[Contents of BDNF, miR-30a-5p and miR-122 during alcohol withdrawal syndrome]. / Uroven' BDNF, miR-30a-5p i miR-122 v syvorotke krovi v dinamike sindroma otmeny alkogolia.

Some BDNF (brain-derived neurotrophic factor)-targeted microRNAs such as miR-30a-5p associate with alcohol dependence phenomenon however their relationship with AWS is not described. We aimed to measure serum BDNF concentration and relative content of miR-30a-5p over the course of alcohol abstinence and compare obtained results with clinics of AWS. Additionally, we studied relative serum content of miR-30a-5p, a microRNA which does not target BDNF but relates to alcohol use disorder. Serum BDNF concentration increased over the course of alcohol abstinence, contrary relative content of miR-122 but not miR-30a-5p decreased. Moreover, during AWS miR-122 but miR-30a-5p negatively correlated with serum BDNF concentrations. Relative content of miR-122 negatively correlated with depression and state anxiety levels on 8th day of abstinence. According to multiple regressions on 21st day of abstinence alcohol craving and cognitive disturbances may be predictors of serum BDNF concentration, and vice versa. Thus, serum BDNF concentration and relative content of miR-122 associate with some aspects of AWS clinics and may dynamically reflect AWS severity.

[A role of inflammasomes in the pathogenesis of neurological and mental diseases]. / Rol' inflammasom v razvitii nervnykh i psikhicheskikh zabolevanii.

Inflammasomes are macromolecular complexes that contain many copies of receptors recognizing molecular patterns of pathogenic agents (PAMP) and damage-associated structures (DAMP), and also include molecules of adapter protein ASC and procaspase-1. Activation of inflammasomes leads to the formation of active caspase-1 that, in turn, provides the maturation of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18. The latter cytokines play an important role in control of neuroinlfammation in the central nervous system contributing to the pathogenesis of a series of neurological, neurodegenerative and mental disorders. The review discusses the involvement of NLRP3 inflammasome and other their types in the development of the traumatic brain injury, ischemic and hemorrhagic stroke, brain tumors, CNS infections, Alzheimer's and Parkinson's diseases, epilepsy, amyotrophic lateral sclerosis, depressiver, and consequences of alcohol abuse. The elucidation of molecular mechanisms and signaling pathways controlled by inflammasomes will allow the development of new therapeutic measures for diseases, in which neuroinflammation plays a leading pathogenetic role.

[Cardiac damage in liver cirrhosis in alcohol abusers]. / Porazhenie serdtsa pri tsirroze pecheni u bol'nykh, zloupotreblyayushchikh alkogolem.

AIM: to estimate the contribution of liver cirrhosis (LC) to the development of heart diseases in alcohol abusers. SUBJECTS AND METHODS: The investigation included 80 patients with alcoholic LC without a history of cardiovascular and respiratory diseases and, as a control group, 32 alcohol abusers without a history of chronic diseases of the liver and cardiovascular and respiratory systems; 45 patients with alcoholic cardiomyopathy (ACM) and congestive heart failure without a history of coronary heart disease and valvular diseases, among whom 11 patients were found to have LC. In addition to standard clinical examination, all the patients underwent electrocardiography, by estimating the corrected QT interval (QTc), standard echocardiography; and those without ACM underwent estimation of left ventricular (LV) kinetics using speckle-tracking echocardiography. RESULTS: The patients with alcoholic LC were found to have a higher LV ejection fraction and a more obvious impairment of LV global longitudinal deformity, and more commonly LV diastolic dysfunction. 16 of the 80 patients with LC were observed to have moderate pulmonary hypertension while the mean pulmonary artery pressure (MPAP) was within the normal range in all the patients without LC. A prolonged QTc interval was revealed in the patients with LC. The duration of QTc was directly correlated with the MELD severity of LC. The patients with chronic heart failure in the presence of ACM and CL showed a more obvious LV diastolic dysfunction, as estimated by E/E', a greater LV mass index, and a higher MPAP than those with ACM without LC. CONCLUSION: The LC patients both with ACM and without a history of diseases of the heart were noted to have its more evident disorders as diastolic dysfunction and elevated MPAP. Those without ACM were observed to have impaired LV global deformity and a prolonged QTc interval.

[The role of lipoprotein-associated enzyme paraoxonase 1 and its polymorphisms in the pathogenesis of endothelial dysfunction and somatic complications in patients with alcoholism: Review ].

A review of recent data on the role of the multifunctional enzyme, associated with high density lipoproteins - paraoxonase 1 (PON1) in maintaining healthy endothelial function by detoxifying both oxidized low density lipoproteins and homocysteine thiolactone. The additional contribution to the protection of the endothelium against damage makes organophosphatase activity of PON1 involved in the detoxification products of tobacco smoke. The reduction of antioxidant activity of PON1 promotes the differentiation of monocytes into macrophages and the development of inflammation. The reduction of thiolactonase activity of PON1 is accompanied by a decrease of methionine re-synthesis from homocysteine causing DNA- hypomethylation and alteratioin of the expression patterns of pro- and anti-atherogenic genes. Global hypomethylation of the genome is regarded as one of the three most important mechanisms of the increased risk of somatic complications of alcoholism. The accumulation of homocysteine thiolactone serving agonist of glutamate receptors and antagonist of dopamine receptors is a prerequisite to increased alcohol abuse. Clinical observations focusing on gene polymorphisms of PON indicate that three different genotypes of polymorphism PON1Q192R have unequal degrees atheroprotective properties.

[Blood Content of Markers of Inflammation and Cytokines in Patients With Alcoholic Cardiomyopathy and Ischemic Heart Disease at Various Stages of Heart Failure].

We conducted a comparative study of content proinflammatory cytokines, biomarkers of inflammatory process, biochemical indicators of congestive heart failure (CHF) and hemodynamic parameters in patients with alcoholic cardiomyopathy (ACMP) and ischemic heart disease (IHD) with various NYHA classes. We examined 62 men with ACMP (n = 45) and IHD (n = 17) and NYHA class III-IV CHF. Patients of both groups had lowered ejection fraction (EF), dilated cardiac chambers, and increased left ventricular (LV) myocardial mass index (MMI). Relative LV wall thickness was within normal limits but in the ACMP group it was significantly lower than in IHD group what corresponded to the eccentric type of myocardial hypertrophy. Higher NYHA class was associated with lower EF and larger end diastolic and end systolic LV dimensions. In ACMP it was also associated with larger dimension of the right ventricle while in IHD--with substantially larger (by 30%) dimension of atria. Substantial amount of endotoxin found in blood plasma of patients with IHD corresponded to the conception of increased intestinal permeability of in CHF. Alcohol abuse was an aggravating factor of endotoxin transmission and its concentration in patients with ACMP was 3 times higher than in patients with IHD. Patients with ACMP had substantially elevated blood concentrations of interleukins (IL) 6, 8, 12, tumor necrosis factor α (TNF-α), and its soluble receptor s-TNF-R; they also had twofold elevation of C-reactive protein concentration. ACMP was associated with manifold rise of blood content of brain natriuretic peptide (BNP). Patients with IHD also had elevated blood concentrations of IL 6, 8 and 12 but their values were 1.5-2 times lower than ACMP group. Blood content of TNF-α and s-TNF-R in IHD group was within normal limits. Higher NYHA class in ACMP patients was associated with higher concentrations of IL 6 and 8, TNF-a, and BNP. In both groups of patients contents of IL-12, s-TNF-R, TGF-1ß and factors of acute phase of inflammation did not reflect severity of CHF. Functional insufficiency of myocardium in IHD patients was best characterized by blood content of IL-6 while in ACMP patients--of BNP.

[Serum markers of fibrosis and endothelial dysfunction in patients with alcoholism, with varying degrees of liver fibrosis].

In the serum of patients with alcoholism with varying degrees of severity of liver fibrosis were studied the content markers of fibrosis, endothelial dysfunction and proinflammatory cytokines. Concentration in blood indicators of fibrogenesis--collagen type 4, hyaluronic acid, TIMP-1, TIMP-2, YKL-40 and MMP-2 is considerably increased at the 4 degree of fibrosis and moderately increased at low and zero degrees of liver fibrosis. Similar results were obtained in respect of proinflammatory cytokines Il-6, IL-8, IL-12/p70 and IL-12/p40. The magnitude of endothelial dysfunc- tion, calculated based on its content in the blood markers--VEGF-A, MCP-1, s-VCAM, s-ICAM and endothelin, was maximal at 4 degrees of fibrosis and less pronounced at low degrees of fibrosis. Correlations between of the average degree of fibrosis, endothelial dysfunction, and blood levels of proinflammatory cytokines were installed. Close relation between the immune cells releasing stimulators of inflammation and fibrogenesis, perisinusoidal fat cells producing collagen, and endothelium secreting vasoconstrictors in the pathogenesis of alcoholic liver fibrosis and cirrhosis was installed.

[Blood Content of Markers of Inflammation and Cytokines in Patients With Alcoholic Cardiomyopathy and Ischemic Heart Disease at Various Stages of Heart Failure].

We conducted a comparative study of content proinflammatory cytokines, biomarkers of inflammatory process, biochemical indicators of congestive heart failure (CHF) and hemodynamic parameters in patients with alcoholic cardiomyopathy (ACMP) and ischemic heart disease (IHD) with various NYHA classes. We examined 62 men with ACMP (n=45) and IHD (n=17) and NYHA class III-IV CHF. Patients of both groups had lowered ejection fraction (EF), dilated cardiac chambers, and increased left ventricular (LV) myocardial mass index (MMI). Relative LV wall thickness was within normal limits but in the ACMP group it was significantly lower than in IHD group what corresponded to the eccentric type of myocardial hypertrophy. Higher NYHA class was associated with lower EF and larger end diastolic and end systolic LV dimensions. In ACMP it was also associated with larger dimension of the right ventricle while in IHD - with substantially larger (by 30%) dimension of atria. Substantial amount of endotoxin found in blood plasma of patients with IHD corresponded to the conception of increased intestinal permeability of in CHF. Alcohol abuse was an aggravating factor of endotoxin transmission and its concentration in patients with ACMP was 3 times higher than in patients with IHD. Patients with ACMP had substantially elevated blood concentrations of interleukins (IL) 6, 8, 12, tumor necrosis factor (TNF-), and its soluble receptor s-TNF-R; they also had twofold elevation of C-reactive protein concentration. ACMP was associated with manifold rise of blood content of brain natriuretic peptide (BNP). Patients with IHD also had elevated blood concentrations of IL 6, 8 and 12 but their values were 1.5-2 times lower than ACMP group. Blood content of TNF- and s-TNF-R in IHD group was within normal limits. Higher NYHA class in ACMP patients was associated with higher concentrations of IL 6 and 8, TNF-, and BNP. In both groups of patients contents of IL-12, s-TNF-R, TGF-1 and factors of acute phase of inflammation did not reflect severity of CHF. Functional insufficiency of myocardium in IHD patients was best characterized by blood content of IL-6 while in ACMP patients - of BNP.

[Oxidative stress in the of alcoholic liver disease].

Parameters reflecting oxidative stress (OS) have been studied in 37 patients with alcoholic liver disease (ALD) during admission to the hospital and 2 weeks after the beginning of therapy. The patients were divided into 3 groups: alcoholic hepatitis (AH), alcoholic cirrhosis with hepatic insufficiency (the group C with Child-Paquet) and terminal stage patients (they subsequently died). All patients were characterized by a significant increase in plasma products of lipid peroxidation (conjugated diene and malondialdehyde) and decrease of the ceruloplasmin level. The coefficient K OS significantly exceeded normal values both on admission and after the 2-week course of traditional treatment. This suggests an important role of the OS with ALD.

[Immunoinflammatory changes (myocarditis?) in chronic heart failure in alcoholic patients].

AIM: To estimate the contribution of immuno-inflammatory changes to the formation of clinical and hemodynamic features in alcoholic patients with chronic heart failure (CHF). SUBJECTS AND METHODS: Forty-five males with CHF in the presence of alcohol-induced heart damage (AIHD) who had been admitted to therapeutic units for decompensated heart failure were examined. A control group consisted of 20 men with the CHF severity comparable with the NYHA classification in the presence of prior myocardial infarction. All the patients underwent examination of the immune-inflammatory status--the cytokines: interleukin (IL) 6, IL-8, IL-12, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta1, endotoxin, cellular immune parameters, and cardiac structure and function by echocardiography. RESULTS: The patients with CHF in the presence of AIHD, as compared to those with ischemic cardiomyopathy, showed the higher levels of inflammatory cytokines (IL-6, TNF-alpha, IL-12, and endotoxin) and cell-mediated immunity changes (the smaller count of suppressor T cells, natural killer cells, and a shift of the T-helper/T-suppressor ratio towards the T-helper population). The magnitude of these changes correlated with the severity of CHF and cardiac morphofunctional changes. CONCLUSION: The relationship of immuno-inflammatory changes to the severity of CHF and the morphofunctional state of the heart irrespective of the etiology of heart failure demonstrated the role of immune inflammation in its pathogenesis particularly in alcoholic patients who were found to have more marked immuno-inflammatory changes than in those with ischemic cardiomyopathy.

Use of HLDF-6 peptide for correction of disturbances in the endogenous opioid system in offspring of morphine-tolerant animals.

We studied the effect of bioactive peptide HLDF-6 on functional activity of the endogenous antinociceptive system in the offspring of morphine-tolerant animals. Disturbances in this system included changes in the thermonociceptive threshold and enkephalinase A activity in various brain structures. The peptide acted as a potent regulator of the homeostasis in systems responsible for the synthesis and catabolism of endogenous opioids. HLDF-6 effectively corrected disorders of the endogenous antinociceptive system.

Formation of morphine tolerance in offspring of morphine-tolerant animals: neurochemical and neuroimmune correlates.

We carried out a complex physiological, neurochemical, and neuroimmunologic study of the formation of tolerance to analgetic effect of morphine and analyzed enkephalinase A activity in different brain structures and serotonin antibodies in the serum. More early development of morphine tolerance and a sharp increase in serum antibody titer was found in the offspring of morphine-tolerant rats. This points to an imbalance in the neurotransmitter system and can serve as a diagnostic marker of endogenous opioid system pathology.

Differences in genetic predisposition to high anxiety in two inbred rat strains: role of substance P, diazepam binding inhibitor fragment and neuropeptide Y.

RATIONALE: Regulatory neuropeptide systems appear to modulate anxiety and emotionality, since anxiety in rats can be increased by intracerebroventricular (ICV) administration of diazepam-binding-inhibitor fragment (DBI) and decreased by ICV administration of neuropeptide Y (NPY) or substance P (SP). OBJECTIVE: Involvement of these three neuropeptides in genetic predisposition to anxiety was studied in two inbred rat strains. METHODS: Levels of anxiety to novel environments were first measured in Fischer-344 (F-344/N) and Wistar Albino Glaxo (WAG/G) rats using open-field conflict, hole-board, black and white box, elevated-plus maze and Vogel lick suppression procedures. Levels of SP, DBI and NPY in the hippocampus, midbrain and hypothalamus of F-344/N and WAG/G rats were then measured without stress (basal levels) or after stress induced by shuttle-box, shock-avoidance testing. Finally, effects of ICV injection of SP or NPY rats were measured in F-344/N and WAG/G rats using the hole-board test. RESULTS: F-344/N rats had elevated level of anxiety compare to WAG/G rats with all five procedures. Levels of SP in the hippocampus, midbrain and hypothalamus of F-344/N rats were significantly lower than in WAG/G rats and levels of SP decreased in WAG/G, but not F-344/N, rats after stress. Levels of DBI in the hippocampus and midbrain of F-344/N rats were also lower than in WAG/G rats, but they increased in F-344/N rats after stress. In contrast, levels of NPY were higher in the midbrain of F-344/N rats than in WAG/G rats, especially after stress. ICV injection of SP or NPY decreased anxiety in the black and white box in both F-344/N and WAG/G rats, but F-344/N rats were more sensitive. CONCLUSIONS: These findings support the hypothesis that decreased levels of SP in certain brain regions may contribute to high levels of anxiety in rats. Decreased levels of DBI and increased levels of NPY in high-anxiety animals may act as compensatory mechanisms.

The use of naloxone in small doses in complex therapy of postabstinent heroin syndrome: enkephalinase mechanisms.

The use of naloxone hydrochloride (0.2-0.4 mg) in complex therapy of adolescent heroin addicts significantly prolonged the half-life of serum leu-enkephalin, slightly elevated the thresholds of thermal nociceptive reactions, and improved some clinical indices (considerably reduced drug addiction, eliminated affective disorders, etc.), which are important for deactualization of drug addiction and promoting remission.

Changes in thermonociceptive thresholds and the role of enkephalinase A in homeostasis in morphine-tolerant rat offspring.

The dynamics of thermonociceptive thresholds as a marker of the state of the endogenous opioid system was studied in the offspring of morphine-tolerant rats. Significant, age-dependent increase in thermonociceptive thresholds and higher levels of enkephalinase A in structures of the endogenous antinociceptive system were observed in the offspring compared with the control. These findings attest to disturbances of the opioid system in the progeny of morphine-tolerant rats and confirm the key role of enkephalinase A in the maintenance of homeostasis disturbed by chronic prenatal morphine treatment.

[A comprehensive study of the neurochemical and immune mechanisms of morphine tolerance: the effects of naloxone]. / Kompleksnoe izuchenie neirokhimicheskikh i immunnykh mekhanizmov morfinnoi tolerantnosti: éffekty naloksona.

To test the authors' hypothesis about the role of endopeptidase (enkephalinase A, in particular) in mechanisms of morphine tolerance and blocking action of small doses of naloxone, they studied nociception reactions, morphine antibodies titres and enkephalinase A activity after morphine, d-phenylalanine and naloxone injection in brain structures. It is shown that activity of enkephalinase A in structures of endogenous antinociceptive system increased simultaneously with morphine antibodies titres in tolerance condition. Injection of small dose naloxone inhibited enkephalinase activity in brain structures and decreased morphine antibodies titres to these in control morphine-sensitive rats and therefore suppressed morphine tolerance. Prolonged naloxone injection decreased morphine antibodies titres to the levels of intact animals and highly increased titers of antiidiotypic morphine antibodies. Thus, these results confirm the role of enkephalinase as a neuromodulator. A strong relationship exists between enkephalinase and immune mechanisms of development of morphine tolerance which can be blocked by small naloxone doses. It is concluded that naloxone in small doses can be used in patients to suppress morphine tolerance.

[Modification by alpha-interferon of ethanol-induced changes in the level of opioid peptides in the rat striatum and hypophysis]. / Modifikatsiia pod vliianiem alpha-interferona vyzvannykh étanolom izmenenii soderzhaniia opioidnykh peptidov v striatume i gipofize krys.

Content of Met-enkephalin in striatum and of beta-endorphin in rat hypophysis were estimated after administration of ethanol and alpha-interferon into the animals. Ethanol decreased Met-enkephalin content in striatum and of beta-endorphin in hypophysis. Preadministration of alpha-interferon into brain ventricles before ethanol administration led to an increase in concentration of Met-enkephalin, while content of beta-endorphin was unaltered. In peripheric administration alpha-interferon normalized content of beta-endorphin in adenohypophysis but did not affect the Met-enkephalin concentration. Effects of alpha-interferon on content of Met-enkephalin and beta-endorphin, related to dissimilar organization of the opiate systems in hypophysis and striatum tissues, are discussed.