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.