The Oxidative Stress Effects in Neonatal Diseases from Molecular Mechanisms to Therapeutic Potential

Free radicals (FRs) are continuously produced during aerobic metabolism and are characterized by high reactivity. They participate in many important physiological processes, but if produced in high concentrations, they lead to oxidative stress (OS) development and disturb pro-oxidative/antioxidative balance toward the oxidation of lipids, proteins, carbohydrates, or nucleic acids.[1] Each of these reactions may have deleterious consequences and differential effects on the distinct cell populations of the body, with certain specific cell types being particularly vulnerable in perinatal period.[2] Pathologies resulting from oxidative damage are grouped together and categorized as “free radical disease in the neonate” (FRD). Such pathologies include retinopathy of prematurity (which in severe cases may lead to blindness), bronchopulmonary dysplasia (a particularly debilitating pulmonary lesion in the preterm infant), periventricular leukomalacia (an important cause of severe neurodisability in premature infants), and necrotizing enterocolitis.

The enormous burden of human suffering and financial cost caused by FRD makes the early diagnosis and prevention a major health care priority.

The aim of this special issue entitled “Oxidative Stress Effects in Neonatal Diseases” is to stimulate the continuing efforts to validate new modalities for clinical and biochemical characterization of OS damage and measuring outcomes from treatment trials; to create advances in molecular diagnostics; to provide new insights into OS-mediated tissue damage, prevention, and treatment of oxidation processes.

First, we present overview of OS involvement in different physiological and pathological processes during pregnancy and neonatal period. OS occurs when the production of FRs exceeds the defense mechanisms. The newborn, especially if preterm, is particularly prone to the development of OS, due to the sudden exposure to the environment relatively hyperoxic than hypoxic intrauterine and to the immaturity of antioxidant systems. Moreover, endogenous sources of FRs such as mitochondrial metabolism, increased free circulating transition metals, inflammation through NADPH oxidase reactions, hypoxia-reoxygenation (through hypoxanthine–xanthine oxidase reaction), and hypoxia contribute to the increased OS susceptibility of the newborn. OS has been supposed to be the link between adverse intrauterine environment and both short-term complications, including altered fetal growth and increased perinatal morbidity and long-lasting effects on offspring's subsequent health. In sight of fetal programming theory, an abnormal stimulus or an “insult” during intrauterine life can lead to adaptations by the fetus to allow its survival but could finally result in permanent structural and physiological changes with long-term consequences in adulthood.

Glutathione has a pilot role in orchestrating the redox balance when there is an excess FRs production or defective antioxidant defenses that may have deleterious consequences.[3] Glutathione recycling and antioxidant enzyme activities in erythrocytes are described in an article written by Belvisi et al that particularly focuses on its involvement in hemolysis during the first days of life when there is no evidence of an immune-mediated hemolytic anemia, no consumptive red blood cell disorder, no morphologic or laboratory data to suggest a problem of the red cell membrane.

Thereafter, a review article written by Lotti addresses the role of mitochondrial dysfunction in pediatric cancer prone genetic diseases. The author discusses the molecular mechanisms that led into the discovery of the first therapeutic approach for the control of cellular redox imbalance consisting in the administration of potassium ascorbate with ribose. This therapeutic option rapidly changed the natural history of patients with Beckwith–Wiedemann's syndrome and Costello syndrome.

The next articles in this special issue report an updated overview of clinical and experimental studies on the antioxidant effects of melatonin and lutein. Some mechanisms, such as antioxidant action, preservation of mitochondrial function, reduction of apoptosis, anti-inflammatory responses could be responsible for the protective effects of lutein and melatonin. There is a need for further research to identify the specific efficacy of antioxidant protection in different neonatal diseases. To underline the importance of antioxidant treatment in perinatal period is one of the “take-home messages” presented in the paper written by Tei et al.

The latest manuscript describes the role of nonprotein-bound iron in intraventricular hemorrhage in developing brain. Authors suggest that hypoxia or ischemia-induced releasing of nonprotein-bound iron is a key regulating event that initiates a vicious circle of excessive FR generation, which in turn participates in inflammatory reaction and endothelial injury.[4] The damaged endothelium is activated in its procoagulant function with coagulation system disturbance in newborns.[5]

According to the growing interest on diseases involving OS worldwide, I hope that this special issue could be helpful for obstetrics, neonatologists, and pediatricians to recognize clinical and biochemical tool for the early identification and management of newborns at high risk for FR-mediated diseases. Given the challenge of balancing oxidant and antioxidants in newborn patients, antioxidant management must be tailored to each patient and should take into account the patient's genetic and acquired risk factors and the acute disturbances in redox status caused by drug administration, painful procedures, and infections.

• References

• 1 Gutteridge JM, Halliwell B. Free radicals and antioxidants in the year 2000. A historical look to the future. Ann N Y Acad Sci 2000; 899: 136-147
• 2 McQuillen PS, Ferriero DM. Selective vulnerability in the developing central nervous system. Pediatr Neurol 2004; 30 (4) 227-235
• 3 Saugstad OD. Oxidative stress in the newborn – a 30-year perspective. Biol Neonate 2005; 88 (3) 228-236
• 4 Buonocore G, Perrone S, Longini M , et al. Non protein bound iron as early predictive marker of neonatal brain damage. Brain 2003; 126 (Pt 5): 1224-1230
• 5 Haller H. Endothelial function. General considerations. Drugs 1997; 53 (Suppl. 01) 1-10