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

Abstract

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.

Altered Blood Molecular Markers of Cardiovascular Function in Rats after Intrauterine Hypoxia and Drug Therapy

“…We found that HSP70 "prolongs" the action of HIF-1a, and also independently maintains the expression of NAD-MDH-mx, thereby maintaining the activity of the compensatory mechanism of ATP production-the malate-aspartate shuttle mechanism-for a long time [58]. Our works have shown that Angiolin can activate the malate-aspartate shuttle mechanism in the myocardium during ischemia [56].…”

“…To date, it is known that the mechanisms of the protective action of HSP70 are realized due to the restoration of the correct tertiary structure of damaged proteins, as well as in the formation and dissociation of protein complexes. Our studies revealed the positive role of HSP70 aimed at reducing the formation of mitochondrial dysfunction in neurons of the sensorimotor cortex and hippocampus in cerebral ischemia [56]. The therapeutic effect of the investigated pharmacological agents after PH can be explained as follows.…”

“…The revealed primary cardioprotective effect of Angiolin, when administered after intrauterine hypoxia, with the preservation of the effect even after a monthly withdrawal, is explained by its following properties. Angiolin, under conditions of acute cerebral ischemia, exhibits pronounced endothelioprotective properties; it preserves the density of endotheliocytes, increases the concentration in the nuclei of RNA, increases the density of proliferating endotheliocytes (BrdU-test), increases the efficiency of utilization of endogenous L-arginine, and increases the expression of vascular endothelial factor (VEGF), as well as eNOS, and the presence of divalent sulfur in its structure determines the property of the NO scavenger [56].…”

Combined Pharmacological Modulation of Translational and Transcriptional Activity Signaling Pathways as a Promising Therapeutic Approach in Children With Myocardial Changes

“…Nitrosative stress also leads to heat shock protein 70 (HSP70) deficiency in the cell by depriving the glutathione linked of the thiol-disulphide system. Cytotoxic forms of NO not only lead to the modification (reversible and irreversible) of macromolecules, including HSP70 itself, but also reduce the expression activity of the genes encoding its synthesis [42,43]. Role of NO derivatives in suppressing gene activity and reducing levels of various transcription factors demonstrated [44].…”

Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection

“…Cu has been found to be repressed in neurons with evidence of apoptosis, while Zn-SOD is known to bind and facilitate the production of significant amounts of endogenous peroxynitrite (ONOO − ) [160][161][162]. Low concentrations of • NO donors have been shown to inhibit neuroapoptosis induced by growth factor deprivation or TNF-α addition, potentially through the activation of the heat shock protein HSP70 or the inhibition of caspase-3 [163,164]. Dinitrosyl iron complexes (DNICs) at concentrations ranging from 5 to 10 µM are believed to suppress IL-1β-induced neuroapoptosis by promoting • NO synthesis.…”