Neonatal Hypoxic–Ischemic Encephalopathy: Perspectives of Neuroprotective and Neuroregenerative Treatments

Abstract

Hypoxic–ischemic encephalopathy (HIE) is a serious condition that could have deleterious neurological outcomes, such as cerebral palsy, neuromotor disability, developmental disability, epilepsy, and sensitive or cognitive problems, and increase the risk of death in severe cases. Once HIE occurs, molecular cascades are triggered favoring the oxidative stress, excitotoxicity, and inflammation damage that promote cell death via apoptosis or necrosis. Currently, the therapeutic hypothermia is the standard of care in HIE; however, it has a small window of action and only can be used in children of more than 36 gestational weeks; for this reason, it is very important to develop new therapies to prevent the progression of the hypoxic–ischemic injury or to develop neuroregenerative therapies in severe HIE cases. The objective of this revision is to describe the emerging treatments for HIE, either preventing cell death for oxidative stress, excitotoxicity, or exacerbated inflammation, as well as describing a new therapeutic approach for neuroregeneration, such as mesenchymal stem cells, brain-derived neurotrophic factor, and gonadotropin realizing hormone agonists.

Targeting the Multiple Complex Processes of Hypoxia-Ischemia to Achieve Neuroprotection

“…Because of this depletion in ATP, the Na + /K + pump fails and lactate production is increased to provide energy but also to help brain recovery [22,23]. The pump failure triggers depolarization of neurons leading to release of glutamate which accumulates in the inter-synaptic space [19,24]. Glutamate is an excitatory mediator that binds to postsynaptic receptors such as the N-methyl-D-aspartate (NMDA), α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors triggering their over-activation leading to massive calcium entry into the post-synaptic element [24,25].…”

Endothelin-1–Endothelin receptor B complex contributes to oligodendrocyte differentiation and myelin deficits during preterm white matter injury

“…However, unlike the extensive death of pre-OLs in infants with moderate or severe WMI (Back and Rosenberg, 2014), hypoxia-ischemia did not induce an excessive loss of OPCs or pre-OLs, as indicated by stable numbers of caspase-3 + and SOX10 + cells. Caspase-3 activation is tightly associated with the severity of cell death (Hisahara et al, 2003), based on the finding that pre-OLs degenerate due to caspase-3 activation in perinatal rodents exposed to moderate hypoxia-ischemia (Calvert and Zhang, 2005;Pedroza-Garcia et al, 2022). In support of our conclusions, it has been reported that the number of pre-OLs increases 2-3-fold within 24 h after hypoxia-ischemia in neonatal rats (Wahl and Schwab, 2014) and that of PDGFRα + OPCs gradually increases with hypoxia-ischemia (Miyamoto et al, 2015), indicating that OPCs and pre-OLs develop normally at the early stage of hypoxia-ischemia.…”

Human chorionic gonadotropin decreases cerebral cystic encephalomalacia and parvalbumin interneuron degeneration in a pro-inflammatory model of mouse neonatal hypoxia-ischemia

“…Therefore, neuroprotective therapies that target the negative inflammatory actions contributing to newborn brain injury may offer added therapeutic benefit in newborns affected by HI and/or exposed to pro-inflammatory conditions that further augment the degree of cerebral injury. Indeed, recent research efforts have explored treatments that target the dysregulated immune response observed in perinatal brain injury with varying levels of success, as it is the case with agents such as erythropoietin, stem cells and melatonin (Molloy et al, 2022; Pedroza-Garcia et al, 2022).…”