Involvement of heat shock proteins HSP70 in the mechanisms of endogenous neuroprotection: the prospect of using HSP70 modulators

This analytical review summarizes literature data and our own research on HSP70-dependent mechanisms of neuroprotection and discusses potential pharmacological agents that can influence HSP70 expression to improve neurological outcomes and effective therapy. The authors formed a systemic concepts of the role of HSP70-dependent mechanisms of endogenous neuroprotection aimed at stopping the formation of mitochondrial dysfunction, activation of apoptosis, desensitization of estrogen receptors, reduction of oxidative and nitrosative stress, prevention of morpho-functional changes in brain cells during cerebral ischemia, and experimentally substantiated new target links for neuroprotection. Heat shock proteins (HSPs) are an evolutionarily integral part of the functioning of all cells acting as intracellular chaperones that support cell proteostasis under normal and various stress conditions (hyperthermia, hypoxia, oxidative stress, radiation, etc.). The greatest curiosity in conditions of ischemic brain damage is the HSP70 protein, as an important component of the endogenous neuroprotection system, which, first of all, performs the function of intracellular chaperones and ensures the processes of folding, holding and transport of synthesized proteins, as well as their degradation, both under normoxic conditions and stress-induced denaturation. A direct neuroprotective effect of HSP70 has been established, which is realized through the regulation the processes of apoptosis and cell necrosis due to a long-term effect on the synthesis of antioxidant enzymes, chaperone activity, and stabilization of active enzymes. An increase in the level of HSP70 leads to the normalization of the glutathione link of the thiol-disulfide system and an increase in the resistance of cells to ischemia. HSP 70 is able to activate and regulate compensatory ATP synthesis pathways during ischemia. It was found that in response to the cerebral ischemia formation, HIF-1a is expressed, which initiates the launch of compensatory mechanisms for energy production. Subsequently, the regulation of these processes switches to HSP70, which “prolongs” the action of HIF-1a, and also independently maintains the expression of mitochondrial NAD-dependent malate dehydrogenase activity, thereby maintaining the activity of the malate-aspartate shuttle mechanism for a long time. During ischemia of organs and tissues, HSP70 performs a protective function, which is realized through increased synthesis of antioxidant enzymes, stabilization of oxidatively damaged macromolecules, and direct anti-apoptotic and mitoprotective action. Such a role of these proteins in cellular reactions during ischemia raises the question of the development of new neuroprotective agents which are able to provide modulation/protection of the genes encoding the synthesis of HSP 70 and HIF-1a proteins. Numerous studies of recent years have noted the important role of HSP70 in the implementation of the mechanisms of metabolic adaptation, neuroplasticity and neuroprotection of brain cells, so the positive modulation of the HSP70 system is a perspective concept of neuroprotection, which can improve the efficiency of the treatment of ischemic-hypoxic brain damage and be the basis for substantiating of the feasibility of using of HSP70 modulators as promising neuroprotectors

Functional nitric oxide conjugate systems state/restored heart thiols of rats in modeling isadrine-pituitrin’s myocardial infarction using metabolite-tropic cardioprotector “Angiolin”

Background: According to modern researches, endothelial dysfunction (ED) is one of the primary pathogenetic elements of cardiovascular diseases (myocardial infarction [MI], ischemic heart diseases, cerebral ischemic stroke, atherosclerosis, arterial hypertension, pulmonary hypertension, heart failure, and dilated cardiomyopathy) as well as obesity, hyperlipidemia, diabetes and hyperhomocysteinemia. The aim of this work was to study the influence of potential metabolitotropic cardioprotector “Angiolin” on the parameters of conjugate systems nitric oxide (NO)/restored thiols in heart under isadrine-pituitrin MI.Methods: This study was performed on Wistar white rats weighing 190-210 g. Biochemical, immune-enzyme analysis and histoimmunechemical study were performed.Results: In histological sections of hearts of the rats receiving Angiolin in parenteral dosing 50 mg/kg 30 mins before each pituitrin injection the density of endothelial NO-synthase (NOS)-positive cells increased by 29% and the density of inducible NOS-positive cells decreased by 23.3%. In cytosolic fraction of myocardium homogenate NOS activity increased by 27%, the concentration of NO stable metabolites increased by 70% and the content of nitrosative stress marker nitrotyrosine decreased by 42% when compared with control group. At the same time in similar samples of heart homogenate the increase of restored thiol groups’ level by 53.3%, methionine - by 35.1%, cysteine - by 170% and activity of glutathione reductase - by 186% was noted. The administration of reference drug mildronate to the animals with MI in dose 100 mg/kg did not result in significant changes of the studied parameters of thiol-disulfide system and NO system of the heart when compared with control group.Conclusions: Angiolin does not influence directly on NOS in MI, but at the same time protects NO from nitrosative stress increasing restored equivalents of thiol-disulfide system

Molecular mechanisms of myocardial damage in the hypertensive rats and hypertensive rats with metabolic disorders (diabetes mellitus, atherosclerosis)

Despite the success which was achieved in the treatment of arterial hypertension, for optimization of the treatment, it is necessary to study the pathogenesis of primary arterial hypertension and target organ damage on the molecular leve