Hypoxia and myelination deficits in the developing brain

Abstract

Myelination is a complex and orderly process during brain development that is essential for normal motor, cognitive and sensory functions. Cellular and molecular interactions between myelin-forming oligodendrocytes and axons are required for normal myelination in the developing brain. Oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into mature myelin-forming oligodendrocytes. In this connection, astrocytes and microglia are also involved in survival and proliferation of OPCs. Hypoxic insults during the perinatal period affect the normal development, differentiation and maturation of the OPCs or cause their death resulting in impaired myelination. Several factors such as augmented release of proinflammatory cytokines by activated microglia and astrocytes, extracellular accumulation of excess glutamate and increased levels of nitric oxide are some of the underlying factors for hypoxia induced damage to the OPCs. Additionally, hypoxia also leads to down-regulation of several genes involved in oligodendrocyte differentiation encoding proteolipid protein, platelet-derived growth factor receptor and myelin-associated glycoprotein in the developing brain. Furthermore, oligodendrocytes may also accumulate increased amounts of iron in hypoxic conditions that triggers endoplasmic reticulum stress, misfolding of proteins and generation of reactive oxygen species that ultimately would lead to myelination deficits. More in-depth studies to elucidate the pathophysiological mechanisms underlying the inability of oligodendrocytes to myelinate the developing brain in hypoxic insults are desirable to develop new therapeutic options or strategies for myelination deficits.

The Potential of Stem Cell Therapy to Repair White Matter Injury in Preterm Infants: Lessons Learned From Experimental Models

“…In addition, disruptions of the oxygen supply leads to oxidative stress through various pathways, ultimately causing production and accumulation of reactive oxygen species within developing OLs (van Tilborg et al, 2016). For example, activation of nitric oxide synthase causes pre-OL injury by nitric oxide production (Gluckman et al, 1992; Khwaja and Volpe, 2008; Lee, 2017; Singh et al, 2018). Further, OPCs are extremely sensitive to oxidative damage, as they lack particular anti-oxidant enzymes (Perrone et al, 2015).…”

“…Further, OPCs are extremely sensitive to oxidative damage, as they lack particular anti-oxidant enzymes (Perrone et al, 2015). Moreover, hypoxia has been shown to further fuel activation of the immune system, including activation of microglia thereby augmenting the release of pro-inflammatory cytokines (Singh et al, 2018).…”

Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia

“…Pro-inflammatory cytokines released by reactive glial cells also produce cytotoxic effects on oligodendrocytes [ 33 ], inducing premature maturation of oligodendrocyte progenitor cells and aberrant myelination, thereby contributing to hypomyelination in the developing brain [ 34 ], and to delays in neurobehavioral development [ 35 , 36 ], and cognitive impairments [ 2 , 37 ], including deficit in recognition memory [ 35 , 38 ], social skills [ 39 ], and increased anxiety [ 6 , 35 ], as well as deficits in motor coordination [ 6 , 35 ].…”

Synaptoprotection in Perinatal Asphyxia: An Experimental Approach

“…Myelination deficits affect nerve conduction velocity and disrupt synaptic transmission. Then, white matter alterations pose a relevant dysfunction regarding PA-induced synaptopathy in the developing brain (Herrera et al, 2017 ) and is one of the most common neuropathologies in premature infants (Barateiro et al, 2016 ; Singh et al, 2018 ). More details on the experimental findings of PA-induced synaptic alterations may be consulted in a related review of ours (Herrera et al, 2017 ).…”