TRPA1 Channel as a Regulator of Neurogenic Inflammation and Pain: Structure, Function, Role in Pathophysiology, and Therapeutic Potential of Ligands.

TRPA1 is a cation channel located on the plasma membrane of many types of human and animal cells, including skin sensory neurons and epithelial cells of the intestine, lungs, urinary bladder, etc. TRPA1 is the major chemosensor that also responds to thermal and mechanical stimuli. Substances that activate TRPA1, e.g., allyl isothiocyanates (pungent components of mustard, horseradish, and wasabi), cinnamaldehyde from cinnamon, organosulfur compounds from garlic and onion, tear gas, acrolein and crotonaldehyde from cigarette smoke, etc., cause burning, mechanical and thermal hypersensitivity, cough, eye irritation, sneezing, mucus secretion, and neurogenic inflammation. An increased activity of TRPA1 leads to the emergence of chronic pruritus and allergic dermatitis and is associated with episodic pain syndrome, a hereditary disease characterized by episodes of debilitating pain triggered by stress. TRPA1 is now considered as one of the targets for developing new anti-inflammatory and analgesic drugs. This review summarizes information on the structure, function, and physiological role of this channel, as well as describes known TRPA1 ligands and their significance as therapeutic agents in the treatment of inflammation-associated pain.

Hevein-Like Antimicrobial Peptides of Plants.

Plant antimicrobial peptides represent one of the evolutionarily oldest innate immunity components providing the first line of host defense to pathogen attacks. This review is dedicated to a small, currently actively studied family of hevein-like peptides that can be found in various monocot and dicot plants. The review thoroughly describes all known peptides belonging to this family including data on their structures, functions, and antimicrobial activity. The main features allowing to assign these peptides to a separate family are given, and the specific characteristics of each peptide are described. Further, the mode of action for hevein-like peptides, their role in plant immune system, and the applications of these molecules in biotechnology and medicine are considered.

Effects of intranasal administration of the peptide antagonist of type I vaniloid receptor (TRPV1) in the rodent central nervous system.

Intranasal administration of the polypeptide APHC3, an antagonist of the TRPV1 receptor, had acute anxiolytic and antidepressant effects, as well as an ability to modify the microglial response to proinflammatory stress and cytokine profile of the hippocampus. However, the acute antidepressant effect of the polypeptide was not related to the attenuation of neuroiflammation and probably had a different mechanism. The use of intranasal administration of the APHC3 peptide as a therapeutic approach aimed at decreasing depression symptoms needs additional studies in order to find the mechanism of action of this polypeptide in the central nervous system (CNS).

Effect of polypeptides from sea anemone Heteractis crispa on the rodent blood pressure, heart rate, and hemostasis.

АРНС1-3 peptides, modulators of TRPV1 receptors, have been administered to SD rats to study their influence on the animal hemostatic system, heart rate, and blood pressure. None of АЗРС1-3 polypeptides have any effect on the hemostatic system. Both АРНС1 and АРНС2 polypeptides increased significantly the heart rate, but they did not affect blood pressure, which was probably caused by an ability of these polypeptides to modify animal thermoregulation.

Biological activity of a polypeptide modulator of TRPV1 receptor.

This paper presents data on the activity of a new APHC2 polypeptide modulator of TRPV1 receptors, which was isolated from the sea anemone Heteractis crispa. It has been shown that APHC2 has an analgesic activity, does not impair normal motor activity, and does not change body temperature of experimental animals, which has a great practical value for design of potent analgesics of a new generation. Further study of the characteristics of binding of the polypeptide to the TRPV1 receptor may show approaches to the development of other antagonists of this receptor that do not influence the body temperature.

[The Biological Activity of the Sevanol and Its Analogues].

Previously, from the plant Thymus armeniacus a new lignan sevanol was isolated, it's structure was elucidated and was shown that it effectively inhibits the acid-sensing channel ASIC3 and also exhibits a pronounced analgesic and anti-inflammatory effect. In this work biological activity of the sevanol analog obtained by chemical synthesis from simple precursors, the stereoisomer of sevanol and a precursor molecule represents a half of sevanol was measured in electrophysiological experiments on human ASIC3 channels expressed in Xenopus laevis oocytes. Measured inhibitory activity of a synthetic analogue coincided with the activity ofthe natural molecule. Stereoisomer showed inhibitory activity drop by about a third part, and the precursor molecule showed much less significant activity. In result the significance of functional groups and a spatial configuration of sevanol in order to biological activity was shown that is important to take into account for the optimal synthesis design as well as for new drugs development on its base.

Acid-sensing ion channels and their modulators.

According to a modern look acid-sensing ion channels (ASICs) are one of the most important receptors that perceive pH change in the body. ASICs represent proton-gated Na+-selective channels, which are expressed in neurons of the central and peripheral nervous system. These channels are attracting attention of researchers around the world, as they are involved in various physiological processes in the body. Drop of pH may occur in tissues in norm (e.g. the accumulation of lactic acid, the release of protons upon ATP hydrolysis) and pathology (inflammation, ischemic stroke, tissue damage and seizure). These processes are accompanied by unpleasant pain sensations, which may be short-lived or can lead to chronic inflammatory diseases. Modulators of ASIC channels activity are potential candidates for new effective analgesic and neuroprotection drugs. This review summarizes available information about structure, function, and physiological role of ASIC channels. In addition a description of all known ligands of these channels and their practical relevance is provided.

Changes in expression of genes encoding antioxidant enzymes, heme oxygenase-1, Bcl-2, and Bcl-xl and in level of reactive oxygen species in tumor cells resistant to doxorubicin.

The relationship between expression of genes encoding key antioxidant enzymes, heme oxygenase-1, Bcl-2, and Bcl-xl and change in production of reactive oxygen species (ROS) resulting from development of resistance of cancer cells K562, MCF-7, and SKOV-3 to the prooxidant chemotherapeutic agent doxorubicin (DOX) has been studied. Significant increase in mRNA level and activity of Mn-superoxide dismutase (Mn-SOD), catalase, and selenium-dependent glutathione peroxidase-1 (GPx-1) and reduced ROS level was found in resistant K562/DOX and SKVLB cells. In contrast, no change in ROS level was observed in MCF-7/DOX cells in parallel with decrease in Mn-SOD and catalase mRNAs and corresponding activities concurrently with high increase in GPx-1 mRNA and activity. As a result of the development of resistance, a similarity was found between the change in ROS level and the change in ho-1 and bcl-2 gene expression, whereas elevation of bcl-xl gene expression was observed in all three types of resistant cells. Particular features of development of adaptive antioxidant response as well as redox-dependent change in bcl-2 gene expression under formation of DOX resistance of cancer cells of different genesis are discussed.