Effect of rifampicin on TLR4-signaling pathways in the nucleus accumbens of the rat brain during abstinence of long-term alcohol treatment.

AIMS: The treatment with the antibiotic rifampicin (Rif) led to a decrease in the frequency of neurodegenerative pathologies. There are suggestions that the mechanism of action of Rif may be mediated by its effect on toll-like receptor (TLR)4-dependent pathways. We evaluated the expression status of TLR4-dependent genes during abstinence from long-term alcohol treatments in the nucleus accumbens (NAc) of the rat brain, and also studied the effects of Rif to correct these changes. METHODS: The long-term alcohol treatment was performed by intragastric delivery of ethanol solution. At the end of alcohol treatment intraperitoneal injections of Rif (100 mg/kg) or saline were made. Extraction of the brain structures was performed on the 10th day of abstinence from alcohol. We used the SYBR Green qPCR method to quantitatively analyze the relative expression levels of the studied genes. RESULTS: The long-term alcohol treatment promotes an increase in the level of TLR4 mRNA and mRNA of its endogenous ligand high-mobility group protein B1 during abstinence drop alcohol in NAc of rats. The use of Rif in our study led to a decrease in the increased expression of high-mobility group protein B1, Tlr4, and proinflammatory cytokine genes (Il1ß, Il6) in the NAc of the rat brain during abstinence of long-term alcohol treatment. In addition, Rif administration increased the decreased mRNA levels of anti-inflammatory cytokines (Il10, Il11). CONCLUSION: The data obtained indicate the ability of Rif to correct the mechanisms of the TLR4 system genes in the NAc of the rat brain during alcohol abstinence.

A brief summary regarding the roles of interleukin-11 in neurological diseases.

Interleukin 11 (IL-11) was discovered in 1990 in fibrocyte-like stromal cells of the bone marrow, but there has recently been an increased interest in the cytokine. Understanding the physiological roles of cytokines will allow their use as pharmacological agents in clinical practice. Studies have indicated that IL-11 affects the mechanism for the development of a number of pathologies of the nervous system. IL-11 plays a significant role in the central nervous system. The local expression of this cytokine by nerve cells has been observed. The current work summarizes the results of studies which found that the cytokine affects the mechanism of development of pathologies of the central nervous system. In the near future, this cytokine may be used clinically to fix the mechanisms that are involved in the development of pathological conditions of the nervous system.

Expression of the growth hormone secretagogue receptor 1a (GHS-R1a) in the brain.

The review presents data on the expression of growth hormone secretagogue receptor 1a (GHS-R1a) in the brain regions in model animals (zebrafish, rodents, primates), and in the human brain. Studies show widespread distribution of the receptor in the brain, which evidences the involvement of the receptor in many physiological processes. Using various organisms, data have been obtained regarding the participation of the GHS-R1a in the regulation of the anti- and pro-inflammatory response, proliferation, and apoptosis. It is known that the receptor plays an important role in eating behavior and is also involved in the pathogenetic mechanisms of drug addiction, obesity, and chronic alcohol consumption. Based on this, research is underway with the use of various therapeutic agents that can be used for the pharmacological correction of these conditions. This review also presents hypothetical pathways of intracellular signaling, in which GHS-R1a may participate. A complete understanding of these mechanisms has not yet been reached. The ghrelin intracellular signaling seem to be specific to brain region and, probably, also depend on the metabolic or stress status of the organism.

The role of Toll-like receptors in neurobiology of alcoholism.

Alcoholism is a global socially significant problem and still remains one of the leading causes of disability and premature death. One of the main signs of the disease is the loss of cognitive control over the amount of alcohol consumed. Among the mechanisms of the development of this pathology, changes in neuroimmune mechanisms occurring in the brain during prolonged alcohol consumption and its withdrawal have recently become the focus of numerous studies. Ethanol consumption leads to the activation of neuroimmune signaling in the central nervous system through many subtypes of Toll-like receptors (TLRs), as well as release of their endogenous agonists (high-mobility group protein B1 (HMGB1), S100 protein, heat shock proteins (HSPs), and extracellular matrix degradation proteins). TLR activation triggers intracellular molecular cascades of reactions leading to increased expression of genes of the innate immune system, particularly, proinflammatory cytokines, causing further development of a persistent neuroinflammatory process in the central nervous system. This leads to death of neurons and neuroglial cells in various brain structures, primarily in those associated with the development of a pathological craving for alcohol. In addition, there is evidence that some subtypes of TLRs (TLR3, TLR4) are able to form heterodimers with neuropeptide receptors, thereby possibly playing other roles in the central nervous system, in addition to participating in the activation of the innate immune system.