Objective. To study the effects of the adamantane derivative hemantane on the bioelectrical activity of mouse brain structures at the early and late (advanced) stages of an experimental model of Parkinson’s disease (PD). Materials and methods. PD was modeled experimentally in C57BL/6J mice using 30 males weighing 25–32 g given systemic (i.p.) proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using two regimens corresponding to different clinical stages of the disease: four doses of MPTP at doses of 12 and 20 mg/kg with intervals of 2 h. Results. The early and late clinical stages of the experimental model of PD showed EEG desynchronization, increases in wave amplitude, and increases in the power spectrum in the δ and β frequency ranges at the late symptomatic stage of experimental PD, along with a decrease in bioelectrical activity in the 4–12 Hz range in the brain structures of mice (sensorimotor cortex, substantia nigra, and caudate nucleus). Prior use of hemantane at a dose of 20 mg/kg at both the early and late clinical stages of PD prevented excessive increases in the amplitudes of all wave groups, normalized θ activity in the 4–12 Hz range, and reduced pathological slowing and dysregulated activity in the δ and β wave ranges, these effects being dominant in the substantia nigra of the brain. Conclusions. The effects of hemantane were more marked at the initial clinical stage of the experiment model of PD than at the late (advanced) stage.

Parkinsonism in rats induced by the pesticide rotenone is one of the most adequate models of Parkinson's disease (PD). Isatin (indole-2,3-dione) is an endogenous regulator found in mammals and humans and exhibiting a wide range of biological activities mediated by numerous isatin-binding proteins, including those associated with neurodegenerative pathology. A course of rotenone administration to rats caused behavioral impairments and changes in the profile and relative content of isatin-binding proteins in the brain. In this study, we have investigated the delayed neuroprotective effect of isatin (5 days after completion of the course of rotenone administration) on behavioral reactions and the relative content of isatin-binding proteins in the brain of rats with rotenone-induced experimental parkinsonism. Although during this period the rats retained locomotor dysfunction, the proteomic analysis data (profile of isatin-binding proteins in the brain and changes in their relative content) differed from the results obtained immediately after completion of the course of rotenone administration. Moreover, all isatin-binding proteins with altered relative content changed during this period are associated to varying degrees with neurodegeneration (many with Parkinson's and Alzheimer's diseases).

Isatin (indoldione-2,3) is an endogenous biological regulator found in the brain, peripheral tissues, and biological fluids of humans and animals. Its biological activity is realized via isatin-binding proteins, many of which were identified during proteomic profiling of the brain of mice and rats. A number of these proteins are related to the development of neurodegenerative diseases. Previously, using a model of experimental Parkinsonism induced by a seven-day course of rotenone injections, we have observed behavioral disturbances, as well as changes in the profile and relative content of brain isatin-binding proteins. In this study, we have investigated behavioral responses and the relative content of brain isatin-binding proteins in rats with rotenone-induced Parkinsonism 5 days after the last administration of this neurotoxin. Despite the elimination of rotenone, animals exhibited motor and coordination impairments. Proteomic profiling of isatin-binding proteins revealed changes in the relative content of 120 proteins (the relative content of 83 proteins increased and that of 37 proteins decreased). Comparison of isatin-binding proteins characterized by the changes in the relative content observed in the brain right after the last injection of rotenone (n=16) and 5 days later (n=11) revealed only two common proteins (glyceraldehyde-3-phosphate dehydrogenase and subunit B of V-type proton ATPase). However, most of these proteins are associated with neurodegeneration, including Parkinson's and Alzheimer's diseases.

Relevance. The complexity of diagnosing and treating autism spectrum disorders (ASD) is attributed to their unknown etiology and pathophysiology. The investigation of ASD models induced by sodium valproate (VPA) holds significant importance in the development of effective pharmacological interventions for this disorder.Objective. The aim of the study was to assess the impact of prenatal and postnatal exposure to VPA on the development of autism-like behavior in Wistar rats for further selection of appropriate therapeutic interventions.Methods. Offspring of Wistar rats were exposed to VPA on the 12.5th day of prenatal development or postnatally on the 14th day. Evaluation included assessment of social behavior, anxiety, working memory, species-typical defensive behavior, exploratory, and locomotor activity.Results. Prenatal VPA exposure led to reduced social interaction, increased anxiety, disruption of species-typical defensive behavior, and decreased locomotor activity in male rats. Female rats prenatally exposed to VPA exhibited social deficits, increased anxiety, hypolocomotion, and cognitive impairments, albeit without displaying aversive odor preference. Postnatal VPA exposure in male and female rats did not significantly alter social interaction and species-typical defensive behavior; however, animals exhibited reduced locomotor activity. Postnatally VPA-exposed female rats demonstrated worsened working memory and decreased exploratory behavior.Conclusion. Both prenatal and postnatal exposure to VPA elicits behavioral disturbances resembling ASD, with gender-specific nuances, which may guide the direction of pharmacological interventions for the disorder.

Abstract—The study of the status of norepinephrine-, dopamine- and serotonergic neurotransmitter systems of BALB/C mice brain structures on 15 and 64 days of postnatal development (PD) in the model of autistic disturbances induced by injection of sodium valproate (SV, 400 mg/kg , s/c) to pregnant females was carried out using the HPLC/ED method. The level of both catechol- and indolamines in the brain structures of control mice at the age of 15 days was significantly lower than in adult animals at the age of 64 days. Prenatal administration of SV caused a decrease in all parameters of monoaminergic neurotransmission in the striatum of offspring at the age of 15 days but had no effect in other brain structures studied. Subsequently, the level of dopamine increased and by the 64th day of PD did not differ from the parameters of the control group. The parameters of the serotonergic system changed in a similar pattern, with the content of serotonin and the serotonin metabolite 5-OIAA in the striatum increasing gradually and reaching maximum values by the 64th day of PD. Our data allows to assume that the administration of SV to pregnant females affects the activity of the dopamine and serotonergic systems of the brain of the offspring causing a decrease in their activity in the striatum by the 15th day of PD followed by restoration to control values by the 64th day, which we previously observed in male pups. Thus, the patterns of dynamic changes in the neurochemical profile do not differ between males and females.

Relevance. Autism spectrum disorder (ASD) is a developmental disorder of the brain with unclear etiology and pathophysiology, characterized by impaired social communication, stereotypic or repetitive behavior, and varying degrees of mental retardation. One of the environmental factors that have an adverse effect on pregnant women and embryo development is propionic acid (PPA), which is a secondary metabolite of the intestinal microbiota and is widely used as a food preservative. Under physiological conditions, PPC modulates cellular signal transduction, neurotransmitter synthesis and release, cellular interactions, gene expression, immune function, and affects mitochondrial and lipid metabolism. Excessive exposure to PPC can have a number of negative consequences on health and behavior, including leading to the development of ASD.The aim of present research was to assess behavioral characteristics in male and female Wistar rats with ASD caused by prenatal administration of sodium salt of propionic acid at the early perinatal and juvenile stages of development.Methods. In a model of ASD induced by prenatal administration of propionic acid at a dose of 500 mg/kg, subcutaneously on days 12–16 of gestation, behavior was assessed in the “nesting” and juvenile periods of life in male and female Wistar rats. Physical and neurological development, social behavior (“Maternal scent”, “Paired test”), repetitive behavior (Y-maze, “Auto-grooming”), motor and exploratory activity (“Mink test”) were assessed.Results. In Wistar rats prenatally treated with propionic acid, there was a slowdown in the formation of a number of reflexes at the stage of early postnatal development, and at a later stage – a decrease in social behavior, increased stereotypy and aggression, hyperlocomotion and low exploratory activity.Conclusion. The ASD model induced by prenatal administration of PPC is adequate and suitable for studying means of pharmacological correction of ASD.

На мышах изучено антипаркинсоническое действие нового соединения дигидро-хлорида 5-этокси-2-{2-[N-адамантант-1-ил-N-метил)амино]-этилтио}бензимидазола (АДК-1113). АДК-1113 в дозах 5, 10 и 20 мг/кг уменьшает продолжительность вызванного галоперидолом (1 мг/кг), каталептогенного состояния у аутбредных мышей, снижает ригидность и олигокинезию у мышей линии C57Bl/6 с модулируемым пронейротоксином 1-метил-4-фенил-1,2,3,6-тетрагидропиридином (МФТП) паркинсоническим синдромом.

Проведена оценка влияния фабомотизола (10 мг/кг ежедневно внутрь с 6 по 14 день постнатального развития) на физическое и неврологическое развитие самцов и самок мышей линии BALB/c в серии тестов: «Переворот на плоскости», «Отрицательный геотаксис», «Избегание обрыва», «Переворот в воздухе», изучение силы передних конечностей в тесте «Веревочка», «Вздрагивание на хлопок». Мышей также ежедневно взвешивали, отмечали сроки прозревания глаз и формирования ушного рефлекса. В результате проведенного исследования установлено, что фабомотизол при субхроническом введении в ранний постнатальный период не оказывает негативного влияния на физиологическое развитие как самцов, так и самок мышей BALB/c: не влияет на прирост массы тела, сроки и скорость формирования базовых рефлексов, мышечную силу, сроки прозревания.

Isatin (indoldione-2,3) is an endogenous regulator found in humans and animals. It exhibits a broad range of biological activity mediated by numerous isatin-binding proteins. Isatin produces neuroprotective effects in several experimental models of diseases, including Parkinsonism induced by the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).Rotenone (a neurotoxin used to modeling Parkinson's disease in rodents) causes significant changes in the profile of isatin-binding proteins of rat brain. Comparative proteomic identification of brain proteins of control rats and the rats with the rotenone-induced Parkinsonian syndrome (PS) revealed significant quantitative changes of 86 proteins under the influence of rotenone. This neurotoxin mainly caused the increase of the quantity of proteins involved in signal transduction and regulation of enzyme activity (24), proteins involved in cytoskeleton formation and exocytosis (23), and enzymes involved in energy generation and carbohydrate metabolism (19). However, only 11 of these proteins referred to isatin-binding proteins; the content of eight of them increased while the content of three proteins decreased. This suggests that the dramatic change of the profile of isatin-binding proteins, found in the development of the rotenone-induced PS, comes from changes in the state of the pre-existing molecules of proteins, rather than altered expression of corresponding genes.

We studied the effects of oral administration of Afobazole in a dose of 10 mg/kg for 5 days on depressive-like behavior of male C57BL/6 mice in the tail suspension test in comparison with amitriptyline (10 mg/kg) or fluoxetine (20 mg/kg) treatment. Afobazole produced an antidepressant effect similar to amitriptyline, but inferior to fluoxetine. The σ1 receptor antagonist BD-1047 in a dose of 5 mg/kg blocked the antidepressant effect of Afobazole, which indicates the involvement of σ1 receptors in the antidepressant effect of the drug.

The neurotoxins rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (МPTP) are used for modeling Parkinson's disease in animals (PD). They induce the mitochondrial respiratory chain dysfunction, which leads to the dopaminergic (DA) neuron degeneration. The advantage of the rotenone model consists in ability of rotenone to cause neurodegeneration showing symptoms and molecular biological characteristics similar to those of PD. Isatin (indoldione-2,3) is an endogenous regulator found in tissues and biological fluids of humans and animals. It exhibits a broad range of biological activity mediated by numerous isatin-binding proteins. In this work we have investigated behavioral reactions and profiles of brain isatin-binding proteins of rats with Parkinson's syndrome (PS) in comparison with the corresponding parameters of MPTP-induced Parkinsonism in mice. Systemic injection of rotenone caused severe PS comparable with the effect of MPTP injection. It was accompanied by significant body weight loss, death, oligokinesia, muscular rigidity, and postural instability of animals. In spite of the same pathogenic basis of PS caused by rotenone and MPTP, the molecular mechanisms of their action differ. In the case of rotenone-induced PS, the pool of isatin-binding proteins common of the control rats and the rats with PS (146) significantly exceeded the pool of the common proteins of control mice and mice with PS induced by MPTP, whether right after neurotoxin injection (27), or (all the more) in a week after the MPTP injection (14). The comparison of isatin-binding proteins specific of the animals with MPTP-induced PS and with the rotenone-induced PS (as compared with the control animals) revealed total absence of proteins common of these two models of PD. It is to be noted that both neurotoxins particularly affected the proteins participating in the signal transmission and enzyme activity regulation. The changes of the profile of isatin-binding proteins in response to the injection of rotenone suggest that the neuroprotector isatin could also influence positively in the case of the rotenone model of PD.

На мышах изучено антипаркинсоническое действие нового соединения дигидро-хлорида 5-этокси-2-{2-[N-адамантант-1-ил-N-метил)амино]-этилтио}бензимидазола (АДК-1113). АДК-1113 в дозах 5, 10 и 20 мг/кг уменьшает продолжительность вызванного галоперидолом (1 мг/кг), каталептогенного состояния у аутбредных мышей, снижает ригидность и олигокинезию у мышей линии C57Bl/6 с модулируемым пронейротоксином 1-метил-4-фенил-1,2,3,6-тетрагидропиридином (МФТП) паркинсоническим синдромом.

Effects of the endogenous neuroprotector isatin and the pharmacological drug afobazole (exhibiting neuroprotective properties) on behavioral reactions and quantitative changes in the brain proteomic profile have been investigated in rats with experimental rotenone Parkinsonism. A single dose of isatin (100 mg/kg subcutaneously on the last day of a 7-day course of rotenone administration) improved the motor activity of rats with rotenone-induced Parkinsonism in the open field test (horizontal movements) and the rotating rod test. Afobazole (10 mg/kg intraperitoneally, daily during the 7-day course of rotenone administration) reduced the manifestations of rigidity and postural instability. Proteomic analysis, performed using brain samples obtained the day after the last administration of rotenone and neuroprotectors, revealed similar quantitative changes in the brain of rats with rotenone Parkinsonism. An increase in the relative content of 65 proteins and a decrease in the relative content of 21 proteins were detected. The most pronounced changes - an almost ninety-fold increase in the alpha-synuclein content - were found in the brains of rats treated with isatin. In animals of the experimental groups treated with "Rotenone + Isatin", as well as "Rotenone + Afobazole", the increase in the relative content of this protein in the brain was almost 60 and 50 times higher than the control values. Taking into consideration the known data on the physiological role of alpha-synuclein, an increase in the content of this protein in the brain upon administration of neuroprotectors to animals with rotenone Parkinsonism may represent a compensatory reaction, at least in the early stages of this disease and the beginning of its treatment.

Расстройства аутистического спектра (РАС) – расстройство развития нервной системы, характеризующееся, наряду с нарушением социального общения, стереотипным или повторяющимся поведением и умственной отсталостью разной степени, а также чрезмерной пролиферацией глии, нейровоспалением, нарушением нейронной сети, желудочно-кишечными симптомами и др. Считается, что РАС является результатом взаимодействия генетической предрасположенности, неблагоприятных воздействий окружающей среды и нарушений иммунной системы матери в ранний период беременности. Определенную роль в развитии РАС играет и дисбиоз кишечника. У пациентов с РАС отмечается сдвиг в микробиоме по сравнению с нейротипичными сверстниками, что сопровождается повышенным уровнем кишечных микроорганизмов Clostridia spp., Bacteriodetes и Desulfovibrio spp., являющихся активными ферментаторами пищевых углеводов и волокон, и приводит к образованию побочных продуктов энергетического обмена, таких как ацетат, бутират и в большей степени пропионовая кислота (ППК). ППК также широко используется в качестве консерванта в пищевых продуктах. ППК легко проходит через ГЭБ, модулируя в норме многочисленные клеточные сигнальные процессы, включая энергетический метаболизм, синтез и высвобождение нейромедиаторов, и липидный метаболизм. Чрезмерный уровень ППК токсичен. ППК вызывает системную митохондриальную дисфункцию, о чем свидетельствует увеличение количества свободного ацил-карнитина и нарушение метаболизма жирных кислот у крыс в эксперименте и более чем у 30% пациентов с РАС. Показано, что изменение микробиома в кишечнике матери во время беременности (повышенное потребление обработанных пищевых продуктов, богатых ППК, в сочетании с уже существующим дисбактериозом) может привести к накоплению ППК в ЖКТ, способной проходить через плацентарный барьер и усиливать пролиферацию и выживание глиальных клеток-предшественников и воспалительный профиль, вызывая нарушение формирования нейронных структур на ранних стадиях развития плода, и влиять на взрослый организм. В данном обзоре проведен анализ механизмов воздействия ППК на нервную систему и связь с возникновением РАС, а также представлены результаты доклинических исследований, подтверждающих данную связь и способы моделирования РАС. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized, along with impaired social communication, stereotypic or repetitive behavior and varying degrees of mental retardation, as well as excessive glial proliferation, neuroinflammation, neural network disruption, gastrointestinal symptoms, etc. It is considered that ASD is the result of the interaction of genetic predisposition, adverse environmental influences and disorders of the maternal immune system in early pregnancy. Intestinal dysbiosis also plays a certain role in the development of ASD. Patients with ASD exhibit a shift in the microbiome compared to neurotypical peers, which is accompanied by increased levels of intestinal microorganisms Clostridia spp., Bacteriodetes and Desulfovibrio spp., which are active fermenters of dietary carbohydrates and fiber, and leads to the formation of energy metabolic by-products such as acetate, butyrate and, to a greater extent, propionic acid (PPA). PPA is also widely used as a preservative in foods. PPA readily crosses the BBB, normally modulating numerous cellular signaling processes, including energy metabolism, neurotransmitter synthesis and release, and lipid metabolism. Excessive levels of PPA are toxic. PPA causes systematic mitochondrial dysfunction, as evidenced by increased levels of free acyl-carnitine and impaired fatty acid metabolism in experimental rats and in more than 30% of patients with ASD. It has been shown that changes in the microbiome in the maternal intestine during pregnancy (increased consumption of processed foods rich in PPA, combined with pre-existing dysbiosis) can lead to the accumulation of PPA in the gastrointestinal tract, which can pass through the placental barrier and enhance the proliferation and survival of glial progenitor cells and inflammatory profile, causing disruption of the formation of neural structures in the early stages of fetal development and affecting the adult body. This review provides an analysis of the mechanisms of the effect of PPA on the nervous system and the connection with the occurrence of ASD, and also presents the results of preclinical studies confirming this connection and methods for modeling ASD.

The study was conducted on a model of fetal valproate syndrome(FVS) induced by a single subcutaneous administration of sodiumvalproate (VPA, 400 mg/kg) to BALB/c mice on day 12.5 of gestation.Young sexually mature mice (postnatal days 52–62 days) with FVSexhibited decreased social interaction, especially pronounced infemales, reduced preference for exploring a novel social object(social novelty) in males, impaired nesting behavior as manifestedin the reduced number of completed nests in both males and females,and decreased defensive behavior upon presentation of predator odor,more pronounced in females. Intragastric administration of afobazole(10 mg/kg, daily) during the period from the early postnatal perioduntil puberty (postnatal days 7–62) leveled most of the social behaviordisorders elicited by prenatal high-dose VPA administration, asmanifested in unchanged (males) or improved (females) behavioral parameterscompared to the control group in the social interaction test, increasedresponsiveness to social novelty in male BALB/c mice with FVS upto control values, improved species activity aimed at ensuring thermoregulationand reproduction, namely ideal nest building and increased predatorodor avoidance in both sexes. The obtained data indicate that afobazole,in the BALB/c mouse model of FVS, promotes the reduction in socialbehavior disorders, specifically, improves the behavior directedat procreation and offspring protection.