Abstract
Hypoxic–ischemic brain damage is an alarming health and economic problem in spite of the advances in neonatal care. It can cause mortality or detrimental neurological disorders such as cerebral palsy, motor impairment and cognitive deficits in neonates. When hypoxia–ischemia occurs, a multi-faceted cascade of events starts out, which can eventually cause cell death. Lower levels of oxygen due to reduced blood supply increase the production of reactive oxygen species, which leads to oxidative stress, a higher concentration of free cytosolic calcium and impaired mitochondrial function, triggering the activation of apoptotic pathways, DNA fragmentation and cell death. The high incidence of this type of lesion in newborns can be partly attributed to the fact that the developing brain is particularly vulnerable to oxidative stress. Since antioxidants can safely interact with free radicals and terminate that chain reaction before vital molecules are damaged, exogenous antioxidant therapy may have the potential to diminish cellular damage caused by hypoxia–ischemia. In this review, we focus on the neuroprotective effects of antioxidant treatments against perinatal hypoxic–ischemic brain injury, in the light of the most recent advances.
Highlights
Perinatal hypoxic–ischemic encephalopathy (HIE) still continues to be an alarming health and economic problem, being associated with approximately 25% of global neonatal deaths [1,2]
Its neuroprotective effects against neonatal HIE have been investigated in depth due to its potent antioxidant properties [136,137]; it does not have any pro-oxidant effect with other antioxidants nor does it interference with other drug actions [138]
Prevention of increased free radical production after intrauterine asphyxia in fetal sheep has been shown [136]. These results indicate the important neuroprotective role of melatonin in reducing oxidative damage resulting from HI, and one of the possible mechanisms of action might be its reduction of endoplasmic reticulum stress and the preservation of sirtuin 1 expression in newborn rat neurons after hypoxia–ischemia [154]
Summary
Perinatal hypoxic–ischemic encephalopathy (HIE) still continues to be an alarming health and economic problem, being associated with approximately 25% of global neonatal deaths [1,2]. The infant brain is susceptible to HI [18,19], because of its specific characteristics: abundant unsaturated fatty acids, high rate of oxygen consumption, few antioxidants, high water content, low myelinization, low concentration of antioxidant enzymes, higher concentrations of free iron and oxygen-induced vasoconstriction [20,21,22,23,24]. The implication of ROS in the HI-induced brain damage is irrefutable; for example, it has been clearly shown that plasma malondialdehyde, a product of lipid peroxidation, and nitrate/nitrite levels were significantly higher in neonates with HIE [25]. Cell membrane are highly susceptible to free radical-induced peroxidation because of their polyunsaturated fatty acids [25] in the immature brain
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