New Hybrid Structures Based on Memanthine and Edaravone Molecules.

New hybrid structures based on memantine and edaravone molecules, in which the pyrazolone ring and adamantane fragments are linked by an alkyl linker, were synthesized. It was found that, in addition to the ability to block the intrachannel site of NMDA receptors, the new hybrid compounds exhibit the property of blockers of the allosteric site of NMDA receptors, which is not inherent in memantine and edaravone preparations. The most active hit compound was determined, which, along with the properties of a two-site blocker of the NMDA receptor, exhibits a pronounced activity as an inhibitor of lipid peroxidation, similarly to the drug edaravone.

Role of Potassium Ions in Regulation of Calcium-Activated Chloride Channels.

Using the patch-clamp method in the whole cell configuration, it was shown that external potassium ions play an important role in the regulation of calcium-activated chloride channels (CaCCs). A clear dependence of the conductivity of the СаССs on the external potassium concentration was shown. The effect of external potassium in the range 0-15 mM on the conductivity of chloride channels was significantly greater than the effect it had on other ionic currents (sodium or potassium). There is reason to believe that these changes in the conductivity of CaCCs may contribute to the development of pathophysiological processes such as hypokalemia or hyperkalemia.

[Calcium-activated chloride channels: structure, properties, role in physiological and pathological processes]. / Kal'tsii-aktiviruemye khlornye kanaly: stroenie, svoistva, rol' v fiziologicheskikh i patologicheskikh protsessakh.

Ca2+-activated chloride channels (CaCC) are a class of intracellular calcium activated chloride channels that mediate numerous physiological functions. In 2008, the molecular structure of CaCC was determined. CaCC are formed by the protein known as anoctamine 1 (ANO1 or TMEM16A). CaCC mediates the secretion of Cl- in secretory epithelia, such as the airways, salivary glands, intestines, renal tubules, and sweat glands. The presence of CaCC has also been recognized in the vascular muscles, smooth muscles of the respiratory tract, which control vascular tone and hypersensitivity of the respiratory tract. TMEM16A is activated in many cancers; it is believed that TMEM16A is involved in carcinogenesis. TMEM16A is also involved in cancer cells proliferation. The role of TMEM16A in the mechanisms of hypertension, asthma, cystic fibrosis, nociception, and dysfunction of the gastrointestinal tract has been determined. In addition to TMEM16A, its isoforms are involved in other physiological and pathophysiological processes. TMEM16B (or ANO2) is involved in the sense of smell, while ANO6 works like scramblase, and its mutation causes a rare bleeding disorder, known as Scott syndrome. ANO5 is associated with muscle and bone diseases. TMEM16A interacts with various cellular signaling pathways including: epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPK), calmodulin (CaM) kinases, transforming growth factor TGF-ß. The review summarizes existing information on known natural and synthetic compounds that can block/modulate CaCC currents and their effect on some pathologies in which CaCC is involved.

Modulation of Calcium-Activated Chloride Currents in Rat Neurons with New 2-Aminotiophene-3-Carboxylic Acid Derivatives.

Using the patch-clamp method in the whole cell configuration, it was shown that new conjugates of 2-aminothiophene-3-carboxylic acid with adamantane derivatives exhibit the ability to modulate CaCC activity in the single Purkinje neurons of rat cerebellum. It was noted that, depending on the nature of the substitution in the thiophene fragment, the nature of the effect on CaCC varies from inhibition to potentiation of CaCC currents. The described compounds are also blockers of the NMDA receptor ifenprodile site, which may have an additional neuroprotective contribution to the spectrum of biological activity of these compounds.

New Positive Allosteric Modulator of AMPA Receptors: in vitro and in vivo Studies.

A new derivative of 3,7-diazabicyclo[3.3.1]nonane, which showed a high activity as a positive allosteric modulator of AMPA receptors of the CNS, was studied in electrophysiological experiments. At doses of 0.01 mg/kg, this compound significantly improved the memory of experimental animals disturbed by maximal electric shock. The results indicate that this compound is a promising candidate for preclinical trials and clinical studies as a drug for treatment of a number of psychoneurological diseases.

Effect of New Derivatives of 2-Aminothiophene-3-Carboxylic Acid on Calcium-Activated Chloride Currents in Rat Neurons.

Using the patch-clamp method in the whole-cell configuration, we showed that the new derivatives of 2-aminothiophene-3-carboxylic acid, which were synthesized by us earlier, can both block (compound 1) and potentiate (compound 2) calcium-activated chloride currents in single rat cerebellar Purkinje cells.

[The FUS protein: Physiological functions and a role in amyotrophic lateral sclerosis].

Certain forms of amyotrophic lateral sclerosis (ALS) are associated with an altered compartmentalization of FUS and its aggregation in the cytoplasm of motoneurons. FUS is a DNA/RNA-binding protein that is involved in DNA repair and the regulation of transcription, splicing, RNA transport, and local translation. Two theories have been proposed to explain the mechanism of the pathophysiological process in ALS. The theories attribute degeneration of motor neurons to either loss or gain of FUS function. The review describes the main physiological functions of FUS and considers evidence for each of the theories of ALS pathogenesis.

Modification of Calcium-Activated Chloride Currents in Cerebellar Purkinje Neurons.

The whole-cell voltage clamp technique was employed to record the total ionic currents in rat cerebellar Purkinje neurons. When intrapipette solution contained 120 mM KCl, replacement of the standard external physiological saline with Na-free solution resulted in appearance of inward tail current after the end of the depolarizing pulse. When intrapipette potassium ions were replaced for cesium ones, the tail currents were observed even in the presence of normal Na+ concentration (140 mM) in the external solution. Tail currents were not observed when external solution contained no Cl- and/or Ca2+ ions. Niflumic acid (25-100 µM) blocked these currents by 80-100%. Complete replacement of external Na+ for Tris ions pronouncedly augmented the amplitude and duration of the tail currents. These findings suggest that the tail transients in rat cerebellar Purkinje neurons are calcium-activated chloride currents whose amplitude and kinetics depend on ionic composition of the extracellular and intracellular solutions.

Novel conjugates of tacrine with 1,2,4,-thiadiazole as highly effective cholinesterase inhibitors, blockers of NMDA receptors, and antioxidants.

Conjugates of tacrine with 1,2,4-thiadiazole derivatives were synthesized for the first time. Their esterase profile and effects on the key NMDA receptor-binding sites as well as antioxidant activity were investigated. The obtained compounds effectively inhibited cholinesterases (with a predominant effect on butyrylcholinesterase), simultaneously blocked two NMDA receptor-binding sites (allosteric and intrachannel sites, and exhibited a high radical-scavenging activity. Our study shows that the obtained compounds are promising to design drugs for the treatment of Alzheimer's disease and other multifactorial neurodegenerative diseases.

Key role of external chloride ions in regulation of fast sodium channels in rat cerebellum Purkinje neurons.

A decrease in the external chloride ion concentration to 4 mM caused a decrease in the fast sodium current to 85-100% in rat cerebellum Purkinje neurons in the whole-cell configuration using the patchclamp method. This effect did not depend on the main cation from the internal side of the cell membrane (120 mM of potassium or cesium) and also appeared when Cl- was substituted with sulfate (SO2-4) or phosphate (H2PO4-) anion outside of the cell. The effect was reversible after washing out the low chloride by the standard saline.

Tetraethylammonium and 4-aminopyridine block calcium-dependent chloride current in rat cerebellum Purkinje cells.

Using patch-clamp method (whole cell configuration), it was shown that tetraethylammonium (TEA) and 4-aminopyridine (4-AP) block calcium-dependent chloride currents in the membrane of freshly isolated cerebellar Purkinje cells of rats (12-15 days). In the concentration range studied (50 µM-10 mM TEA and 100 µM-1 mM 4-AP), both compounds blocked the chloride current at IC50 130 µM for TEA and 110 µM for 4-AP. TEA blockade was reversible after washing. The effect of 4-AP at concentrations greater than 100 µM was irreversible: both outward and inward chloride currents were blocked even after the removal of 4-AP from the incubation medium.

Glutamate release and uptake processes are altered in a new mouse model of amyotrophic lateral sclerosis.

In this paper, we showed that in the cortex of mice expressing an abberant form of FUS protein that model amyotrophic lateral sclerosis (ALS), the processes of KCl-induced and basal [(3)H]glutamate release and uptake are altered at the presymptomatic stage as compared to the non-transgenic littermates. The change in these three parameters in transgenic animals causes excitotoxicity, which, in turn, may lead to massive loss of motor neurons and the onset of ALS symptoms.

Neuropeptide cycloprolylglycine is an endogenous positive modulator of AMPA receptors.

We have previously shown that neuropeptide cycloprolylglycine (CPG) increases the content of brain-derived neurotrophic factor (BDNF) in the culture of neuronal cells under normal conditions and in pathology. This is the first study to show that CPG at a physiological concentration of 10-6 M significantly enhances the transmembrane AMPA currents in rat cerebellar Purkinje cells. Thus, CPG is a positive endogenous modulator of AMPA receptors. It was assumed that the neuropsychotropic effects of CPG are implemented as a result of BDNF accumulation after the activation of AMPA receptors by this neuropeptide.

Synthesis, structure and magnetic ordering of the mullite-type Bi2Fe(4-x)CrxO9 solid solutions with a frustrated pentagonal Cairo lattice.

Highly homogeneous mullite-type solid solutions Bi2Fe(4-x)CrxO9 (x = 0.5, 1, 1.2) were synthesized using a soft chemistry technique followed by a solid-state reaction in Ar. The crystal structure of Bi2Fe3CrO9 was investigated using X-ray and neutron powder diffraction, transmission electron microscopy and (57)Fe Mössbauer spectroscopy (S.G. Pbam, a = 7.95579(9) Å, b = 8.39145(9) Å, c = 5.98242(7) Å, RF(X-ray) = 0.022, RF(neutron) = 0.057). The ab planes in the structure are tessellated with distorted pentagonal loops built up by three tetrahedrally coordinated Fe sites and two octahedrally coordinated Fe/Cr sites, linked together in the ab plane by corner-sharing forming a pentagonal Cairo lattice. Magnetic susceptibility measurements and powder neutron diffraction show that the compounds order antiferromagnetically (AFM) with the Néel temperatures decreasing upon increasing the Cr content from TN ∼ 250 K for x = 0 to TN ∼ 155 K for x = 1.2. The magnetic structure of Bi2Fe3CrO9 at T = 30 K is characterized by a propagation vector k = (1/2,1/2,1/2). The tetrahedrally coordinated Fe cations form singlet pairs within dimers of corner-sharing tetrahedra, but spins on the neighboring dimers are nearly orthogonal. The octahedrally coordinated (Fe,Cr) cations form antiferromagnetic up-up-down-down chains along c, while the spin arrangement in the ab plane is nearly orthogonal between nearest neighbors and collinear between second neighbors. The resulting magnetic structure is remarkably different from the one in pure Bi2Fe4O9 and features several types of spin correlations even on crystallographically equivalent exchange that may be caused by the simultaneous presence of Fe and Cr on the octahedral site.

Calcium-dependent chloride current in rat cerebellar Purkinje cell membranes.

The presence of calcium-dependent potential-activated chloride currents in the membranes of freshly isolated rat cerebellar Purkinje cells (12-15 days) was shown by the whole-cell patch clamp technique. Chloride currents appeared in a sodium-free external solution and reversibly disappeared in the absence of external chloride and calcium ions.

Binary mechanism of action of cognition enhancer NT1505 on glutamate receptors.

Compound NT1505 potentiates AMPA receptors in rat brain neurons and simultaneously noncompetitively blocks NMDA receptors via two different mechanisms. Considering previously obtained data on strong cognition-enhancing properties of this compound we can conclude that NT1505 is a novel cognition stimulator exhibiting properties of a positive modulator of AMPA receptors and a blocker NMDA receptor.

Effect of somatostatin on presynaptic and postsynaptic glutamate receptors and postsynaptic GABA receptors in the neurons of rat brain.

We studied the effect of somatostatin on presinaptic NMDA receptors and postsinaptic GABA, NMDA, and AMPA receptors in rat brain. It was shown that somatostatin inhibits NMDA-induced (45)Ca(2+) uptake into synaptosomes isolated from rat brain cortex (IC50=2.8×10(-11) M). Somatostatin potentiates AMPA receptors and inhibits hippocampal NMDA receptors in the entire range of examined concentrations (10(-14)-10(-7) M); it also potentiates or inhibits GABA receptor currents in a concentration-dependent manner. Our results suggest that somatostatin modulates the function of ionotropic glutamate and GABA receptors and is involved in cognitive and neurodegenerative processes in the mammalian brain.

Effect of corticotropin-like intermediate lobe peptide on presynaptic and postsynaptic glutamate receptors and postsynaptic GABA receptors in rat brain.

We studied the effect of corticotropin-like intermediate lobe peptide (CLIP) on presynaptic NMDA receptors and postsynaptic GABA, NMDA, and AMPA receptors in rat brain. CLIP inhibited presynaptic and postsynaptic NMDA receptors, but potentiated postsynaptic GABA and AMPA receptors. Our results indicate that CLIP modulates function of ionotropic receptors for glutamate and GABA.

Effect of muramyl dipeptides on postsynaptic GABA, NMDA, and AMPA receptors and presynaptic NMDA receptors in rat brain.

We studied the effect of muramyl dipeptides on postsynaptic GABA, NMDA, and AMPA receptors and presynaptic NMDA receptors. L,D-Dipeptide more potently than L,L-dipeptide inhibited postsynaptic NMDA receptors, potentiated GABA and AMPA receptors, and inhibited (45)Ca(2+) uptake in synaptosomes from of rat brain cortex. Our results indicate that muramyl dipeptides modulate function of glutamate and GABA receptors.