The effect of rifampicin on expression of the toll-like receptor system genes in the forebrain cortex of rats prenatally exposed to alcohol.

Ethanol causes long-term changes in the toll-like receptor (TLR) system, promoting activation of neuroinflammation pathways. Alcohol use during pregnancy causes neuroinflammatory processes in the fetus; this can lead to the development of symptoms of fetal alcohol spectrum disorder (FASD). Our study has shown that prenatal alcohol exposure (PAE) induced long-term changes in the TLR system genes (Tlr3, Tlr4, Ticam, Hmgb1, cytokine genes) in the forebrain cortex of rat pups. Administration of rifampicin (Rif), which can reduce the level of pro-inflammatory mediators in various pathological conditions of the nervous system, normalized the altered expression level of the studied TLR system genes. This suggests that Rif can prevent the development of persistent neuroinflammatory events in the forebrain cortex of rat pups caused by dysregulation in the TLR system.

Prolonged alcohol consumption influences microRNA expression in the nucleus accumbens of the rat brain.

The microRNA (miR) species analyzed in this study are involved in molecular mechanisms of TLR4 and TLR7 signaling, mediating the development of neuroinflammation and neurodegeneration. We have investigated the expression levels of miR-let7b, miR-96, miR-182, miR-155, and the mRNA content of HMGB1, TLR3, TLR4 in the nucleus accumbens (NAc) of the brain of rats exposed to long-term alcoholization. The long-term alcoholization caused a decrease in miR-let7b, miR-96, miR-182, and TLR7 mRNA levels; this was accompanied by an increase in miR-155, TLR4, and Hmgb1 mRNA levels in the NAc of rat brain. TLR7 is functionally linked to miR-let7b. The data of a simultaneous decrease in miR-let7b and TLR7 mRNA are of interest for further studies; they may indicate on the lack of functionally significant links between Hmgb1 and the miR-let7b-TLR7 system in NAc. The existing evidence of a functional relationship between TLR4 with miR-155 and miR-182 and our observations on their expression changes during chronic alcoholization are very interesting and require further investigation. The suggestion about the development of neuroinflammatory process in NAc under prolonged alcohol exposure are relevant for studying the level of TLR gene expression in NAc, as well as the expression of miR species, which may have a functional relationship with the TLR system.

Interleukin-11 in Pathologies of the Nervous System.

The study of the role of cytokines in various pathological conditions of the body is a topical area in modern biomedicine. Understanding the physiological roles played by cytokines will aid in finding applications for them as pharmacological agents in clinical practice. Interleukin 11 (IL-11) was discovered in 1990 in fibrocyte-like bone marrow stromal cells, but there has been increased interest in this cytokine in recent years. IL-11 has been shown to correct inflammatory pathways in the epithelial tissues of the respiratory system, where the main events occur during SARS-CoV-2 infection. Further research in this direction will probably support the use of this cytokine in clinical practice. The cytokine plays a significant role in the central nervous system; local expression by nerve cells has been shown. Studies show the involvement of IL-11 in the mechanisms of development of a number of pathologies of the nervous system, and therefore it seems relevant to generalize and analyze the experimental data obtained in this direction. This review summarizes information that shows the involvement of IL-11 in the mechanisms of development of brain pathologies. In the near future this cytokine will likely find clinical application for the correction of mechanisms that are involved in the formation of pathological conditions of the nervous system.

[Interleukin-11 in Pathologies of the Nervous System].

The study of the role of cytokines in various pathological conditions of the body is a topical area in modern biomedicine. Understanding the physiological roles played by cytokines will aid in finding applications for them as pharmacological agents in clinical practice. Interleukin 11 (IL-11) was discovered in 1990 in fibrocyte-like bone marrow stromal cells, but there has been increased interest in this cytokine in recent years. IL-11 has been shown to correct inflammatory pathways in the epithelial tissues of the respiratory system, where the main events occur during SARS-CoV-2 infection. Further research in this direction will probably support the use of this cytokine in clinical practice. The cytokine plays a significant role in the central nervous system; local expression by nerve cells has been shown. Studies show the involvement of IL-11 in the mechanisms of development of a number of pathologies of the nervous system, and therefore it seems relevant to generalize and analyze the experimental data obtained in this direction. This review summarizes information that shows the involvement of IL-11 in the mechanisms of development of brain pathologies. In the near future this cytokine will likely find clinical application for the correction of mechanisms that are involved in the formation of pathological conditions of the nervous system.

[Ginsenosides affect the system of Toll-like receptors in the brain of rats under conditions of long-term alcohol withdrawal]. / Ginzenozidy vliiaiut na sistemu Toll-podobnykh retseptorov v strukturakh golovnogo mozga krys v usloviiakh otmeny dlitel'noi alkogolizatsii.

Long-term alcohol consumption causes the development of neuroinflammation in various brain structures. One of the mechanisms involved in this process is the increased activity of TLR-signaling intracellular pathways. Studies confirm the ability of ginseng extract or its individual ginsenosides to reduce the increased activity of TLR-signaling pathways. The aim of our study was to study the effect of the amount of ginsenosides obtained from the extract of the Panax japonicus cell line on the state of the TLR-signaling system in the nucleus accumbens and hippocampus of the rat brain in a model of long-term alcohol consumption during alcohol withdrawal. The results of the study showed that ginsenosides were able to make changes in the TLR signaling system, which has been altered by long-term alcohol consumption. A significant effect of ginsenosides on the level of TLR3 and TLR4 mRNA in the nucleus accumbens was found, while in the hippocampus, ginsenosides significantly affected the level of TLR7 mRNA. The effect of ginsenosides on the level of mRNA of transcription factors and cytokines involved in TLR-signaling was evaluated. Thus, results of our study confirm that ginsenosides are able to influence the state of TLR-signaling pathways, but this effect is multidirectional in relation to different brain structures. In the future, it seems interesting to evaluate the role of individual ginsenosides in relation to genes of TLR-signaling, as well as the effect of ginsenosides on other brain structures.

[The effect of rifampicin on the system of Toll-like receptors in the nucleus accumbens of the brain of long-term alcoholized rats during alcohol withdrawal]. / Vliianie rifampitsina na sistemu Toll-podobnykh retseptorov v prilezhashchem iadre mozga dlitel'no alkogolizirovannykh krys v period otmeny alkogolia.

Nucleus accumbens (NAc) is the ventral part of the striatum of the brain; it is an important part of the mesolimbic pathway involved in the reward system that mediates the formation of various forms of addiction, in particular alcohol addiction. Neuroimaging data and in vitro studies indicate the development of a pronounced neurodegenerative process in the NAc, with long-term alcohol use, but the key mechanisms mediating this process remain unknown. In recent years, the attention of researchers has been focused on studying the system of Toll-like receptors (TLRs), the increased activity of which is clearly shown in the cerebral cortex and hippocampus during prolonged alcohol exposure, but there is a need to study the role of this system in other brain structures. In this study, we have shown that prolonged alcohol exposure (2 months) with moderate doses of ethanol (2 g/kg) promotes a pronounced increase in the expression of the Tlr4 gene and its endogenous ligand Hmgb1 in NAc during the period of alcohol withdrawal in rats. Injections of rifampicin (100 mg/kg) reduced the elevated expression level of Hmgb1, Tlr4, as well as pro-inflammatory cytokine genes (IL1ß, IL6), while the administration of the drug increased the reduced level of mRNA of anti-inflammatory cytokines (IL10, IL11).

[Effect of ethanol on platelet biology]. / Vliianie étanola na biologiiu trombotsitov.

In recent years, interest in the study of platelets, significantly increased due to recent discoveries providing convincing evidence that their functions by are not limited to their participation in the blood coagulation mechanism. Many works are devoted to the study of the functional state of platelets under conditions of acute and chronic alcohol exposure. The results of such studies can be useful for the development of new markers of the degree of alcohol intoxication of the body for the subsequent choice of the method drug correction of disorders caused by acute or chronic alcohol effects. The review summarizes results in vivo and in vitro of studies performed during more than 60 years on the effect of ethanol on the biogenesis, number, morphology and biochemistry of platelets.

[Prenatal exposure to alcohol alters TLR4 signaling in the prefrontal cortex in rats]. / Prenatal'noe vozdeistvie alkogolia izmeniaet TLR4-oposredovannuiu signalizatsiiu v prefrontal'noi kore golovnogo mozga u krys.

Prenatal alcohol exposure (PAE) can lead to developmental disorders of the central nervous system (CNS) and mental retardation. Toll-like receptor (TLR) 4 plays an important role in the development of defects in the nervous system caused by PAE. However, how PAE affects the TLR4 response in the brain remains unclear. Using the model of semi-forced alcoholization of pregnant rats, we investigated TLR4-mediated signaling on the 30th day of postnatal development in their offspring. Rats exposed to PAE showed a higher expression of proinflammatory cytokines in the prefrontal cortex, but TLR4-mediated signaling in response to lipopolysaccharide (LPS) was weakened. These data suggest that PAE can lead to neuroinflammation and suppression of the TLR4-mediated response to LPS in the prefrontal cortex of young rats. Since innate immunity plays an important role in brain development, PAE-induced suppression of the TLR4-mediated response may be one of the mechanisms for the development of CNS pathology.

[Increase in the level of orexin receptor 1 (OX1R) mRNA in the brain structures of rats prone to impulsivity in behavior]. / Povyshenie urovnia mRNK retseptora oreksina pervogo tipa (OX1R) v strukturakh golovnogo mozga u krys, sklonnykh k impul'sivnosti v povedenii.

Orexin and its receptors are involved in the mechanisms of pathological craving for alcohol and psychoactive drugs. The orexin system is also involved in the mechanisms of non-chemical forms of addiction: binge eating and gambling. The aim of this work was to study the level of orexin receptor mRNA in the hypothalamus, hippocampus, and prefrontal cortex of rats prone to impulsivity in behavior in a model for studying the elements of gambling addiction (a variant of the Iowa Gambling Task test). Brain structures were isolated on the 22nd day of the experiment. The expression of the OX1R gene was higher in the hypothalamus by 122% and in the hippocampus by 149% in rats that preferred to receive a high reward, but with a low probability as compared with a group of animals that preferred a low level of reinforcement, but with a 100% probability. In the prefrontal cortex, on the contrary, no significant changes were observed in the level of OX1R mRNA. The level of OX2R mRNA insignificantly changed in the hypothalamus, hippocampus, and prefrontal cortex of rats prone to impulsivity in behavior. The data indicate involvement of OX1R in the hypothalamus and hippocampus in mechanisms mediating impulsive behavior and the choice of the significance of positive reinforcement in terms of its varying strength and probability.

[The TLR3 induction increases content of interferons in rat's brain by TRAIL signaling during long-term alcoholization]. / Induktsiia TLR3 pri dlitel'noi alkogolizatsii uvelichivaet soderzhanie interferonov v golovnom mozge u krys posredstvom TRAIL-signalizatsii.

The pathogenetic mechanisms associated with alcohol use include dysregulation of the innate immune system mechanisms in the brain. TLR3 expression is increased in the postmortem material of the prefrontal cortex of humans. An increase in the TLR3 signaling activity leads to the induction of interferons (IFN). IFN are associated with depressive symptoms and, therefore, may play a role in the pathogenesis of alcoholism; however, the exact mechanisms of intracellular signaling mediated by the influence of ethanol are not fully elucidated and their study was the purpose of this work. The experimental results showed that ethanol and the TLR3 agonist Poly (I:C) increased the content of TLR3, IFNß, and IFNγ mRNA in the prefrontal cortex. In addition, expression of the TRAIL encoding gene also increased, and this increase positively correlaed with the mRNA content of TLR3, IFNß and IFNγ both under alcoholization conditions and after injections of the TLR3 agonist. The data obtained may indicate that alcoholization is able to activate TLR3-TRAIL-IFN-signaling in the prefrontal cortex of the brain.

[Expression of Ghrelin Receptor GHS-R1a in The Brain (Mini Review)].

The review presents data on the expression of ghrelin receptor GHS-R1a in the brain in model animals (Danio rerio, rodents, primates), and in the human brain. Studies show widespread localization of GHS-R1a in the brain, which indicates the involvement of the receptor in many physiological processes. Using various models, information has been obtained regarding the participation of the receptor in the regulation of the pro- and anti-inflammatory response, apoptosis and proliferation. It is known that the ghrelin receptor plays an important role in eating behavior and is also involved in the pathogenetic mechanisms of obesity, drug addiction, and alcoholism. With this in mind, research is underway with the use of various therapeutic agents (receptor agonists and antagonists) that can be used for the pharmacological correction of these pathological conditions. This review also presents hypothetical mechanisms of intracellular signaling, in which GHS-R1a may participate; however, a complete understanding of these mechanisms has not yet been reached. The ghrelin intracellular pathways seem to be specific to brain region and, probably, also depend on the metabolic or stress status of the organism.

[HMGB1gene expression changes in the striatum and amigdal of the rat's brain under alcoholization and ethanol withdrawal]. / Ékspressiia gena HMGB1 izmeniaetsia v striatume i amigdale mozga krys pri dlitel'noi alkogolizatsii i otmene étanola.

Intracellular signaling mediated by the HMGB1 protein, an agonist of TLRs, is considered as a possible target for the correction of pathologies of the neuroimmune system, however, the expression level of the Hmgb1 gene has not been previously studied in various brain structures of rats exposed to prolonged alcoholization followed by ethanol withdrawal. The study showed that long-term use of ethanol caused to an increase in the level of Hmgb1 mRNA in the striatum of rat brain. Alcohol withdrawal changed the level Hmgb1 mRNA in the striatum and amygdala on the 1st and 14th day. The data obtained may indicate that in different structures of the brain there are multidirectional changes in the molecular mechanisms of the neuroimmune response with prolonged use of ethanol and its withdrawal.

[Ethanol induced increase of fibroblast growth factor 2 mRNA content in emotiogenic brain structures of rats]. / Étanol sposobstvuet uvelicheniiu soderzhaniia mRNK faktora rosta fibroblastov-2 v émotsiogennykh strukturakh mozga u krys.

We studied the effects of acute, subacute, and chronic alcohol treatment of rats on the content of fibroblast growth factor 2 (FGF2) mRNA in various brain structures. Results suggest a possible role of FGF2 in the functioning of dopaminergic neurons in the midbrain. In our experiment, ethanol treatment of rats was accompanied by an increase in the FGF2 mRNA level in the emotiogenic structures of the brain. This effect was blocked by pretreatment of animals with chlorpromazine. This suggests FGF2 involvement in the mechanisms of alcohol dependence and can be considered as a possible diagnostic and therapeutic target in alcoholism.

[Molecular mechanisms of the cytoprotector cramizol effect in the experimental dyslipidemia model]. / Molekuliarnye mekhanizmy gipolipidemicheskogo deistviia tsitoprotektora kramizola pri éksperimental'noi dislipidemii.

The tested drug cramizol exhibits lipid-lowering and anti-atherogenic effects. Cramizol reduces blood cholesterol and triglycerides. It also increases HDL and reduces the atherogenic index in rats with the chronic dyslipidemia model induced by a hypercholesterol diet. Cramizol is effective as a hypolipidemic agent and its efficiency is comparable with the reference drug, phenofibrate. Cramizol increases expression of the ApoA1 and ApoC2 genes, and also reduces expression of the Scarb1 gene in rats with experimentally induced hyperlipidemia. These mechanisms could be the basis of its hypolipidemic and anti-atherogenic actions.

[Involvement of TOLL-like receptors in the neuroimmunology of alcoholism]. / Rol' TOLL-podobnykh retseptorov v neiroimmunologii alkogolizma.

Alcohol use is a global socially significant problem that remains one of the leading risk factors for disability and premature death. One of the main pathological characteristics of alcoholism is the loss of cognitive control over the amount of consumed alcohol. Growing body of evidence suggests that alterations of neuroimmune communication occurring in the brain during prolonged alcoholization are one of the main mechanisms responsible for the development of this pathology. Ethanol consumption leads to activation of neuroimmune signaling in the central nervous system through many types of Toll-like receptors (TLRs), as well as the release of their endogenous agonists (HMGB1 protein, S100 protein, heat shock proteins, extracellular matrix breakdown proteins). Activation of TLRs triggers intracellular molecular cascades leading to increased expression of the innate immune system genes, particularly proinflammatory cytokines, subsequently causing the development of a persistent neuroinflammatory process in the central nervous system, which results in massive death of neurons and glial cells in the brain structures, which are primarily associated with the development of a pathological craving for alcohol. In addition, some subtypes of TLRs are capable of forming heterodimers with neuropeptide receptors (corticoliberin, orexin, ghrelin receptors), and may also have other functional relationships.

Catalytic Subunit of PKA as a Prototype of the Eukaryotic Protein Kinase Family.

The catalytic subunit of protein kinase A (PKAc) is conserved in all eukaryotic protein kinases. PKAc consists of two lobes that form the catalytic cleft containing the ATP-binding, peptide-binding site, and catalytic sites. During folding, PKAc secondary structures organize so that the non-polar regions form a globular core, while mobile loops and tails are exposed and can act as regulatory elements. De novo synthesized PKAc is phosphorylated at the T-loop, resulting in the formation of the active center capable of high-affinity binding of co-substrates. The ATP-molecule "sticks" the two lobes together, whereas the binding of peptide substrate completes the active center formation. The resulting catalytic triad (γ-phosphate of ATP, hydroxyl of Ser/Thr residue of the protein substrate, and Asp166 carboxyl) occupies a position optimal for catalysis. During the catalytic cycle, dynamic reorganization of polar and hydrophobic interactions ensures PKAc transition from the open to the closed conformation and vice versa. Understanding the structural basis of functioning of eukaryotic protein kinases (ePKs) is essential for successful design of ePK modulators.

[Effect of etimizole structural analogues on protein kinase CK2, protein phosphorylation and transcription of chromatin in rat brain cortex and hippocampus]. / Vliianie strukturnykh analogov étimizola na proteinkinazu SK2, fosforilirovanie belkov i transkriptsiiu khromatina neironov kory i gippokampa mozga krys.

Protein kinase CK2 is an important enzyme in the nervous system. The nuclear forms of CK2 regulate chromatin structure and gene expression, the key processes for long-term memory formation. Memory modulators, the Structural Analogues of Etimizole (SAE), were able to increase or decrease the activity of chromatin-associated CK in the cortex and hippocampus of rat brain in vitro. In vivo memory enhancers from SAE-group (3 mg/kg) stimulated CK2 activity and the transcriptional ability of chromatin in the cortex and hippocampus, starting from 30 min with a peak for 60 min and a duration up to 180 min. At these periods the memory inhibitor from the SAE-group reduced CK2 activity and chromatin transcription. It is assumed that the modulating effect of SAE on CK2 activity and transcription underlies the effects of these compounds on long-term memory.

[The time course of changes in the state of monoaminergic systems in the brain of mice under the acute hypoxia with hypercapnia]. / Dinamika izmenenii sostoianiia monoaminergicheskikh sistem golovnogo mozga myshei pod vliianiem ostroi gipoksii s giperkapniei.

In socially isolated male outbred albino mice, the changes of monoaminergic systems under acute hypoxia with hypercapnia were studied. In cerebral cortex, hippocampus and striatum of the right and left sides of the brain, the concentrations of norepinephrine, dopamine, serotonin and their metabolites - dihydroxyphenylacetic, homovanillic and 5-hydroxyindoleacetic acids were investigated using the HPLC method. In isolated mice, which were not subjected to hypoxia with hypercapnia, higher levels of dopamine and serotonin in the left cortex were found. There was no asymmetry in monoamines and their metabolites in other studied brain structures. 10 min after the onset of exposure, acute hypoxia with hypercapnia resulted in a right-sided increase in norepinephrine levels and a decrease in dopamine levels in the striatum and serotonin levels in the hippocampus. In the cerebral cortex, 10 min after of hypoxic exposure beginning, there was a left-sided decrease in the dopamine content, while the original asymmetry found in the cortex of intact animals disappeared. In isolated mice perished of hypoxia with hypercapnia, almost all parameters returned to the control level. The exception was the ratio of serotonin metabolite level to the neurotransmitter, which in the right cortex became lower than in control animals. In white outbred mice, the brain monoaminergic systems are suggested to be relatively resistant to the negative consequences of hypoxia and hypercapnia, and corresponding shifts resulting in the reflex brain response to changes in the gas composition of the respiratory air.

Effect of Surfagon on Open Field and Elevated Plus Maze Behavior of Gonadectomized and Non-Gonadectomized Male Rats.

We studied the effect of gonadotropin-releasing hormone agonist surfagon (2 µg/kg, once, intraperitoneally) on anxious behavior of adult gonadectomized and non-gonadectomized male rats. It was shown that surfagon significantly increased anxiety of both gonadectomized and non-gonadectomized rats in the open-field test and in elevated plus maze.

[Alcoholization and ethanol withdrawal leads to the activation of neuroimmune response in the prefrontal rat brain]. / Alkogolizatsiia i otmena étanola privodiat k aktivatsii neiroimmunnogo otveta v prefrontal'noi kore mozga krys.

The effects of acute (single) and chronic ethanol administration on the level of pro-inflammatory cytokines (IL-1ß and TNF-α), as well as on the level of mRNA NF-κB, TLR4 and its endogenous agonist, HMGB1 protein, were investigated in rats. It was shown that the level of TLR4, HMGB1 and cytokines was significantly higher than in control group. The ethanol withdrawal after prolonged administration resulted in dysregulation of cytokine levels, TLR4 and HMGB1. Changes in the level of TLR4 and HMGB1 mRNA demonstrated a similar pattern. The obtained data confirm that prolonged alcoholization leads to the activation of TLR4-dependent signaling in the prefrontal cortex of rats, and this can lead to a prolonged neuro-inflammatory process in the brain.