[Signaling molecules in the brain and epigenetic factors in neurodegenerative and mental disorders].

The literature on a role of signaling molecules in the organization of memory and cognitive functions is analyzed basing on mechanisms of memory physiology determined by a complex of biochemical processes initiated by the transmission of the signal to the synapse and completed by the synthesis of functionally significant molecules in the neuronal genetic apparatus. The center of these processes is a coordinated system of signal transduction, transcription, epigenetic and neurotrophic molecules. The dissonance of signal mechanisms is a prime cause of memory impairment and cognitive dysfunction as social maladaptation factors.

[Cortexin. Molecular mechanisms and targets of neuroprotective activity].

Neurotrophic drug cortexin, a lyophilized extraction of animal cortex, comprises neuropeptides, amino acids and trace elements. The nucleoprotein complexes of the cerebral cortex can also retain elements of chromatin with DNA fragments. All of these components of cortexin have a specific range of "targets" for the specific correction of the molecular and cellular processes at various stages of the pathological process.

[EPIGENETIC ENZYMES AS THERAPEUTIC TARGETS FOR TREATING BRAIN DISORDERS].

At present, epigenetic regulation is considered as a dynamic mechanism by means of which cells realize adaptive response to signals from both the inner medium and environment. DNA methylation, as bidirectional balance of the activity of histone-acetylation and -deacetylation (HDAC) enzymes, determines the conformation of chromatin thus playing the main role in "appropriate" gene expression. HDACs represent emerging therapeutic targets in the context of treating various forms of neurological and mental illness.

[Transformation of neural stem cells and reparative processes in the brain].

The results of recent publications on a role of stem cells in the processes of neurogenesis, adaptation and neuroplasticity are summarized. An aim of the paper was to present evidence for a possibility of development and regeneration of cellular elements in the adult brain in normality and pathology. The latter was driven by the discussion of the studies on Alzheimer's disease, Parkinson's disease, schizophrenia and affective disorders.

[Current conceptions of neurocytoprotective therapy].

The review is devoted to pharmacological effects and clinical effectiveness of one of the "oldest" neurocytoprotective drugs cerebrolysin. Experimental data that have revealed molecular mechanisms of the drug action as well as the results of clinical trials demonstrating the efficacy of cerebrolysin in the treatment of acute and chronic brain ischemia, Alzheimer's disease, moderate and mild cognitive disorders are described in details. It has been concluded that the efficacy o this drug has been supported by fundamental research, using animal models and cell cultures, and multiple clinical trials in patients with different pathologies.

Endothelin-converting enzyme inhibition in the rat model of acute heart failure: heart function and neurohormonal activation.

Endothelin-1 (ET-1) has been implicated in many cardiovascular diseases, including acute heart failure (AHF) due to myocardial ischemia. Previously we described the oral endothelin-converting enzyme (ECE) inhibitor, PP36, and in this study, we investigated its cardioprotective effect in more detail, and examined the role of PP36 in the neurohormonal activation in rats that had been subjected to acute myocardial ischemia due to the microsphere embolization of coronary microcirculation. PP36 treatment (3.

[Chronic theatment with an endothelin-converting enzyme inhibitor reduces the development of hypoxia-induced pulmonary hypertension in rat].

The aim of this study was to investigate how blocking functional endothelin-converting enzyme activity may offer a new approach to inhibition of changes in pulmonary vessels reactivity due to development of hypoxia-induced pulmonary arterial hypertension in rats. This data shows that treatment with endothelin-converting enzyme blocker PP36 significantly reduced pathological changes due to hypoxia-induced pulmonary hypertension. One of the reasons may be the increased production and role of nitric oxide in pulmonary artery tone.

[Neurotrophic and growth factors of the brain: regulatory specificity and therapeutic potential].

Neurotrophic and growth factors are major subgroups of polypeptides that are synthesized naturally and characterized by the following effects: neuronal differentiation, survey of nerve cell functional integrity, protection against degeneration and lesions, which maintain nerve cells alive. Neurotrophic and growth factors increase the resistance of neuronal tissue to the noxious influence such as hypoxia, exitotoxicity, trauma, stress injury, hypoglycemia, etc. Neurotrophic and growth factors are important in the synaptic plastivcity, activity of learning and cognitive proecesses, regulation of depressive and anxiogenic states.

[The systems of neurochemical regulation at brain pathologies].

The paper summarises the comprehensive concept on main groups of chemical substances and on their diverse regulatory function in the brain. Neurotransmitters, neuropeptides, neurotrophic and growth factors, and cytokines are considered as many-storied, integral structure. The proper analysis of ischemic and neurodegenerative brain disturbances evidently demonstrates the active participation of basic families of these chemical regulators at all stages of the pathogenesis.

[Regulatory molecular mechanisms of the neurochemical processes. History and the present time].

Multiple neurochemical mechanisms (neurotransmitters, regulatory peptides, neurotrophic growth factors, and proteins of the signaling transducer systems) maintain the integrity of nerve cell circuits, facilitate the responses to environmental demands and promote the recovery of a function after injury. The recent application of modern approaches of molecular and cellular biology to the problem of "diseased (bad) brain" reveals a remarkable capacity within brain cells for adaptation to aging and resistance to a disease. The death of neurons in different neurological disorders involves apoptotic biochemical cascades leading to mitochondrial alterations, upstream pro-apoptotic effectors, and caspases activation.

Computer-aided selection of potential antihypertensive compounds with dual mechanism of action.

The prediction of biological activity spectra for substances as an approach for searching compounds with complex mechanisms of action was studied. New compounds with dual mechanisms of antihypertensive action were found by this approach. Biological activity spectra for substances were predicted on the basis of their structural formulas by the computer program PASS.

[Apoptosis in neuronal structures and the role of neurotrophic growth factors. Biochemical mechanisms of brain derived peptide preparations].

Phenomenology of neurodegenerative disorders of any genesis corresponds to modern concepts of apoptosis as a morphobiochemical mechanism for programmed death of certain nervous cell populations. Neuroapoptosis is assumed to be a basic cause of all kind of neuropathology. Neuropeptides synthesized in certain brain regions and neurotrophic growth factors playing an important role in brain function control get involved in neurodestructive process realization as pro- or antiapoptotic components.

[ACE-dependent and sympathetic components of blood pressure regulation in patients with essential hypertension].

Unlabelled: The development of arterial hypertension is accompanied by impairment of the normal ratio of the "ACE-depending" and of the sympathetic nervous system, correlates with the action on the main pharmacological "targets": I-I-imidazoline receptors (moxonidine) or the ACE activity (enalapril). The aim of the present investigation was to determine the hypotensive and metabolic effects of moxonidine and enalapril depending on the basal ACE activity in patients with arterial hypertension, complicated with the metabolic syndrome. Effectiveness of moxonidine and enalapril administration (during 24 weeks) depended on the basal ACE activity in the hypertensive patients: (a) in the group of patients with low basal ACE activity moxonidine very effectively decreased systolic and diastolic blood pressure, compared with the group of patients with high basal ACE activity; (b) influence of enalapril on the level of arterial blood pressure was more pronounced with high basal ACE activity.

[The molecular and physiological aspects of endothelial dysfunction. The role of endogenous chemical regulators].

Monolayer of endothelial cells that cover the vascular channels are the major regulator of haemo-vascular homeostasis. Endothelium secretes the chemical factors that affect contraction of the muscular vascular cells, permeability of tissue, blood fluidity, intercellular interaction in vascular structure of the channel as a whole and of different regions. In its turn, the secretory function of endothelial cells is stimulated by mechanical or hormonal factors under a feedback system principle.

[Correction of cardiac functions in rats with experimental myocardial ischemia by chronic administration of endothelin-converting enzyme inhibitor].

Experiments on chronically instrumented Wistar rats demonstrated that 15 mm microsphere embolization of coronary arteries led to a significant decrease in the systemic (APsyst) and maximal left ventricular systolic pressures (LVSPmax) to 10.1 and 21.1%, respectively (p < 0.

[The endothelin peptide system: mechanisms of cardiovascular pathology].

A rapidly growing body of data support the concept of endothelin as a paracrine acting endothelial regulators. The system of endothelin peptides--their chemical structure, physiological activity and role in cardiovascular pathological processes are reviewed. Molecular specificity, isoforms, and physicochemical parameters of the endothelin-converting enzyme (ECE) characterize this novel metalloproteinase as important regulator, that catalyses final step in the biosynthesis of endothelins.

Inhibitor analysis of angiotensin I-converting and kinin-degrading activities of bovine lung and testicular angiotensin-converting enzyme.

Inhibition of bovine lung and testicular angiotensin-converting enzyme (ACE) by some well-known ACE inhibitors (lisinopril, captopril, enalapril), new substances (Nalpha-carboxyalkyl dipeptides PP-09, PP-35, and PP-36), and phosphoramidon was investigated using Cbz-Phe-His-Leu and FA-Phe-Phe-Arg (C-terminal analogs of angiotensin I and bradykinin, respectively) as the substrates. The somatic (two domains) and testicular (single domain) isoenzymes demonstrated different kinetic parameters for hydrolysis of these substrates. All of the inhibitors were competitive inhibitors of both ACE isoforms, and the Ki values were substrate-independent.

[Peptide mediators in adrenal chromaffin cells: regulation of catecholamine selective secretion].

The data obtained suggest a potential mechanism that may account for the selective control of adrenaline and noradrenaline release from adrenal chromaffin cells. Some neuropeptides seem to affect in a different way the release from A- and NA-adrenal cells by means of regulating a set of cytochemical events: specific reception of cholinergic transmitters, expression of the second messenger system including cGMP and changes in Ca channels activity, changes in the catecholamine biosynthesis in adrenal chromaffin cells. Modulating function of substance P, endothelins, PACAP, and ANF, is discussed.

Endothelin-converting enzyme: its functional aspect.

The system of endothelin peptides and their structure, biological activity, and role in physiological and pathological processes are reviewed with emphasis on endothelin-converting enzyme (ECE), which catalyzes the terminal processing of endothelin. Molecular specificity, structure, isoforms, physicochemical characteristics, substrate preference, and tissue localization characterize this enzyme as a novel and highly important metalloendopeptidase. The role of ECE in pathological processes and data on inhibitors of the enzyme which can have medical implication are summarized.

Effect of new peptide inhibitors on the ratio of angiotensin I-converting and kinin-degrading activities of dipeptidyl carboxypeptidase (angiotensin-converting enzyme).

The effect of N(alpha)-carboxyalkylated dipeptides on angiotensin-converting and kinin-degrading activity of angiotensin-converting enzyme (ACE, dipeptidyl carboxypeptidase) was studied. These inhibitors selectively affected ACE-induced hydrolysis of angiotensin I-like and bradykinin-like (hippuryl-His-Leu and hippuryl-Phe-Arg, respectively) substrates in microsomal fractions of rat lungs and kidneys and rat blood serum. The inhibition constants of both types of activity were determined for these enzyme preparations and also for ACE from porcine seminal fluid and highly purified ACE from porcine lung.