Clinical Drug Experience Knowledgebase

Evaluation of the Antioxidant Activity of Lutein/Zeaxanthin Early Administered to Premature Newborns

Lutein is the most important carotenoid present selectively in certain tissues of the human body, mainly at the level of the retina, macula (hence the name) and lens. In tissues and serum, lutein is found together with a carotenoid dihydroxide, its isomer, zeaxanthin. Lutein and zeaxanthin are present at the level of the umbilical cord and pass through the placental barrier and are also present in the plasmatic ones, in breast milk and especially in the colostrum. Concerning the way of administrating, the lutein presents, through its specific characteristics, an elevated bioavailability after oral administration. The hematic levels of lutein, after providing nutriments rich in carotenoids, are increased with 67% from the 14% observed at beta-carotene. Through interdisciplinary and coordinated studies, performed both in vitro and in vivo, there were identified different action mechanisms; particularly, investigators have demonstrated a defense mechanism of the tissue function by lutein, which is produced through the neutralization (quench) phenomenon of the singlet oxygen and reactive oxygen species (ROS). This action provides molecules with different activities: an antioxidant function, anti-inflammatory properties, properties which promote anti-tumoral effects, induction of detoxification enzymes and positive effect on proteins promoting the communication between joints (up-regulation). Recently, there have appeared experimental and chemical data proving that the oxidative stress and harmful actions determined by ROS can play an important role in the pathogenesis of many neurological diseases as Alzheimer, Parkinson in adult and ROP and NEC in newborns.

This is due to the fact that the nervous system is characterized by membranes rich in polyunsaturated fats, the first cellular compounds affected by ROS attack through the lipid peroxidation. A similar mechanism can appear to certain ocular tissues (macula, lens, retina) which, containing high amounts of polyunsaturated fat acids, are more vulnerable than other structures with oxidative degradations induced by ROS.

Due to the fact that carotenoids are amongst the most powerful antioxidants existing in nature, there are being developed new researches concerning the functional role of these substances in preventing neurodegenerative diseases in newborns.

Because these polyunsaturated fat acids are very sensitive to oxidation, the modification of their plasmatic levels influences the state of the antioxidant systems on the mother and subsequently to the foetus. Many studies have proved that the increase of the susceptibility to the peroxidation of polyunsaturated fat acids on pregnant women is accompanied by an equivalent increase of the tocopherol plasmatic concentration which, immediately after birth, decrease sharply.

The plasmatic concentrations of the newborns' antioxidants were lower than those of the mothers. In the umbilical cord, the levels of tocopherols and carotenoids are significantly lower than the ones registered in the maternal plasma and the concentration of polyunsaturated fat acids on the newborn is significantly higher and a lot more increased than on the mother.

Furthermore, specific studies showed a growing interest towards the oxidative stress and oxygen reactive species which supposedly accumulate after birth. Many practices usually used in the delivery room (for example the drugs given to pregnant woman to ease her pain, the newborns' extraction methods, the techniques to minimize body temperature decrease, blocking the umbilical cord and especially the use of oxygen to 100 % or a ventilated room for newborns presenting asphyxia signs) do not always prove to be efficient and can also compromise the health of the newborn because of a significant increase of free radicals.

Some specific studies have compared the levels of free radicals, highlighted with markers, in the plasma of the umbilical cord of newborns with asphyxia treated 100% with oxygen or 21% with oxygen, comparative to a control group of children without asphyxia. The levels of free radicals were significantly increased immediately after birth in all three groups and grew in the two groups of newborns with asphyxia. In the group treated 21% with oxygen, these values decreased and have reached the same level of the newborns without asphyxia at 28 days after birth, whereas at the group treated 100% with oxygen the levels of free radicals remained very high.

Thus, a short exposure of the newborn to 100% oxygen is the cause of an extended oxidative stress state and a consistent increase of free radicals, which seem to be involved in different diseases and pathologies during the first months of life, especially in the preterm infant increasing significantly the incidence of ROP, IVH, BPD, NEC and infections.

These results show that the newborn need to increase the level of antioxidant protection to establish the redox balance and to prevent the problems occurred from an extended exposure to high levels of free radicals and oxygen reactive species.

The premature birth is the most frequent cause of mortality, morbidity and disability. Premature babies have an extremely high risk to develop ocular or neurological lesions. The main complication at visual level that may appear is called retinopathy of prematurity, so called ROP. Oxidative stress is involved in the etiology of this disease. In fact, premature babies, because of respiratory issues, are often exposed to potentially damaging oxygen concentrations or to phototherapy with high blue light intensity. These therapeutic practices are sources of free radicals.

The studies performed on the babies showed that the levels of carotenoids in the first four / six months of life are much reduced. This is due to the fact that the baby's diet is based exclusively on milk, without any solid elements (as vegetables or green leaves), sole sources of this nutrient. Nevertheless, breastfed babies, in average, present high plasmatic lutein levels than babies fed with prepared milk. Different milk formulas for newborns found at present time on the market are not enriched with this type of carotenoids, thus their content of lutein and zeaxanthin is very low, except certain formulas which are not traded in Italy and prepared using egg mixes. Breast milk, is thus the only source of lutein for the newborn before weaning, and breast feeding proves to be of considerable importance as primary source of these micronutrients for the newborn, proper development and visual function protection. Taking into consideration the correlation between the lutein in the blood and breast milk and the reduction of its levels, similar to all carotenoids, in milk, after 6 days from birth, there is already an important contribution of nutriments high in lutein during breast feeding. Such diet enriched in lutein is particularly important especially for the mothers of premature babies or babies having a small body weight when born. In fact, premature babies and underweight babies need more nutritive essential substances for a fast grow. These babies have not benefit from the contribution of highly nutritive and energetic substances transferred from their mothers during the last weeks of pregnancy. Also, the gastrointestinal and renal functions which are not completely developed reduce the absorption and withhold of important micronutrients, amongst which important antioxidants that protect the newborn from the exposure to high level of free radicals produced excessively at birth and several times as a result of the resuscitation techniques used. Breast feeding is important for the antioxidant contribution to the protection of the newborn and the nutritional state of the mother has subsequently an essential part because it influences the nutrition of the newborn, especially concerning certain solvable nutritive elements, such as lutein and zeaxanthin.

In the literature are already present researches and results with the use of lutein / zeaxanthin in the newborn.

The recent Gong's work has evaluated the role of lutein / zeaxanthin comparing the data obtained from various studies, including those of Romagnoli, Dani and Manzoni. Furthermore, thanks to RCT analysis of Rubin on the subject, investigators concluded that lutein / zeaxanthin is well tolerated and well absorbed from preterm infants also after oral administration.

The extremely interesting result that has emerged although not statistically significant (probably due to the small sample) is that supplementation with lutein / zeaxanthin reduced the incidence and severity of ROP.

This protocol is born from the idea that given the interesting results of earlier work is considered important to deepen a dosage of at least 1 ml / kg equal to 0,5 mg of lutein and 0.05 mg of zeaxanthin.

The evaluation of the key markers for oxidative stress is necessary along with the study of the biological antioxidant potential (BPT) and total hydroperoxide (TH) during and after treatment.

Already in a previous work, S. Perrone and M. Longini have demonstrated a reduction of the free radicals in term infants, during and after administration of lutein / zeaxanthin by determination of the BTP and TH.

Preparations based on lutein and zeaxanthin have never revealed on humans negative or harmful effects after administration, or to the gastrointestinal or systemic level. In recent studies there were not reported adverse phenomena after administrating 20 mg/day of lutein or zeaxanthin for a period of 6 months, or interactions with other liposoluble nutritive elements.