endothelium were measured, and the researchers evaluated the effects of the studied phenibut combinations on biochemical parameters in rats with focal ischemia. Compositions of phenibut with salicylic, nicotinic, and glutamic acids in subtotal and transient cerebral ischemia were found to have the most pronounced cerebroprotective effect in doses of 30, 50 and 50mg/kg, respectively. Under reversible 10min occlusion of the common carotid arteries, prophylactic administration of the studied phenibut compositions prevented a decrease in cerebral blood flow during ischemia and reduced the severity of postischemic hypoperfusion and hyperperfusion. At a course of 7days of therapeutic administration of compounds, their pronounced cerebroprotective effect was observed. The data obtained can be considered as promising the pharmacological search in this series of substances for the treatment of patients with cerebrovascular disease.

Morphological changes in the myocardium of rats with chronic alcohol intoxication after treatment with new GABAand glutamic acid derivatives

Aim. To study pathohistological changes in the myocardium of rats with chronic alcohol intoxication (CAI) after treatment with a new glutamic acid derivative glufimet (compound RSPU-238) and a new gamma-aminobutyric acid (GABA) derivative (compound RSPU-260).Materials and methods. Experiments were performed on female Wistar rats aged 10 months. The rats were divided into the following groups: group 1 – intact females; group 2 – a control group which included animals after CAI simulated by replacing drinking water with 10% ethanol solution for 24 weeks; groups 3 and 4 – experimental groups, in which females were intraperitoneally administered with glufimet at a dose of 28.7 mg / kg and RSPU260 at a dose of 25 mg / kg once a day for 14 days after cessation of alcohol solution consumption; group 5 – a group of animals receiving a reference listed drug mildronate at a dose of 50 mg / kg according to a regimen similar to that of the studied compounds. Changes in microstructural and morphometric parameters of the left ventricular myocardium were assessed using light microscopy.Results. In animals after CAI, the cardiomyocyte volume fraction decreased, while the interstitial and vascular volume fractions increased. Degeneration of cardiomyocytes, such as their wave-like deformation, loss of transverse striation, foci of plasmolysis, and fragmentation of muscle fibers were revealed. In rats treated with glufimet, the structural changes in cardiomyocytes were minimal. Lower vascular plethora was observed; blood vessels were characterized by single stasis and sludge. The cardiomyocyte volume fraction was 9.7% greater than in control animals, while the interstitial and vascular volume fractions were 66.0 and 70.0% smaller, respectively. The animals treated with the RSPU-260 compound had no significant degenerative changes in cardiomyocytes and small vessels similar to the experimental animals injected with glufimet. Mildronate had a less pronounced cardioprotective effect.Conclusion. Administration of new GABA and glutamic acid derivatives to animals with simulated chronic alcohol intoxication leads to improvement of the microstructure in cardiomyocytes compared with control rats. This indicates pronounced cardioprotective effects of the studied neuroactive amino acid derivatives.

Pharmacological use of gamma-aminobutyric acid derivatives in osteoarthritis pain management: a systematic review

BackgroundPain is the major complication of osteoarthritis (OA) patients and is a decisive symptom for medical intervention. Gamma-aminobutyric acid (GABA) derivatives are optional painkillers but not widely used in pain management of OA patients. We synthesized the efficacy and safety of GABA derivatives for OA pain management.MethodsWe searched Medline, Cochrane CENTRAL, Embase, and ClinicalTrals.gov from inception to 13 October 2021 and included randomized controlled trials (RCTs) comparing the efficacy and safety of GABA derivatives with placebo or standard control in OA pain management. Two independent reviewers extracted data and assessed these studies for risk of bias using Cochrane Collaboration’s tool for RCT.ResultsIn total, three eligible RCTs (n = 3) meeting the eligibility criteria were included. Among these RCTs, one focused on hand OA pain management, while two RCTs focused on knee OA. In hand OA, pregabalin reduced numerical rating scale (NRS) score and the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain score significantly compared with placebo, and caused 55 AEs. In knee OA, pregabalin reduced visual analogue scale (VAS) score and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score significantly with no recorded adverse event (AE). Meanwhile, in knee OA, gabapentin reduced both VAS score and WOMAC pain score compared with acetaminophen and caused 9 AEs.ConclusionsGABA derivatives seem to be effective and safe in OA pain management. However, future researches with large sample size are needed to further prove the efficacy of GABA derivatives in OA pain control.Trial registration: CRD42021240225.

Changes in the Deformability and Resistance of Erythrocyte Membranes under the Action of Gamma-Aminobutyric Acid Derivatives in the Offspring of Rats with Experimental Preeclampsia

INTRODUCTION: Preeclampsia is a severe complication of pregnancy associated with the negative consequences for the mother and child. Such complications can be a reduction in the resistance of erythrocyte membranes to damaging agents and alteration of rheological properties of the blood in offspring. Promising compounds for the correction of these negative consequences of preeclampsia are gamma-aminobutyric acid (GABA) derivatives, which showed membraneprotective, antioxidant, and antihypoxic effects in previous studies.
 AIM: To evaluate the effect of GABA derivatives Succicard (4-phenylpiracetam and ethane-1,2-dicarboxylic acid, 2:1), Salifen (4-amino-3-phenylbutanoic acid and 2-hydroxybenzoic acid, 2:1), and Phenibut (aminophenylbutyric acid) on the deformability and resistance of erythrocyte membranes in 8- and 14-month-old offspring of rats with experimental preeclampsia (EP).
 MATERIALS AND METHODS: The study involved offspring (male and female) of white non-inbred female rats with a normal pregnancy and EP that was modeled by replacement of drinking water with a 1.8% sodium chloride solution during gestation (121 days). For 30 days (from day 40 to day 70 of life), pup rats intragastrically received Succicard (22 mg/kg), Salifen (7.5 mg/kg), and Phenibut (25 mg/kg), along with a comparison drug Pantogam (calcium gopantenate) (50 mg/day) once a day. The offspring of the positive and negative control groups were injected with distilled water in a similar mode. In offspring aged 8 and 14 months, the resistance of erythrocyte membranes to the action of hydrochloric acid and their deformability were determined.
 RESULTS: In 8-month-old male offspring of rats with EP, a shorter time of achievement of half the maximal amplitude of erythrogram was noted in acid hemolysis relative to the positive control group, and the erythrocyte elongation index was reduced. Relative to the negative control group, Succicard, Salifen, Phenibut, and Pantogam promoted the prolongation of hemolysis and the erythrocyte elongation index in 8-month-old male rats in the experimental groups. In 14-month-old male and female rats of different ages, no statistically significant differences were found between the groups.
 CONCLUSION: Changes in the stiffness and strength of erythrocyte membranes were noted only in male offspring of rats with EP. Succicard, Salifen, Phenibut, and Pantogam produced membrane-protective effects on the erythrocytes of 8-month-old male rats of the experimental groups.

Synthesis of (±)-Baclofen using Wittig Olefination–Claisen Rearrangement

Baclofen, a lipophilic derivative of GABA (gamma-Aminobutyric acid), which acts as an inhibitory neurotransmitter in CNS (central nervous system) was synthesized by Witting olefination-Claisen rearrangement protocol. 4-Chlorobenzaldehyde was subjected to Wittig reaction with ((allyloxy)methylene)triphenyl-phosphane to give 1-(2-(allyloxy)vinyl)-4-chlorobenzene which on heating under reflux condition in toluene underwent Claisen rearrangement to give 2-(4-chlorophenyl)pent-4-enal. Aldehyde was reduced to corresponding alcohol 2-(4-chlorophenyl)pent-4-en-1-ol as an important precursor which can be used for the synthesis of Baclofen and different GABA derivatives. Further tosylation, formation-reduction of azide group and oxidative ozonolysis of terminal double bond yields 4-amino-3-(4-chlorophenyl)butanoic acid in excellent yield. Therefore, an efficient method was developed for the synthesis of (±)-Baclofen in a simple seven step procedure.

Poststroke Aphasia Treatment

Aphasia is a common complication of stroke, often causing significant morbidity. To the authors' knowledge, no stroke recovery practice guidelines incorporating pharmacologic or noninvasive brain stimulation (NIBS) therapies for poststroke aphasia (PSA) exist. The aim of this article is to provide a comprehensive review of the evidence regarding pharmacologic and NIBS treatment in PSA. An exhaustive single database search assessing treatment for PSA was performed from 2010 to 2020, resulting in 1876 articles. Articles evaluating either pharmacologic management or NIBS were included. Case reports, case series, original research, systematic reviews, and meta-analyses were allowed. Pharmacologic treatment studies included were represented by the following medication classes: cholinergic, dopaminergic, gamma-aminobutyric acid agonists and derivatives, N-methyl-D-aspartate receptor antagonists, serotonergic, and autonomic agents. NIBS treatment studies regarding transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) were evaluated. No strong evidence was found for any medication to improve PSA. However, the benefit of a medication trial may outweigh the risk of side effects as some evidence exists for functional recovery. Regarding NIBS, weak evidence exists for the treatment effect of tDCS and rTMS on PSA. While additional research is needed, the literature shows promise, especially in chronic phase of stroke when traditional treatment options may be exhausted. More evidence with larger studies and standardized study design is needed.

Effect of early and late pharmacological correction with GABA derivatives on cognitive disorders in offspring of rats with experimental preeclampsia

BACKGROUND: Preeclampsia is a serious complication of pregnancy which augments the risk of cognitive disorders in the offspring at different stages of life. Presently, there are no methods with proven effectiveness for correction of post-hypoxic disorders in children of mothers with preeclampsia. AIM: To assess the cognitive functions of the offspring of rats with experimental preeclampsia (EP) through early (40th to 70th day of life) and late (24th to 25th month of life) pharmacological correction with gamma aminobutyric acid (GABA) derivatives: Succicard, Salifen, Phenibut, and the drug of comparisonPantogam. MATERIALS AND METHODS: EP was modeled by replacing drinking water with 1.8% sodium chloride solution in rats from the first day of pregnancy to delivery. In the offspring, short-term and long-term memory was studied at the age of 34, 1819, and 2526 months in the Novel object recognition test and Barnes Maze test. The functioning of the GABAergic and dopaminergic systems (which play an essential role in the development of memory) was evaluated by cases of convulsions after administering corazol at a dose of 20 mg/kg intraperitoneally (model of corazol kindling) and by haloperidol-induced catalepsy (haloperidol at a dose of 0.3 mg/kg intraperitoneally), respectively. RESULTS: Early and late pharmacological correction with GABA derivativessuccicard, Salifen, Phenibut, and comparison drug, Pantogamneutralized the negative effect of EP on the function of GABAergic and dopaminergic systems in the offspring of the experimental groups. Therapy with Succicard in puberty and long-term periods of life contributed to the improvement of short-term and long-term memory in the offspring of rats with EP. Thus, it could be reasonable enough to develop a drug against cognitive disorders in children of mothers with preeclampsia. CONCLUSION: In the offspring of rats with EP, short-term and long-term disorders of memory in the functioning of the GABAergic and dopaminergic systems were noted in the early and late stages of the individual development. Pharmacological correction with GABA derivatives improves cognitive processes and the functioning of neurotransmitter systems in the offspring of rats with complicated pregnancy. The highest effectiveness was demonstrated by succicard, and was comparable with or superior to the Pantogam (standard drug).

MOLECULAR DESIGN OF N-ACYL DERIVATIVES OF 2-(2-OXOPYROLIDIN-1-YL)-ACETAMIDE WITH GABA-ERGIC AND GLUTAMATERGIC ACTIVITIES

The first of the most successfully implemented nootropic drugs in medical practice is piracetam, which should be attributed to cyclic derivatives of gamma-aminobutyric acid. The production of new piracetam derivatives with high nootropic activity is a promising direction in the development of new neuroprotective drugs.The aim of the study is to predict GABA-ergic and glutamatergic activities of N-acyl derivatives of 2-(2-oxopyrolidin-1-yl)- acetamide by a molecular docking method through the energy analysis of interaction of modeled structures with GABAA and AMPA receptors with their subsequent targeted synthesis.Materials and methods. The objects of the research are new N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide and a virtual model of the GABAA receptor of the Homo sapiens organism with the identification code 6D6U and a three-dimensional model of the AMPA-receptor of the Rattus norvegicus organism with the identification code 3LSF from the RCSB PDB database. The simulated compounds were designed in the HyperChem 8.0.8 program. This program was also used to optimize geometry using the force field of molecular mechanics MM+. Molecular docking was carried out using the Molegro Virtual Docker 6.0.1 program. The preparation of N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)-acetamide was carried out by the interaction of 2-(2-oxopyrrolidin-1-yl)-acetamide with an excess of the corresponding anhydride under conditions of acid catalysis.Results. Based on the results of molecular docking, a high affinity of all simulated compounds for the binding site of GABAA and AMPA receptors can be estimated. According to the predict, the maximum GABA-ergic activity should be expected for (N-[2-(2-oxopyrrolidin-1-yl)-acetyl]-butyramide. N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide form a more stable complex with amino acid residues Arg207, Phe200, Thr202, Tyr97, Tyr157, Tyr205 and Phe65 of the GABAA receptor binding site than the GABA molecule. In terms of the minimum interaction energy, the N-acyl derivatives of 2-(2-oxopyrrolidin-1-yl)- acetamide are superior to a number of known ligands such as GABA, piracetam, anipiracetam, picamilon and pramiracetam. The tested compounds have also shown a high affinity for the binding site of the AMPA receptor. The leader compound is also the compound PirBut, as in the case of the GABAА receptor.Conclusion. Molecular modeling of the ligands interaction with the active binding site of gamma-aminobutyric acid of the GABAA receptor by molecular docking showed that all virtual N-acyl derivatives of 2-oxo-1-pyrrolidineacetamide can exceed a number of nootropic drugs by activity. In the course of molecular design, a method for predicting a glutamatergic activity for 2-pyrrolidone derivatives has been developed. It suggests a significant nootropic activity for N-[2-(2-oxopyrrolidin-1-yl)- acetamide amides.

EFFECT OF THE GABA DERIVATIVE SUCCICARD ON THE LIPID AND CARBOHYDRATE METABOLISM IN THE OFFSPRING OF RATS WITH EXPERIMENTAL PREECLAMPSIA IN EARLY AND LATE ONTOGENY

Maternal preeclampsia can bring about metabolic disorders in the offspring at different stages of ontogeny. Up to date, no ways of preventive pharmacological correction of lipid and carbohydrate metabolism disorders developing in different periods of ontogeny in the children born to mothers with this pregnancy complication, have been developed.The aim of the experiment was to study the effect of the gamma-aminobutyric acid derivative succicard (22 mg/kg) and its reference drug pantogam (50 mg) administered per os in the course of treatment in puberty (from 40 to 70 days after birth), on the parameters of lipid and carbohydrate metabolism in the offspring of the rats with experimental preeclampsia, in different periods of ontogeny.Materials and methods. To assess the activity of lipid and carbohydrate metabolism in the offspring, an oral glucose tolerance test was performed at 40 days, 3, 6, 12 and 18 months of age. The level of glycosylated hemoglobin was measured at the age of 6, 12, and 18 months, and the concentrations of total cholesterol, high-density lipoprotein cholesterol and triglycerides were tested at 40 days, 3, 6, 12, and 18 months of age.Results. The offspring of the rats with experimental preeclampsia, were found out to have lipid and carbohydrate metabolism disturbances during early (40 days and 3 months of age) and late (6, 12, and 18 months of age) ontogeny. In comparison with the offspring of healthy females, these disturbances were manifested by significantly higher levels of glucose revealed during the oral glucose tolerance test, by high glycosylated hemoglobin in males, and with elevated concentration of total cholesterol and triglycerides and a low level of high-density lipoprotein cholesterol in the negative control rats. Both the gamma-aminobutyric acid derivative succicard and its reference drug pantogam, reduced the negative effect of experimental preeclampsia on lipid and carbohydrate metabolism in the offspring in late ontogeny (6, 12 and 18 months of age). The effectiveness of succicard was either higher or comparable with pantogam.Conclusion. Thus, the negative impact manifestations of experimental preeclampsia on lipid and carbohydrate metabolism, are revealed in the offspring in early (40 days and 3 months) and late (6, 12 and 18 months of age) ontogeny. The gamma-aminobutyric acid derivative succicard reduces the negative effect of experimental preeclampsia. Based on this finding, the drug implies the possibility of the development of a safe and highly effective medicine for preventive correction of lipid and carbohydrate metabolism disorders in the children born to mothers with preeclampsia.

HISTOMORPHOLOGICAL ALTERATIONS IN THE LUNGS IN ACUTE COMBINED BACLOFEN AND ETHANOL POISONING

A generic Baclofen, also known under the brand name of Lioresal, is a derivative of gamma-aminobutyric acid. Due to its psychotropic effect it is often used as a drug of abuse and for criminal poisoning. An experimental study was carried out on 5 Wistar rats (versus 5 intact rats of the control group) exposed to combined Baclofen (at a dose of 85 mg/kg) and ethanol (7 ml/kg of 40% ethanol) poisoning. We have identified a complex of pathological changes in the lungs of the rats in the early period after the experiment. The outcomes included circulatory disorders of the pulmonary microvasculature (plethora of capillaries, venules), emphysema, atelectasis and dystelectasis, infiltration of white blood cells into intraalveolar septa and thickening of intraalveolar septa due to edema. To quantify the severity of histomorphological changes in the lungs a morphometric study is required.

Pregabalin-Induced Myopathy in a Double Lung Transplant Recipient

Pregabalin is a gamma-aminobutyric acid (GABA) derivative that was commercially approved by the Food and Drug Administration (FDA) in 2004. It is commonly used in the treatment of diabetic neuropathy, peripheral neuropathy, and spinal cord injury. We present the case of a 36-year-old Caucasian male double lung transplant recipient who presented with an 18-month history of fatigue and muscle weakness. He had elevated creatinine kinase level and his muscle biopsy showed evidence of drug-induced myopathy that improved after the cessation of pregabalin. We present a case of drug-induced myopathy as a rare complication of pregabalin therapy in a double lung transplant recipient.

Neuroisualization of Pharmaco-EEG Effects of Leutragine by Normalized Cat Brain Electrograms

The central mechanisms of leutragine during inhalational administration were investigated by analyzing normalized brain cat electrograms obtained by the method of Fast Fourier Transform (FFT). According to the conducted pharmaco-electroencephalography (pharmaco-EEG) analysis, Leutragine demonstrates a maximum effect on the parameters of brain electrograms approximately 30 minutes after administration followed by its persistence for about 2 hours. The observed effect is characterized predominantly by a deprimation of all analyzed rhythms compared to the initial values. Normalized brain electrograms (NBE) are less pronounced in the area of the hippocampus, although being more pronounced in the area of the cingulate gyrus and posterior hypothalamus. This may indicate the leucinencephaline regulation of intracentral relations of the brain. The most significant effects obtained in high-frequency β- and γ-rhythms (about 20–25, 40 and 60 Hz) indicate an increase in the γ-activity of interneurons and inhibition of pyramidal cells, which may indicate an anti-anxiety, antidepressant, antiepileptic, analgesic and similar actions of the substance under study. The NBE parameters were found to identical under the action of Leutragine and the derivatives of gamma-aminobutyric acid (glutamine, gabapentin, pregabalin, and phenibut), mainly at frequencies of about 40 and 60 Hz. Similar NBE parameters were obtained under the action of nootropics (semax), which is expressed in the activation of the hippocampus and the hypothalamus posterior at frequencies of about 60–65 Hz. This suggests that the action of Leutragine reflects the mechanisms of GABAergic modulation of the hippocampus and prefrontal neocortex, at the same time as having a positive effect on mental performance, memory consolidation and cognitive function. Leutragine can be used to model and study mechanisms exhibiting a positive effect in the treatment of diseases caused, among other things, by the new coronavirus infection COVID-19.

Conformational Change of Ovalbumin Induced by Surface Cavity Binding of N-Phthaloyl Gamma-Aminobutyric Acid Derivative: a Study Theoretical and Experimental

In this work is reported the study of the interaction between ovalbumin protein (OVA) and N-Phthaloyl gamma-aminobutyric acid derivative (NPG). The ovalbumin is a kind of globular protein present in chicken eggs, as part of serpins globular family proteins present in many biological systems and natural environment; is commonly used in the food industry and the pharmaceutical field as an alternative material for microencapsulation of water-soluble drugs. However, this egg protein has discrete binding sites for ligands as occur in their homologs in mammalian. Association constants and thermodynamic parameters for the interaction of OVA with PNG were determined by linear and 2D fluorescence techniques, zeta-potential, acoustic densimetry, molecular modeling (docking), and molecular dynamics simulations in water as solvent at physiological pH. Fluorescence quenching of the internal fluorophore (tryptophan/tyrosine) in the range of temperature 296.15 K - 308.15 K resulted in values for the association constants of the order of 103 L mol-1, indicating an interaction between the NPG and the albumin. The negative values of ΔG° indicate a spontaneous process; ΔH° is positive indicates an endothermic process of association, and ΔS° is positive, and TΔS° is the dominant term, which shows that the interaction is mainly due to hydrophobic factors, although, other experimental techniques suggest contributions from neutralization charge and hydrogen bonds there is also. The binding of NPG induced changes in OVA protein spatial conformation. The results of fluorescence and acoustic densimetry showed that the interaction promoted the unfolding of protein with a modest increase in the molar partial volume and loss of water molecules. The fluorescence quenching occurs through a static mechanism. Molecular docking and molecular dynamics simulations studies support that NPG can interact with OVA accommodated in a superficial cavity involving hydrophobic forces and hydrogen bonds. The generally accepted criterion about the dependence of Stern-Volmer constant with temperature for a dynamic mechanism is not rigorous and should be handled with caution.

Between Cognitivity and Neuropathies: Neuroimaging of the Effects of GABAergic Modulation of the Hippocampus and Prefrontal Neocortexis by Normalized Brain Electrograms

A comparative analysis conducted across the entire range of normalized brain electrograms (NBE) revealed the selective effect of gamma-aminobutyric acid (GABA) derivatives in the hippocampus and frontal pole of the neocortex. A signifi cant similarity in the level of activation of these brain regions was revealed under the action of glutamine and, particularly, gabapentin. For gabapentin, the activity of the hippocampus is more comparable to that in the anterior suprasilvius gyrus. Under the action of pregabalin, NBE revealed a similarity between the hippocampus and the proreal gyrus, with a more pronounced activity being registered in the range of 1–10 Hz. The NBE activity in the anterior suprasilvian gyrus was lower than that in the proreal gyrus. Under the action of phenibut, the activity of the hippocampus was higher than that of the prefrontal cortex across the 30–40 Hz range; however, under the action of aminalon, this phenomenon was observed for all the analysed rhythms. The predominant effect of GABA derivatives on the high-frequency components of the γ-rhythms of NBE was established. The most pronounced activation effects in γ-rhythms were characteristic of aminalon, while the most pronounced effects of deprimation were characteristic of gabapentin. The overall picture of the γ-rhythm activity was similar under the administration of glutamine, pregabalin and phenibut, as well as being generally close to the background level. The effects of glutamine and pregabalin in the analysis of NBE showed similarities across the frequency ranges of about 40–44 Hz and 60–64 Hz. The effects of pregabalin, gabapentin, and phenibut were similar across the frequency range of about 52–62 Hz. In the high-frequency γ-rhythms, gabapentin, pregabalin and phenibut were characterized by peaks in the range of 44–50 Hz, 40–55 Hz and 35–40 Hz, respectively. Aminalon showed no similarities with other GABA derivatives and was characterized by an extremum in the γ-rhythm at a frequency of about 41 Hz. Using instrumental methods for assessing cognitive behaviour and the mathematical analysis of NBE, the signifi cant role of the intercalary neurons (basket cells) of the hippocampus and prefrontal cortex in the implementation of glutamate and GABA effects was established. It was confi rmed that GABA derivatives function as the main mediator of intercalary neurons in the systemic activity of the brain. The maximum values of NBE under the action of all the GABA derivatives under study coincide with the pharmacodynamic and pharmacokinetic parameters of these drugs. A comparative analysis of the effects of glutamate and all the studied GABA derivatives revealed the greatest similarity of the former with phenibut. Aminalon, being a synthetic analogue of GABA, differs from all other drugs under study by the highest activation of the general level of NBE. The effects of neuroimaging refl ect the properties and nature of the effect of drugs on cognitive functions, intra-centre relations of the brain and higher nervous activity. New mechanisms of the systemic action of GABA derivatives were studied. The obtained results confi rm that the normalized electrographic activity of various parts of the brain can be used to identify certain physiological and pathogenetic mechanisms of the most important functions of the brain and their disorders. Activation of the GABAergic stress-limiting system can be considered as one of the promising methods for the selection of approaches to preventing and treating diseases associated with neurogenic and psychogenic factors.

Recent Uses of Piracetam in Pediatric Neurology.

Abstract Piracetam (2-oxo-1-pyrrolidine acetamide) is a cyclical derivative of GABA (gamma-aminobutyric acid). It was first synthesized during the 1950s by Corneliu E. Giurgea. There are reports of its use for epilepsy in the 1950s. Piracetam can beneficially influence impaired brain function by improving neuronal and cognitive functions without acting as a sedative or stimulant, increasing blood flow and oxygen consumption in the brain and improving the function of the neurotransmitters and brain neurotransmission.