Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration

Abstract

This review focuses on the role of prenatal hypoxia in the development of brain functions in the postnatal period and subsequent increased risk of neurodegenerative disorders in later life. Accumulating evidence suggests that prenatal hypoxia in critical periods of brain formation results in significant changes in development of cognitive functions at various stages of postnatal life which correlate with morphological changes in brain structures involved in learning and memory. Prenatal hypoxia also leads to a decrease in brain adaptive potential and plasticity due to the disturbance in the process of formation of new contacts between cells and propagation of neuronal stimuli, especially in the cortex and hippocampus. On the other hand, prenatal hypoxia has a significant impact on expression and processing of a variety of genes involved in normal brain function and their epigenetic regulation. This results in changes in the patterns of mRNA and protein expression and their post-translational modifications, including protein misfolding and clearance. Among proteins affected by prenatal hypoxia are a key enzyme of the cholinergic system-acetylcholinesterase, and the amyloid precursor protein (APP), both of which have important roles in brain function. Disruption of their expression and metabolism caused by prenatal hypoxia can also result, apart from early cognitive dysfunctions, in development of neurodegeneration in later life. Another group of enzymes affected by prenatal hypoxia are peptidases involved in catabolism of neuropeptides, including amyloid-β peptide (Aβ). The decrease in the activity of neprilysin and other amyloid-degrading enzymes observed after prenatal hypoxia could result over the years in an Aβ clearance deficit and accumulation of its toxic species which cause neuronal cell death and development of neurodegeneration. Applying various approaches to restore expression of neuronal genes disrupted by prenatal hypoxia during postnatal development opens an avenue for therapeutic compensation of cognitive dysfunctions and prevention of Aβ accumulation in the aging brain and the model of prenatal hypoxia in rodents can be used as a reliable tool for assessment of their efficacy.

Hydrogen Sulfide Alleviates Anxiety, Motor, and Cognitive Dysfunctions in Rats with Maternal Hyperhomocysteinemia via Mitigation of Oxidative Stress

“…These epigenetic mechanisms may interfere with the gene expression during the early prenatal period the consequences of which are manifested in postnatal life. Indeed, prenatal stress and hypoxia in critical periods of brain development via genetic and epigenetic mechanisms result in significant changes of cognitive functions and increases the risk of neurodegeneration in later life [ 86 , 87 , 88 ].…”

Features of Postnatal Hippocampal Development in a Rat Model of Sporadic Alzheimer’s Disease

“…One of such risk factors is the formation of aberrant neural circuits under the influence of genetic and/or environmental factors (Kovács et al, 2014;Axelrud et al, 2019). Recently, it was reported that prenatal hypoxia (Nalivaeva et al, 2018) and low weight at birth (Heinonen et al, 2015) may be among these factors determining the brain development trajectory as well as the risk of AD. Such conditions can be caused by preterm birth (including 1st degree preterm birth, which usually is not accompanied by cognitive deficits) as well as by trophic insufficiency during gestation owing to a number of causes (Lesuis et al, 2018).…”

Genetic factors and the risk of drug-resistant epilepsy in young children with epilepsy and neurodevelopment disability: A Prospective Study and Updated Meta-Analysis

“…Perinatal and prenatal insults are major risk factors for infantile epilepsy [29]. The proposed pathophysiological mechanism is that hypoxia-ischemia that can have deleterious effects on the vulnerable regions of the developing brain lead to substantive injuries that could affect not only seizure threshold but also cognition [30]. Studies have also explored the mechanisms underlying neuronal injury, which could be a cause of epilepsy; rst, hypoxic-ischemic encephalopathy (HIE) initially affects various processes that potentially contribute to energy failure and loss of mitochondrial function, including brain edema, membrane depolarization, increased levels of neurotransmitter release and uptake inhibition, and increased levels of intracellular calcium (which can cause the initiation of further pathological cascades) [31].…”