The diversity of AMPA receptor inhibition mechanisms among amidine-containing compounds.

Amidine-containing compounds are primarily known as antiprotozoal agents (pentamidine, diminazene, furamidine) or as serine protease inhibitors (nafamostat, sepimostat, camostat, gabexate). DAPI is widely recognized as a fluorescent DNA stain. Recently, it has been shown that these compounds also act as NMDA receptor inhibitors.

Light-Sensitive Open Channel Block of Ionotropic Glutamate Receptors by Quaternary Ammonium Azobenzene Derivatives.

Glutamate ionotropic receptors mediate fast excitation processes in the central nervous system of vertebrates and play an important role in synaptic plasticity, learning, and memory. Here, we describe the action of two azobenene-containing compounds, AAQ (acrylamide-azobenzene-quaternary ammonium) and QAQ (quaternary ammonium-azobenzene-quaternary ammonium), which produced rapid and fully reversible light-dependent inhibition of glutamate ionotropic receptors. The compounds demonstrated voltage-dependent inhibition with only minor voltage-independent allosteric action.

Adaptation memory in photoreceptors: different mechanisms in rods and cones.

Vertebrate rods and cones operate over a wide range of ambient illumination, which is provided by light adaptation mechanisms regulating the sensitivity and speed of the phototransduction cascade. Three calcium-sensitive feedback loops are well established in both rods and cones: acceleration of the quenching of a light-activated visual pigment and cGMP synthesis by guanylate cyclase, and increased affinity of ion channels for cGMP. Accumulating evidence suggests that the molecular mechanisms of light adaptation are more complex.

Modulators of mitochondrial ATP-sensitive potassium channel affect cytotoxicity of heavy metals: Action on isolated rat liver mitochondria and AS-30D ascites hepatoma cells.

Heavy metals are ubiquitous environmental pollutants that are extremely dangerous for public health, but the molecular mechanisms of their cytotoxic action are still not fully understood. In the present work, the possible contribution of the mitochondrial ATP-sensitive potassium channel (mK(ATP)), which is usually considered protective for the cell, to hepatotoxicity caused by heavy metals was investigated using polarography and swelling techniques as well as flow cytometry. Using isolated liver mitochondria from adult male Wistar rats and various potassium media containing or not containing penetrating anions (KNO, KSCN, KAcet, KCl), we studied the effect of mK(ATP) modulators, namely its blockers (5-hydroxydecanoate, glibenclamide, ATP, ADP) and activators (diazoxide, malonate), on respiration and/or membrane permeability in the presence of hepatotoxins such as Cd, Hg, and Cu.

Mechanisms of NMDA receptor inhibition by nafamostat, gabexate and furamidine.

N-methyl-D-aspartate (NMDA) receptors are affected by many pharmaceuticals. In this work, we studied the action of the serine protease inhibitors nafamostat, gabexate and camostat, and an antiprotozoal compound, furamidine, on native NMDA receptors in rat hippocampal pyramidal neurons. Nafamostat, furamidine and gabexate inhibited these receptors with IC values of 0.

Screening for Activity Against AMPA Receptors Among Anticonvulsants-Focus on Phenytoin.

The interest in AMPA receptors as a target for epilepsy treatment increased substantially after the approval of perampanel, a negative AMPA receptor allosteric antagonist, for the treatment of partial-onset seizures and generalized tonic-clonic seizures. Here we performed a screening for activity against native calcium-permeable AMPA receptors (CP-AMPARs) and calcium-impermeable AMPA receptors (CI-AMPARs) among different anticonvulsants using the whole-cell patch-clamp method on isolated Wistar rat brain neurons. Lamotrigine, topiramate, levetiracetam, felbamate, carbamazepine, tiagabin, vigabatrin, zonisamide, and gabapentin in 100-µM concentration were practically inactive against both major subtypes of AMPARs, while phenytoin reversibly inhibited them with IC50 of 30 ± 4 μM and 250 ± 60 µM for CI-AMPARs and CP-AMPARs, respectively.

Modeling SELEX for regulatory regions using Royal Road and Royal Staircase fitness functions.

The field of evolutionary algorithms (EAs) emerged in the area of computer science due to transfer of ideas from biology and developed independently for several decades, enriched with techniques from probability theory, complexity theory and optimization methods. In this paper, we consider some recent results form the EAs theory transferred back into biology. The well-known biotechnological procedure SELEX (Systematic Evolution of Ligands by EXponential enrichment) is viewed as an experimental implementation of an evolutionary algorithm.

[Features of autonomic regulation of the cardiovascular system in human late ontogenesis.].

Using the method of arterial piezopulsometry, statistical and spectral analyzes of variable parameters (VmaxPP and TNN) of pulse waves of blood pressure in patients aged 18 to 85 years were performed. The individual characteristics of the autonomous (vegetative and neuroendocrine) regulation of the muscular effectors (ME) of the cardiovascular system (CVS) in an elderly man (75 years old) and a young woman (20 years old) were estimated with high accuracy. These data, as well as the results of a comparative study of patients of different ages, made it possible to identify a certain pattern of directed change in the sympathoadrenal regulation of ME CVS in human ontogenesis.

Mitigating effect of paxilline against injury produced by Cd in rat pheochromocytoma PC12 and ascites hepatoma AS-30D cells.

On two rat cell lines, pheochromocytoma PC12 and ascites hepatoma AS-30D, and on rat liver mitochondria we studied action of paxilline (lipophilic mycotoxin from fungus Penicillium paxilli which is blocker of large-conductance potassium channels) against harmful effects of Cd(II) - one of the most dangerous toxic metals and environmental pollutants. We investigated an influence of paxilline on cell viability and mitochondrial function in the presence and in the absence of Cd. As found, paxilline protected partially from the Cd-induced cytotoxicity, namely taken in concentration of 1 μM it decreased the Cd-induced cell necrosis in average by 10-14 or 13-23% for AS-30D and PC12 cells, respectively.

[Substantiation of the drug «Cytoflavin» application and cognitive-behavioral therapy in complex treatment of deforming coxarthrosis in elderly patients.].

The article presents the results of a study of the effectiveness of the addition of a standard course of conservative therapy to 104 patients of the older age group with coxarthrosis deforming the drug «Cytoflavin» and cognitive-behavioral therapy courses. It was found that such scheme increases the effectiveness of therapeutic interventions, which manifests itself as the improvement of the mental and physical components of quality of life by reducing pain and increasing the functionality of some of the affected hip. At the heart of positive clinical effect is a decrease in processes of inflammation and reduction of tension of regulatory processes in the organism.

[The effect of high-dose metformin on the metabolic parameters and functional state of the liver of agouti-mice with the melanocortin obesity.].

In recent years, the effectiveness of high-dose metformin (MF) to treat the endocrine and oncological diseases has been shown. However, the use of high-dose MF may be associated with the lactic acidosis and the liver dysfunctions. The aim of the work was to study the effect of long-term (10 days) oral administration of a relatively high dose of MF (600 mg/kg per day) into yellow C57Bl/6J (Ay/a) Agouti line mice with the melanocortin type obesity on the liver function, which was evaluated by the morphology of hepatocytes and the severity of steatosis, the expression of the inflammatory and apoptotic factors of and the activity of aminotransferases, as well as on the plasma lactate level in the animals.

[The effect of different types of bariatric surgery on the metabolic and hormonal parameters in rats with decompensed form of type 2 diabetes mellitus.].

Currently, one of the approaches to correct metabolic disorders in the type 2 diabetes mellitus (DM2) with obesity are bariatric surgery (BS), including sleeve gastrectomy (SG), gastric bypass (GB) and ileal transposition (IT). However, their effectiveness and impact on the hypothalamic signaling and hormonal status in severe forms of DM2 without obesity remain little studied. The aim of the work was to study the effect of IT, SG and GB on the insulin, leptin, ghrelin and glucagon-like peptide-1 (GLP-1) levels in the blood and on the expression of the genes encoding the main components of the hypothalamic signaling systems in rats with decompensated form of DM2, which was induced by a high-fat diet (3 months) and a single low dose of streptozotocin (25 mg/kg, 2 months after the start of the diet).

Hydrophobic Amines and Their Guanidine Analogues Modulate Activation and Desensitization of ASIC3.

Acid-sensing ion channel 3 (ASIC3) is an important member of the acid-sensing ion channels family, which is widely expressed in the peripheral nervous system and contributes to pain sensation. ASICs are targeted by various drugs and toxins. However, mechanisms and structural determinants of ligands' action on ASIC3 are not completely understood.

[The decrease in the basal and luteinizing hormone receptor agonist-stimulated production of testosterone in aging male rats.].

The aging leads to a weakening of the steroid function of the testes and a decrease in their sensitivity to gonadotropins. However, the mechanisms of this are poorly understood. The aim of this work was to study the stimulating effects of human chorionic gonadotropin (hCG) and TP03, a low-molecular-weight agonist of luteinizing hormone (LH)/hCG receptor, on testosterone (T) production and the expression of steroidogenic proteins in young (3 months) and aging (15 months) male rats, and to investigate the activity of the adenylyl cyclase system in the membranes isolated from the testes of rats.

[Mast cells of the human pineal gland.].

The purpose of this study was to assess the possibilities of identifying mast cells using different histochemical and immunohistochemical methods and elucidating the features of their localization in the human pineal gland. The undertaken study showed that mast cells are an essential component of the human pineal gland, regardless of age. The data obtained indicate an increase in the number of mast cells in the pineal gland with age.

[Features of the changes in lipid peroxidation and activity of Na+/K+-ATPase in the brain of the aged rats in the conditions of two-vessel cerebral ischemia/reperfusion.].

The success of preclinical neuroprotection studies depends on the model used in animal research. The methodological approaches developed on young animals and widely used for modeling cerebral ischemia/reperfusion injury may not be so effective or not suitable for its modeling on senescent animals, which usage is recommended for preclinical trials. The aim of this study was to investigate the age-related features on the effect of brain reperfusion with different duration (1 and 3 h) after 2-vessel forebrain ischemia on the level of lipid peroxidation (LPO) products and on the activity of Na+/K+-ATPase in the cerebral cortex of rats aged 22-24 months.

[U-133, a heat shock proteins inducer, precludes sleep disturbances in a model of the preclinical stage of Parkinson's disease in aged rats.].

Parkinson's disease (PD) is a chronic progressive neurodegenerative disease, closely associated with aging. It is considered incurable due to both late diagnosis and symptomatic treatment, which is able to alter neither molecular mechanisms of sleep disruption nor the neurodegenerative processes, developing with aging and PD progression. In the present study, we assess the therapeutic potential of a novel chaperone inducer U-133 (acetyl 2,3,7-tris-O-glucoside echinochrome) in the preclinical stage of PD modelled in aged rats by the inhibition of the proteasomal system in the brain.

Multiple modes of action of hydrophobic amines and their guanidine analogues on ASIC1a.

Hydrophobic monoamines containing only a hydrophobic/aromatic moiety and protonated amino group are a recently described class of acid-sensing ion channel (ASIC) modulators. Intensive studies have revealed a number of active compounds including endogenous amines and pharmacological agents and shown that these compounds potentiate and inhibit ASICs depending on their specific structure and on subunit composition of the target channel. The action of monoamines also depends on the application protocol, membrane voltage, conditioning and activating pH, suggesting complex mechanism(s) of the ligand-receptor interaction.

Respiratory complex II in mitochondrial dysfunction-mediated cytotoxicity: Insight from cadmium.

In the present work we studied action of several inhibitors of respiratory complex II (CII) of mitochondrial electron transport chain, namely malonate and thenoyltrifluoroacetone (TTFA) on Cd-induced toxicity and cell mortality, using two rat cell lines, pheochromocytoma PC12 and ascites hepatoma AS-30D and isolated rat liver mitochondria (RLM). It was shown that malonate, an endogenous competitive inhibitor of dicarboxylate-binding site of CII, restored in part RLM respiratory function disturbed by Cd. In particular, malonate increased both phosphorylating and maximally uncoupled respiration rates in KCl medium in the presence of CI substrates as well as palliated changes in basal and resting state respiration rates produced by the heavy metal on the mitochondria energized by CI or CII substrates.

[Study of age changes in compensatory processes on the model of neurodegeneration of nigrostriatal system in rats.].

It is generally accepted that advanced age is the main risk factor for the development and progression of Parkinson's disease (PD). However, data that experimentally confirm the dependence on the age of the rate of neurodegeneration progression and the activity of compensatory processes in the nigrostriatal system in the development of PD are absent in the modern literature. The present study uses a model of neurodegeneration of the nigrostriatal system in rats of different age groups, created by the microinjections of the proteasome inhibitor lactacystin (LC) into the substantia nigra pars compacta (SNpc).

Sub-cellular Electrical Heterogeneity Revealed by Loose Patch Recording Reflects Differential Localization of Sarcolemmal Ion Channels in Intact Rat Hearts.

The cardiac action potential (AP) is commonly recoded as an integral signal from isolated myocytes or ensembles of myocytes (with intracellular microelectrodes and extracellular macroelectrodes, respectively). These signals, however, do not provide a direct measure of activity of ion channels and transporters located in two major compartments of a cardiac myocyte: surface sarcolemma and the T-tubule system, which differentially contribute to impulse propagation and excitation-contraction (EC) coupling. In the present study we investigated electrical properties of myocytes within perfused intact rat heart employing loose patch recording with narrow-tip (2 μm diameter) extracellular electrodes.

Potentiation and Block of ASIC1a by Memantine.

Acid-sensing ion channels (ASICs) are modulated by various classes of ligands, including the recently described hydrophobic monoamines, which inhibit and potentiate ASICs in a subunit-specific manner. In particular, memantine inhibits ASIC1a and potentiates ASIC2a homomers. The aim of the present work was to characterize action mechanism of memantine on recombinant ASIC1a expressed in CHO (Chinese hamster ovary) cells.

Ligands of histamine receptors modulate acid-sensing ion channels.

Recently we found that synthetic compounds containing amino group linked to hydrophobic or aromatic moiety are potent modulators of the proton-gated channels (ASICs). These structures have clear similarity with ligands of histamine receptors. We have also demonstrated that histamine potentiates homomeric ASIC1a by shifting its activation dependence to less acidic conditions.