Cytoprotective Effects of Dinitrosyl Iron Complexes on Viability of Human Fibroblasts and Cardiomyocytes

Nitric oxide (NO) is an important signaling molecule that plays a key role in maintaining vascular homeostasis. Dinitrosyl iron complexes (DNICs) generating NO are widely used to treat cardiovascular diseases. However, the involvement of DNICs in the metabolic processes of the cell, their protective properties in doxorubicin-induced toxicity remain to be clarified. Here, we found that novel class of mononuclear DNICs with functional sulfur-containing ligands enhanced the cell viability of human lung fibroblasts and rat cardiomyocytes. Moreover, DNICs demonstrated remarkable protection against doxorubicin-induced toxicity in fibroblasts and in rat cardiomyocytes (H9c2 cells). Data revealed that the DNICs compounds modulate the mitochondria function by decreasing the mitochondrial membrane potential (ΔΨm). Results of flow cytometry showed that DNICs were not affected the proliferation, growth of fibroblasts. In addition, this study showed that DNICs did not affect glutathione levels and the formation of reactive oxygen species in cells. Moreover, results indicated that DNICs maintained the ATP equilibrium in cells. Taken together, these findings show that DNICs have protective properties in vitro. It was further suggested that DNICs may be uncouplers of oxidative phosphorylation in mitochondria and protective mechanism is mainly provided by the leakage of excess charge through the mitochondrial membrane. It is assumed that the DNICs have the therapeutic potential for treating cardiovascular diseases and for decreasing of chemotherapy-induced cardiotoxicity in cancer survivors.</p

Experimental Study of Neuroprotective Properties of Inhaled Argon-Oxygen Mixture in a Photoinduced Ischemic Stroke Model

Acute ischemic stroke is a serious problem for healthcare systems worldwide. Searching for the optimal neuroprotector is a contemporary challenge. Various studies have demonstrated neuroprotective properties of argon in ischemic brain damage models. However, the published data are inconsistent.The aim of the study was to evaluate the effect of 24-hour argon-oxygen mixture (Ar 70%/O₂ 30%) inhalation on the severity of neurological deficit and the extent of brain damage in rats after a photoinduced ischemic stroke. Material and methods. The experiments were carried out on male Wistar rats weighing 430–530 g (N=26). Focal ischemic stroke was modeled in the sensorimotor cortex of the rat brain using photochemically induced vascular thrombosis. The animals were randomly divided into 3 groups: sham procedure + N₂ 70%/O₂ 30% inhalation (SP, N=6); stroke + N₂ 70%/O₂ 30% inhalation (Stroke, N=10); Stroke + Ar 70%/O₂ 30% inhalation (Stroke+iAr, N=10). The limb placement test (LPT) was used for neurological assessment during 14 days. Additionally, on day 14 after the stroke, brain MRI with lesion size morphometry was performed. Summarized for days 3,7 and 14 LPT scores were lower in the Stroke and Stroke + iAr groups as compared to the SP group.Results. Statistically significant differences in LPT scores between SP, Stroke, and Stroke+iAr groups were revealed on day 3 post-stroke: (scores: 14 (13; 14), 6.5 (4; 8), and 5 (3; 8), respectively, P=0.027). However, there was no statistical difference between the Stroke and Stroke+iAr groups.Conclusion. 24-hour inhalation of argon-oxygen mixture (Ar 70%/O₂ 30%) after stroke does not reduce the extent of brain damage or the severity of neurological deficit

Механизмы повреждения и защиты клетки при ишемии/реперфузии и экспериментальное обоснование применения препаратов на основе лития в анестезиологии

Pharmaceuticals based on lithium ions have been already used in clinical practice for over 60 years for the treatment of bipolar disorders and remain a basic pharmacological therapy for patients with this disease. In spite of this, the therapeutic mechanisms of action of lithium ions have not been fully investigated. In the past decade, in vitro and in vivo experiments have provided a good deal of data suggesting that lithium ions have previously undescribed neuro-, cardio-, and nephro-protective properties. Numerous investigations have demonstrated that glycogen synthase kinase-3/3, the key enzyme of different pathological and protective signaling pathways, is the target of lithium ions in displaying these effects. This review deals with just these new properties of lithium ions, which make them utterly promising for clinical use in circulatory arrest-associated conditions, which is particularly relevant for anesthesiology and resuscitation. Key words: lithium ions, brain, heart, kidney, postresuscitation disease.Фармакологические препараты на основе ионов лития уже более 60 лет используются в клинической практике для лечения биполярных расстройств и остаются основой фармакотерапии пациентов с этой группой заболеваний. Несмотря на это, терапевтические механизмы действия ионов лития изучены не в полной мере. В течение последних 10 лет в экспериментах in vitro и in vivo было получено множество данных, свидетельствующих о наличии у ионов лития ранее не описанных нейро-, кардио- и нефропротекторных свойств. Основной мишенью ионов лития при реализации этих эффектов является киназа гликогенсинтазы-3в, ключевой фермент различных патологических и защитных сигнальных путей. Данный обзор посвящен новым свойствам ионов лития, делающих их чрезвычайно перспективными для клинического применения при состояниях, связанных с остановкой кровообращения, что особенно актуально для анестезиологии и реаниматологии. Ключевые слова: ионы лития, мозг, сердце, почка, постреанимационная болезнь

Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

Mitochondrial abnormalities have been identified as a central mechanism in multiple neurodegenerative diseases and, therefore, the mitochondria have been explored as a therapeutic target. This review will focus on the evidence for mitochondrial abnormalities in the two most common neurodegenerative diseases, Parkinson's disease and Alzheimer's disease. In addition, we discuss the main strategies which have been explored in these diseases to target the mitochondria for therapeutic purposes, focusing on mitochondrially targeted antioxidants, peptides, modulators of mitochondrial dynamics and phenotypic screening outcomes

Neuroprotective Effects of Mitochondria-Targeted Plastoquinone in a Rat Model of Neonatal Hypoxic–Ischemic Brain Injury

Neonatal hypoxia&ndash;ischemia is one of the main causes of mortality and disability of newborns. To study the mechanisms of neonatal brain cell damage, we used a model of neonatal hypoxia&ndash;ischemia in seven-day-old rats, by annealing of the common carotid artery with subsequent hypoxia of 8% oxygen. We demonstrate that neonatal hypoxia&ndash;ischemia causes mitochondrial dysfunction associated with high production of reactive oxygen species, which leads to oxidative stress. Targeted delivery of antioxidants to the mitochondria can be an effective therapeutic approach to treat the deleterious effects of brain hypoxia&ndash;ischemia. We explored the neuroprotective properties of the mitochondria-targeted antioxidant SkQR1, which is the conjugate of a plant plastoquinone and a penetrating cation, rhodamine 19. Being introduced before or immediately after hypoxia&ndash;ischemia, SkQR1 affords neuroprotection as judged by the diminished brain damage and recovery of long-term neurological functions. Using vital sections of the brain, SkQR1 has been shown to reduce the development of oxidative stress. Thus, the mitochondrial-targeted antioxidant derived from plant plastoquinone can effectively protect the brain of newborns both in pre-ischemic and post-stroke conditions, making it a promising candidate for further clinical studies

Study of the Molecular Mechanisms of the Therapeutic Properties of Extracellular Vesicles

Extracellular vesicles (EVs) are small biological structures that are released by cells and have important roles in intercellular communication [...