New targets for pharmacological correction of cognitive disorders in prenatal hypoxia action

Abstract

The review presents modern concepts of the mechanisms of brain cells damage in the conditions of prenatal action of the chronic hypoxia. Based on modern data of the adaptation mechanisms of an organism to the hypoxia state, new perspective directions for the search of effective drugs are proposed for the pharmacological correction of the prenatal hypoxia effects. Prenatal hypoxia is the most common cause of the newborns death and disability. Prenatal hypoxia leads to significant changes in the development of cognitive functions in the postnatal period of life, which are based on morphological changes in the brain structures involved in learning and memory. The results of recent years studies have made a great contribution to the disclosure of the formation mechanisms of a hypoxia state of different genesis and the metabolic and functional processes induced by it at the level of a cell and subcellular structures. A range of morphological and functional determinants (specific receptors, regulatory proteins, intracellular enzymes, mitochondrial ion channels, etc.) have been identified. They are directly involved in the development of immediate and long­term adaptation of the cell and the whole organism to hypoxia. An analysis of the literature as to studies of the molecular mechanisms of the prenatal hypoxia action showed that the basis of hypoxic damage of the newborn brain is a cascade of biochemical and molecular processes leading to excitotoxicity, oxidative and nitrosating stress and inflammation. At the same time, during hypoxia, compensatory­adaptive mechanisms begin to function, increasing the body's resistance to oxygen deficiency. In the review special attention was paid to the discussion as to the role of endogenous neuroprotection molecular determinants, such as HSP70 and HIF­1a. The HIF­1 transcriptional system is a key regulator of adaptive mechanisms of responses to hypoxia at the local and systemic levels. Changes in the expression of HIF­1 gene in prenatal development trigger the epigenetic mechanisms leading to negative changes in the nervous system development. An important component of the endogenous neuroprotective system is the HSP70 heat shock proteins family, which contributes to a wide range of processes of protein folding, refolding, membrane translocation of organellar and secretory proteins, and also controls the activity of regulatory proteins. The effect of HSP on the HIF­1 stabilization provides activation of processes of proliferation, apoptosis and angiogenesis in conditions of a hypoxia. Proteins HSP70/HIF­1a­system may be specific targets for exposure of pharmacological agents to regulate of the organism's adaptation for hypoxia. Therefore, the search of the new effective neuroprotective agents should be aimed to activation of HSP70/ HIF­1a­system and using of agents capable for providing of modulation of genes encoding the synthesis of HSP70­ and HIF­1a­ proteins.