Molecular targets in the search for endothelium-protecting compounds

Impairment of endothelial function forms basis for many cardiovascular diseases, therefore today it becomes an independent target for therapeutic action, and the search for new compounds possessing endothelium-protective properties is one of the prospective goals of the pharmacotherapy and medicinal chemistry. An efficient instrument to solve the problem is the use of methods of molecular modeling. Application of the methods is possible only if detailed information on three-dimensional structure and function of molecular targets—receptors and enzymes responsible for signal transduction both inside and outside endothelial cells—is available. In the review we collected the data on the structure and functions of various macromolecules involved in the process of regulation of vascular tone. The structure of endothelial NO-synthase (EC 1.14.13.39) (eNOS) responsible for synthesis of nitrogen oxide and involved in the process of vascular tone regulation is described. The importance of its substrate, L-arginine, from the point of view of eNOS activity regulation is emphasized; the data on structure and functions of L-arginine transport system are presented. Also, various pathways of eNOS activity regulation are described, including activation and competitive inhibition through binding of exogenous substances in its active center and inhibition through caveolin binding at eNOS oxygenase domain among them, as well as regulation by means of phosphorylation of individual eNOS amino acid residues by protein kinases and their dephosphorylation by phosphatases. The importance of membrane receptors of endotheliocytes as targets for substances possessing endothelium-protective activity is emphasized. Receptors of endothelin, thrombocyte activation factor, prostaglandins, bradykinin, histamine, serotonin, and protein kinase-activated receptors are among them. The importance of calcium and potassium ion channels in vessel cells for endothelium protection is emphasized. Finally, the macromolecules discussed in the review are considered as targets in the search for endothelium-protective therapeutic agents by the proposed approaches and methods of molecular modeling.     

Cortical cerebral atrophy in patients with Parkinson’s disease: New opportunities for in vivo diagnostics

The Parkinson’s disease (PD) pathology is not limited to degeneration of the nigrostriatal dopaminergic system, but also includes the wide lesion of various regions of cerebral cortex. In our study we aimed to identify differences in the brain cortical thickness in patients with early and advanced PD using MRI morphometry. Sixty-seven patients with Hoehn–Yahr stages 2 and 3 were examined. All patients underwent MRI with subsequent post-processing and estimation of cortical thickness values in different brain regions. Significant differences in the visual and cingulate cortex, fusiform gyri, frontopolar zone of a dominant hemisphere, and Brodmann’s areas 1, 2, 3, and 4 of a non-dominant hemisphere were obtained. These data show relationship between the non-motor manifestations of PD and degeneration of certain cortical regions of the brain.     

Pharmabiotic Based on Lactobacillus fermentum Strain U-21 Modulates the Toxic Effect of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine as Parkinsonism Inducer in Mice

Human Physiology - The states of the intestinal microbiota and the nervous system have repeatedly been shown to affect each other in experimental and clinical studies, changes in microbiota being...     

Experience of experimental modelling of Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by choreic involuntary movements, decline in cognitive functions, behavioral disturbances, and progressive neuronal death affecting primarily the striatum. The fatal nature of HD makes it important to search for new effective methods of its treatment, which requires the development of experimental models of the disease. These models can be created using 3-nitropropionic acid (3-NPA), which is a neurotoxin causing typical changes in motor skills and memory impairment in animals due to induction of oxidative stress, impaired glutathione defense, and destruction of striatal cells. We modeled HD in rats by chronic daily intraperitoneal administration of 3-NPA for 17 days. Systemic administration of a low dose of 3-NPA (10 mg/kg) induced hyperactivity of animals in the open field test (including movement redundancy as a hyperkinesia analogue) and had no effect on the behavior of the animals in the X-maze test. On the contrary, rats administered with a toxic dose of 3-NPA (20 mg/kg) exhibited a significant decrease in their motor activity and a cognitive decline in behavioral tests. A histopathological analysis revealed damage and loss of neurons and a decrease in expression of dopaminergic markers (tyrosine hydroxylase and plasma membrane dopamine transporter) in the striatum. The gliotoxic effect of 3-NPA was also found in the striatum, which was confirmed by immunohistochemical staining for astrocytic proteins: GFAP, glutamine synthetase, and aquaporin-4. This HD model may be helpful for testing new experimental therapies at different stages of HD-like neurodegeneration, including therapies based on cell neurotransplantation.     

The influence of hypothermia on the restoration of neural activity of brain slices from hibernating ground squirrels

1. 1. Neural activity was recorded in hippocampal slices from deep hibernating Yakut ground squirrels and in hippocampal and septal slices from non-hibernating animals.

2. 2. Slices were placed immediately after preparation in hypothermic conditions (3–4°C). Their activity was tested under standard conditions at 31°C in the incubation chamber. Some of the prepared slices were tested after maintenance in hypothermia for 2 or 24 h.

3. 3. In the hippocampal slices of hibernating ground squirrels, neural activity was present, irrespective of the period in hypothermia.

4. 4. Slices from guinea-pigs and hamsters did not possess neural activity after either 2 or 24 h of hypothermic treatment.

     

Computer modeling of mechanisms of the information processing in the olfactory bulb. I. Model of the structure-functional organizations of neuronal elements in the olfactory bulb and receptor epithelium

A computer model of the olfactory bulb was constructed. The paper describes: 1) the general architecture of a model neuron network that reflects the neurophysiological experimental and theoretical data on the structural and functional organization of the peripheral part of the olfactory system, the olfactory bulb with inputs from olfactory receptor neurons; 2) the organization of each of three levels of the model: receptors, olfactory glomeruli, and basic neurons; and 3) a scenario of the computer model work. In some aspects, in particular, in the principle of information presentation, the treatment of the role of basic neurons (mitral and tufted cells), and their interrelations in modules, the model favorably differs from the available olfactory bulb models. The model is basic and provides further refinement of the architecture, an increase in the number of modules, and the modeling of the learning process.     

Computer modeling of mechanisms of the information processing in the olfactory bulb. II. Mechanisms of identification and short-term storage in the olfactory bulb: results of the computer experimentation

The results of experimentation with the computer model of the olfactory bulb are presented. The architecture and scenario of the work of the model were described previously. The dynamic character of the identification process and the mechanism of memorizing short-term of smell stimuli are described. During the identification, a self-adjustment of the olfactory bulb to incoming signals occurs. The self-modification of mitral and tufted cell synapses enhances responses of the cells; upon subsequent presentation of the stimulus, the olfactory bulb responds with a higher activity. The modeling confirmed the validity of the assumption that the functions of mitral and tufted cells are to identify the components of a complex smell and the image of the smell as the whole.