[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. The results of experimental and clinical studies of a role of the multilevel signaling system in age-related, neurodegenerative (Alzheimer's disease) and mental (depression) disorders are discussed. At the same time, signaling molecules may be considered as particular targets for new therapeutic approaches.

[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. A modern concept of neurosignaling considers the associated processes - from the synaptic level to the epigenetic patterns of neuron nucleus, in which an important place belongs to corrective peptide molecules. Peptide components of cortexin derived from the animal brain, which interact with cellular and molecular "targets", provide a new view on mechanisms of neuroprotection.

[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. A wide range of brain diseases are associated with imbalance between protein acetylation levels and tran- scriptional dysfunctions. Increasing evidence supports the notion that histone hypoacetylation and transcriptional dysfunction are involved in a large number of neurodegenerative conditions in vivo and in vitro. Histone deacetylase inhibitors (HDACIs) that affect the acetylation status of histones and other important cellular proteins--have been recognized as potentially useful therapeutic means for a broad range of human disorders. This review summarizes the current state of development of HDACIs based therapeutics and their application for the treatment of human brain neurodegenerative, ischemic, and cognitive pathologies. Treatment with various HDACIs can correct these deficiencies and has emerged as a promising new strategy for therapeutic intervention based on the experimental search and clinical testing of HDACIs representing compounds of various classes.

[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. Pharmacological effects on the neurogenesis and perspectives of this research are reviewed.

[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.

[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. Analysis of clinical and experimental data suggested tha main role of neurotrophins and growth factors in the pathogenesis of ischemic and neurodegenerative brain processes. Some factors are considered as specific markers or targets for concrete diseases; but for any other factors the protective function and therapeutically opportunity for treatment of some pathologies have been revealed. There is some evidence for antiapoptic effects of neurotrophic and growth factors as a basic principle for their neuroprotective function.

[The systems of neurochemical regulation at brain pathologies]. / Sistemy neirokhimicheskoi reguliatsii pri patologii mozga.

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. The main theoretical positions involving these regulatory substances in the control of normal and pathological situations include: (a) dogma on the imbalance of chemical regulators, as the initial pathogenetic principle; (b) genetically heterogeneity of brain structures, which demonstrate selective vulnerability or, to the contrary, steadiness for damaging exposure. As a general principle for increasing number of clinical and experimental pathologies, the induction of apoptic cascade processes is postulated; their "normal" biological function in nervous tissues is a key factor for development of majority of brain diseases.

[Regulatory molecular mechanisms of the neurochemical processes. History and the present time]. / Molekuliarnye mekhanizmy reguliatsii neirokhimicheskikh protsessov. Istoria i sovremennyi vzgliad.

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. At the cellular level, neuronal apoptosis in ischemic and neurodegenerative disorders may be triggered by oxidative stress, mitochondrial compromise and disruption of calcium homeostasis. Both genetic and environmental factors, and the aging process itself, contribute to initiation of such neuronal apoptosis. Neuroprotective (antiapoptotic) signal pathways involving neurotrophic factors, neuropeptides, and mediators able to counteract with effects of aging and genetic predisposition in experimental models and clinical events of neuro-destructive disorders.

[Apoptosis in neuronal structures and the role of neurotrophic growth factors. Biochemical mechanisms of brain derived peptide preparations]. / Apoptoz neironal'nykh struktur i rol' neirotroficheskikh rostovykh faktorov. Biokhimicheskie mekhanizmy éffektivnosti peptidnykh preperatov mozga.

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. On the basis of above concepts it is suggested that therapeutic efficacy of cerebrolysin, successfully used for therapy of wide spectrum of ischemic, neurodegenerative and other brain pathologies lies in inhibiting influence on apoptosis-dependent processes in the nervous cell. This medication including a neuropeptide and neurotrophic factors complex has many targets, which may be used for neuroapoptosis correction on different stages of pathological process.

[ACE-dependent and sympathetic components of blood pressure regulation in patients with essential hypertension]. / APF-zavisimyi i simpaticheskii komponenty reguliatsii arterial'nogo davleniia u patsientov s éssentsial'noi gipertoniei.

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. IN CONCLUSION: choosing a hypotensive treatment for patients with the metabolic syndrome, it is advisable to take into account the basal ACE activity levels.

[Correction of cardiac functions in rats with experimental myocardial ischemia by chronic administration of endothelin-converting enzyme inhibitor]. / Korrektsiia funktsional'nogo sostoianiia serdtsa krys s éksperimental'noi ishemiei miokada pri khronicheskom primenenii ingibitora éndotelin-prevrashchaiushchego fermenta.

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 < 0.05). To evaluate the role of endothelin in this pathology, the inhibitor of endothelin-converting enzyme (ECE), PP-36, was used. PP-36 abolished hemodynamic changes caused by embolization after 4 days per os treatment (starting 2 days before surgical procedure). Dobutamine test revealed marked decrease of LVSPmax and +dP/dtmax responses in the embolized versus sham operated animals. PP-36 normalized ischemical heart response to beta-adrenergic stimulation. Maximal APsyst and LVSPmax increases were observed in embolized rats. PP-36 abolished this effect and led to parallel rising reaction to aminoguanidin in embolized (APsyst: +12.4 +/- 1.6 vs. +6.8 +/- 2.3 mmHg, p < 0.05) as well as in sham operated rats (APsyst: +8.5 +/- 1.1 vs. +5.6 +/- 0.7 mmHg, p < 0.05). Thus, the present research showed the possibility to correct ischemical heart disturbance by using a new ECE inhibitor, PP-36. One possible mechanism of this drugs action may include systemic or myocardial changes in NO contribution to the maintenance of normal arterial pressure.

[The molecular and physiological aspects of endothelial dysfunction. The role of endogenous chemical regulators]. / Molekuliarnye i fiziologicheskie aspekty éndotelial'noi disfunktsii. Rol' éndogennykh khimicheskikh reguliatorov.

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. Special features of morphology and biochemistry of vascular endothelium cells determine the micro-organs heterogeneity of the vascular channel depending on phenotine, gene expression, size and growth of endothelium cells. On this basis the processing biochemical disintegration develop either selectively or in a generalised form, and results in development of endothelial dysfunctions, as the original factor of many cardiovascular pathologies. Endothelial disfunction is a systemic pathology related to pathology of microstructure and hormonal function of endothelial cells representing a major tissue system of the vascular channel. Formation of hypertension states, ischemic cardiopathology, haemostasis changes, metabolic pathology (hypercholesterinemia and hyperglycemia) that lead to pathogenesis of arteriosclerosis, diabetes (etc.) as result of modified function of endothelium, and above all, pathology of production by dilator and constrictor substances, and the factors regulating interaction of endothelium with blood cells. The basic mechanism for development of the endothelial dysfunction is related to modification of synthesis and releasing of nitrogen oxide, a key regulator of the endothelial-vasal system. Physiologically active peptides (angiotensin II, endothelin-I, bradykinin, adrenomedullin and ANP) contribute to development of the processes related to the endothelium function and dysfunction. An important role is played, apparently, by growth peptide factors and specific proteins of cellular adhesion and membrane interaction--to integrins and selectins.

[The endothelin peptide system: mechanisms of cardiovascular pathology]. / Sistema éndotelinovykh peptidov: mekhanizmy kardiovaskuliarnykh patologii.

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. The role of the general endothelial system for various cardiovascular pathological states, including congestive heart failure and myocardial infarction, arterial hypertension, atherosclerotic vascular diseases is discussed. Therapeutic approaches with some endothelin receptor antagonists and ECE inhibitors are discussed, and endothelin system therefore represents a likely target for the development for the novel pharmaceutical agents.

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. The relative potencies of the inhibitors for both enzymes were: lisinopril > captopril > PP-09 > enalapril > PP-36 > PP-35 > phosphoramidon. The inhibition efficiency of PP-09 was comparable with those of the well-known ACE inhibitors. Captopril was more effectively bound to the somatic ACE (Ki = 0.5 nM) than to the testicular isoform (Ki = 6.5 nM).

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.

[Peptide mediators in adrenal chromaffin cells: regulation of catecholamine selective secretion]. / Peptidnye mediatory v khromaffinnykh kletkakh nadpochechnikov: reguliatsiia izbiratel'noi sekretsii katekholaminov.

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.