Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives

Abstract

Free radicals play a role of paramount importance in the development of neonatal brain injury. Depending on the pathophysiological mechanisms underlying free radical overproduction and upon specific neonatal characteristics, such as the GA-dependent maturation of antioxidant defenses and of cerebrovascular autoregulation, different profiles of injury have been identified. The growing evidence on the detrimental effects of free radicals on the brain tissue has led to discover not only potential biomarkers for oxidative damage, but also possible neuroprotective therapeutic approaches targeting oxidative stress. While a more extensive validation of free radical biomarkers is required before considering their use in routine neonatal practice, two important treatments endowed with antioxidant properties, such as therapeutic hypothermia and magnesium sulfate, have become part of the standard of care to reduce the risk of neonatal brain injury, and other promising therapeutic strategies are being tested in clinical trials. The implementation of currently available evidence is crucial to optimize neonatal neuroprotection and to develop individualized diagnostic and therapeutic approaches addressing oxidative brain injury, with the final aim of improving the neurological outcome of this population.

Melatonin: A Potential Candidate for the Treatment of Experimental and Clinical Perinatal Asphyxia

“…At the cellular level, energy failure and a reduction in adenosine triphosphate result in a lack of pumping of ions from the cell and, consequently, an excessive influx of sodium and calcium ions with the accompanying flow of water into the cell [ 28 ]. A consequence of this process is cell swelling and/or cell lysis due to the flow of water [ 4 , 30 , 31 , 32 , 33 ]. The subsequent depolarization of the cell membrane opens the voltage-sensitive calcium channels and leads to an excessive influx of calcium into the cell cytoplasm [ 28 , 34 ].…”

“…The increase in intracellular calcium leads to the generation and release of excitatory amino acids, especially glutamate [ 34 ]. In the next step, excess glutamate activates receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid and N-methyl-D-aspartate receptors [ 30 , 31 , 32 , 33 , 35 ]. Activation of these receptors additionally increases the influx of calcium into cells affected by hypoxia or ischemia.…”

“…Activation of these receptors additionally increases the influx of calcium into cells affected by hypoxia or ischemia. Finally, an increase in intracellular calcium promotes the generation of reactive oxygen species, the release of pro-radicals, such as free ions, and the synthesis of excess nitric oxide by neuronal nitric oxide synthase, which is modulated via the N-methyl-D-aspartate receptor [ 30 , 31 , 32 , 33 , 35 ]. In addition, the activation of proteases, lipases and endonucleases increases, which causes the release of fatty acids and damage to the cell membrane and triggers a cascading series of reactions that lead to cell death via apoptosis [ 30 , 31 , 32 , 33 , 35 ].…”

“…The death of neurons after perinatal asphyxia occurs either through necrosis or through apoptosis. Necrotic death of neurons occurs immediately after injury and is the predominant cell death after perinatal asphyxia [ 4 , 30 , 31 , 32 , 33 ]. Apoptosis or programmed neuronal death is an essential phenomenon of delayed cell death.…”

Hypothermia combined with neuroprotective adjuvants shortens the duration of hospitalization in infants with hypoxic ischemic encephalopathy: Meta-analysis

“…Approximately 6-15 h later, there is a secondary surge of delayed cell death that is driven by excitotoxicity, mitochondrial failure and oxidative stress, and is accompanied by chronic inflammation, seizures and cytotoxic edema (Fatemi et al, 2009;Cotten and Sankaran, 2010;Yıldız et al, 2017). These deleterious effects are compounded by the intrinsic vulnerability of the neonatal brain attributed, in part, to immature antioxidant defense mechanisms and rising metabolic demands as the cerebral energy source shifts from anaerobic glycolysis to aerobic metabolism in order to fuel complex maturational processes (Liu et al, 2014;Martini et al, 2021). Clinical magnetic resonance spectroscopy studies have supported this biphasic model of cell death within the brain.…”