Skip to main content

Lutein levels in arterial cord blood correlate with neurotrophic calcium binding S100B protein in healthy preterm and term newborns



S100B is an established biomarker of brain development and damage. Lutein (LT) is a naturally occurring xanthophyll carotenoid mainly concentrated in the central nervous system (CNS), but its neurotrophic role is still debated. We investigated whether LT cord blood concentrations correlate with S100B in a cohort of preterm and term healthy newborns.


We conducted a prospective study on the distribution of LT and S100B in arterial cord blood of healthy preterm (n = 50) and term (n = 50) newborns.


S100B and LT showed a pattern of concentration characterized by higher levels (P < 0.01, for all) at 33-36 weeks gestation (GA) followed by a progressive decrease (P < 0.01, for all) from 37 onwards with a dip at term. Both S100B and LT were gender-dependent with significantly (P < 0.01, for all) higher levels in females in preterm and term groups. S100B (R = 0.68; P < 0.001) and LT (R = 0.40; P = 0.005) correlated with GA at sampling. A positive significant correlation (R = 0.87; P < 0.001) between S100B and LT was found.


The present data showing a correlation between S100B and LT supports the notion of a LT trophic role in the CNS. Further investigations in high-risk infants are needed to elucidate LT involvement in the pathophysiological cascade of events leading to CNS development and damage.


S100B is a brain-specific acidic calcium binding protein of the EF-hand family mainly concentrated in glial cells and in neuronal sub-populations [1]. There is evidence that the protein is a consolidated marker of central nervous system (CNS) growth and damage mimicking a Janus face: when secreted, S100B is believed to have paracrine/autocrine trophic effects at physiological (nanomolar) concentrations, and neurotoxic effects at higher (micromolar) concentrations [2].

In different biological fluids (i.e. amniotic, cerebrospinal, blood, urine, saliva and milk) of fetuses, newborns and pediatric patients S100B correlates with clinical, laboratory and radiologic parameters suggestive of CNS development and damage [2,3,4,5,6,7,8,9].

In the last decade, Food and Drugs Administration (FDA), European Medical Agency (EMA) and more recently the National Institute of Health (NIH) supported investigations on neurobiomarkers (NB) in the perinatal period. The aim was to encourage the integration of NB in drug development and their appropriate use in clinical practice, promoting NB qualification programs [10].

Among different new NB, to date still matter of investigation Lutein (LT) is a naturally xanthophyll carotenoid not synthesized by humans. In biological fluids and tissues LT concentration depends on daily dietary intake since it is found at high levels in fruits and vegetables (i.e. spinach and kale) [11,12,13,14]. In the perinatal period, LT has been shown to be highly concentrated in different biological fluids (blood and human milk) and in CNS specific areas (i.e. neuro-retinal, frontal, occipital cortex and hippocampus) [15,16,17,18]. In this regard, LT has been shown to be involved in CNS development through a not still understood mechanism [19, 20]. LT trophic role has been suggested by its clinical and biochemical correlation: the former with gestational age (GA) and gender in healthy preterm/term newborns; the latter with a consolidated brain growth factor such as Activin A [20].

Therefore, in the present study we aimed at investigating whether LT arterial cord blood levels correlated with S100B in healthy preterm and term infants, thus supporting its CNS trophic role.

Materials and methods


The local Ethics Committees approved the study protocol and informed and signed consent was obtained from all parents of patients.

We recruited 100 women with consecutive healthy pregnancies (preterm n = 50; term n = 50), delivering between 33+6d and 41+6d weeks of GA (Fig. 1).

Fig. 1
figure 1

Flow chart showing patient recruitment

GA was determined by clinical data and by ultrasound scan performed in the first trimester. Appropriate growth was defined as follows: i) a biparietal diameter and abdominal circumference between 10th-90th centiles in agreement with Campbell and Thoms [21], and ii) birth weight (BW) between 10th-90th centiles according to our population standards, after correction for the mother’s height, weight, parity, and the sex of the newborn [22]. Preterm and term newborns were classified when they were born before or after 37 GA, respectively. We include into the study only preterm and term infants showing the following perinatal outcomes: no maternal illness; no signs of fetal distress; pH > 7.2 in cord or venous blood; and Apgar scores at 1-5 min > 7.

Exclusion criteria were: the presence of any maternal CNS illness, multiple pregnancies, intrauterine growth retardation, gestational hypertension, diabetes and infections, any fetal malformations, chromosomal abnormalities, perinatal asphyxia and dystocia.

Arterial cord blood samples were collected at birth to assess standard laboratory monitoring parameters, S100B and LT. All samples collected for NB measurement were centrifuged at 900 g (S100B) and 2500 g (LT), respectively, and stored at − 70 °C.

Neurological examination

Neurological examination was performed daily during hospital staying according to a qualitative approach by Prechtl [23] that assigned each infant to one of three diagnostic groups: normal, suspect or abnormal. An infant was considered abnormal when one or more of neurological syndromes such as hyper- or hypokinesia, hyper- or hypotonia, hemisyndrome, apathy and hyperexcitability syndromes were present. An infant was classified as suspect in absence of a defined syndrome or when only isolated signs were present. Neurological examination was performed by a single examiner who was blind to NB results.

S100B measurement

S100B levels were measured using an immunoluminometric assay (Liaison S100, Dietzenbach, Germany) according to the manufacturer’s instructions. The detection limit of the assay was 0.02 μg/L, the coefficient of variation was ≤2.8% within-assay and ≤ 5.3% interassay for concentrations ranging between 0.09 and 18.9 μg/L.

Lutein measurement

LT extraction and high-performance liquid cromatography (HPLC) analysis were performed using analytical conditions as previously reported [18, 20]. Briefly, an aliquot of 500 μL of serum was treated with 500 μL of ethanol (1% BHT) to precipitate proteic pellet. Hydroalcoholic fraction and pellet were separately extracted twice with 500 μL of hexane. Hexanic fractions, containing serum carotenoids, were combined, evaporated under nitrogen and solubilized in 50 μL of chloroform before HPLC analysis. Chromatographic separation of LT was performed on a LC-10 AD Shimadzu HPLC system equipped with binary pump and a column compartment, coupled to a UV-diode array detector.

Separation was performed on a Develosil 5 μm RP-AQUEUOUS C30, 250 × 4,6 mm column (Phenomenex Torrance, CA, USA) using chromatographic conditions previously reported [18]. Quantification of LT was done by the external standard method using a calibration curve built with LT as reference standard. The limit of detection was 0.017 nmol/mL.

The identification of LT and its metabolite was performed by liquid chromatography coupled to a tandem mass spectrometer. The chromatographic separation was performed by HPLC connected with two micro-pumps 200 (Perkin Elmer, Carlsbad, CA, USA), using the same column and the same chromatographic conditions described for HPLC analysis.

The API 3000 tandem mass spectrometer (API 3000, Applied Biosystem, Waltham, MA, USA) equipped with an atmospheric pressure chemical ionization source (APCI) was used for mass spectrometry analysis. The optimum settings of the mass spectrometer were: probe temperature 500 °C, the nebulizer current 4 μA, declustering potential 45 V and focusing potential 300 V.

Cerebral ultrasound

CUS was performed during the first 72 h of life or at discharge from hospital in all the study population. Recordings were performed by real-time ultrasound machine (Acuson 128SP5 Mountain View CA, USA) at the predetermined monitoring time-points. A single examiner who did not know the results of the cord blood test and clinical data reviewed images. Cerebral haemorrhage was classified according to Papile et al. criteria [24].

Monitoring parameters

In all recruited infants pulsed arterial oxygen saturation (SaO2) and the main laboratory parameters such as red blood cell count (RBC); hemoglobin blood concentrations (Hb); hematocrit rate (Ht); venous blood pH; partial venous carbon dioxide pressure (pCO2); partial venous oxygen pressure (pO2); base excess (BE); blood ions were recorded at the admission into the study.

Statistical analysis

For sample size calculation, we used changes in S100B arterial cord blood concentrations in healthy preterm and term infants at birth as the main parameter [25]. We assumed a decrease of 0.5 standard deviation (SD) in S100B to be clinically significant. Considering an α = 0.05 and using a two-sided test, we estimated a power of 0.95, recruiting 45 preterm and 45 term infants. We added n = 5 infants per group to allow for dropouts, cross-over and consent retirement (Fig. 1).

Clinical data is reported as mean and SD. Biochemical data is reported as median and interquartile centiles. The results of fetal and neonatal monitoring parameters were compared between groups by the two-sided Mann–Whitney U test and by Kruskal–Wallis one-way ANOVA followed by the Dunn post-hoc test when the data did not follow a Gaussian distribution. Comparisons between proportions were performed with the Fisher exact test. Linear regression analysis was performed for correlations between S100B, LT and GA, respectively. Statistical analysis was performed using Sigma Stat 3.5 (GmBH, Germany). A value of P < 0.05 was considered significant.


Table 1 shows maternal and perinatal characteristics in the term and preterm newborns at admission into the study. In particular, maternal age, delivery mode and gender were comparable between the two groups (P > 0.05, for all).

Table 1 Perinatal characteristics in preterm and term newborns

As expected, significant differences (P < 0.001, for both) were observed between preterm and term newborns regarding GA and BW. No significant differences (P > 0.05, for all) were detectable between studied groups regarding Apgar scores at 1st and 5th minutes, SaO2 and the main laboratory parameters (RBC, Hb, Ht, venous blood pH; pCO2, pO2, BE and blood ions).

Neurological examination and cerebral ultrasound patterns did not differ between groups. Moreover, at discharge from hospital, no overt neurological syndrome was detectable in all infants admitted to the study.

S100B protein measurements

S100B arterial blood levels were detectable in all the samples collected. S100B pattern of concentration was characterized by higher levels in the early GA (P < 0.01, for all) with a peak at 33-36 GA (S100B median: 1.51 μg/mL; 25th–75th centile: 1.12-1.90 μg/mL) and by a progressive decrease, with a dip at 41 GA (S100B median: 0.60 μg/mL; 25th–75th centile: 0.33-0.75 μg/mL). Moreover, S100B has been found to be GA dependent (R = − 0.68; P < 0.001).

When S100B levels were corrected for gender, we found higher (P < 0.01, for all) protein levels in females than males both in preterm and term infants (Fig. 2, panel A).

Fig. 2
figure 2

Panel A S100B (μg/L) arterial cord blood concentrations in term (T) and preterm (PT) newborns and when corrected for gender (male: M; female: F). Data are given as median and 5th–95th centiles. (*) P < 0.01. Panel B Lutein (pmol/mL) arterial cord blood concentrations in term (T) and preterm (PT) newborns and when corrected for gender. Data are given as medians and 5th–95th centiles. (*) P < 0.01

Lutein measurements

LT arterial blood levels were detectable in all the samples collected. LT showed a pattern of concentration characterized by higher levels in the early GA (P < 0.01, for all) with a peak at 33-36 GA (LT median: 82.06 pmol/mL; 25th–75th centile: 57.45–133.50 pmol/mL), followed by a progressive decrease from 37 GA onwards, with the lower dip at 42 GA (LT median: 57.60 pmol/mL; 25th–75th centile: 42.50–65.07 pmol/mL). Moreover, LT has been found to be GA dependent (R = − 0.40; P = 0.005). When LT levels were corrected for gender, we found higher (P < 0.01, for all) LT levels in females than males both in preterm and term infants (Fig. 2, panel B).

S100B and lutein correlation

In Table 2 S100B and LT correlations are reported. There were significant positive correlations (P < 0.05, for all) between S100B and LT when considered total populations and when sub-groups for GA and gender.

Table 2 Correlation between S100B protein and Lutein arterial cord blood levels (LT) at different gestational ages and after correction for gender


In the last decade there has been an emerging request of new diagnostic tools to include in daily clinical practice for early detection of cases at risk for perinatal brain injury [2,3,4]. On this light, FDA, EMA and more recently NIH approved the inclusion of NB such as S100B, Ubiquitin carboxyl-terminal hydrolase L1a and glial fibrillary acidic protein (G-FAP) in clinical protocols of adult and pediatric diseases such as traumatic brain injury [26].

In the perinatal period, there is growing evidence that the pathophysiological cascade of events involved in CNS development and damage are still not fully elucidated and are subjects of investigation. More recently, it has been shown that among a series of NB, S100B appears the only one fulfilling the majority of the criteria requested by FDA, EMA and NIH statements [10, 19, 27].

In the present study, we provide evidence that, in preterm and term healthy infants, arterial cord blood LT levels correlated with a consolidated NB of CNS development/damage namely S100B protein. Furthermore LT, as S100B, were GA- and gender-dependent with higher LT and S100B levels detectable in the early weeks of the third trimester of gestation (i.e. 33-36 wks) and lower in the near term.

The fact that both LT and S100B were GA and gender-dependent agrees with previous observations [5,6,7,8,9, 18, 20]. S100B trophic role is not surprising since the protein has been recently shown to fulfill all FDA, EMA, and NIH criteria. Nonetheless, LT trophic role is far to be fully elucidated. Results showed that LT was higher in the late preterm period (i.e. 33+6d-36+6d wks) mimicking S100B pattern. The finding deserves further consideration bearing in mind that at this time period the brain volume, weight and structure are at their highest growing level [28,29,30,31]. In particular: i) magnetic resonance imaging (MRI) patterns were suggestive of the timing and duration of different myelinisation processes at the stage under investigation [30], ii) the assessment in biological fluids of NB such as S100B, activin A, G-FAP were in agreement with MRI patterns and with the biochemical, morphological and electrophysiological maturation of the CNS [2,3,4, 19, 28, 31], and iii) near infrared spectroscopy patterns in the late preterm period, in healthy infants, showed an improved oxygenation status and increased tissue function suggestive of CNS development [32,33,34]. On the basis of the present findings, it is reasonable to support a LT CNS trophic role. The explanation may reside in LT site of concentration, metabolic and signal transmission actions. In particular LT: i) is mainly located in CNS areas crucial for learning and memory [16, 17], ii) correlates with, metabolites (i.e. 1-octadecanol, phosphate, NADH) involved in energy pathways leading to the peak of myelinisation during CNS development [17, 35, 36], iii) correlates with fatty acids and lysophospholipids involved in cortical development and folding, oligodendrocyte maturation and intracellular and cell-cell signalling [36,37,38], and iv) correlates with neurotransmitters (i.e. γ-aminobutyric acid, aspartate) involved in the main CNS developmental cascade of events (i.e. modulation of neuronal proliferation and maturation, neurite outgrowth, synapse formation, neurotransmission) [17, 39,40,41,42,43]. On the other hand, S100B: i) is mainly concentrated in the CNS where is located in glial and neuronal cells [2,3,4], ii) interacts with dopamine D2 receptor that belongs to the G protein-coupled receptor family with seven transmembrane domains and is widely distributed in neurons of the CNS [44], iii) extracellularly, it binds to receptor for advanced glycation end products, which activates several intracellular signalling pathways such as regulations of phosphorylation mediated by protein kinases, modulation of enzymatic activity, maintenance of cell shape and motility, influence of some signal transduction pathways, and promotion of calcium homeostasis [45, 46], and iv) depending on the concentration secreted, it exerts either trophic or toxic effects. At lower concentrations (nanomolar), S100B is thought to stimulate neuronal growth and enhancement of neuronal survival during development, while at higher concentrations (micromolar), S100B may have deleterious effects by increasing expression of the pro-inflammatory cytokine IL-6 and inducing apoptotic neuronal death [2,3,4]. On the basis of the present findings, it is reasonable to argue that LT and S100B are involved in a cascade of events modulating CNS development and neuroprotection.

Lastly, in the present series we also showed that LT and S100B are gender dependent. The finding deserves further consideration bearing in mind the different fetal/neonatal: i) pattern of CNS development in the two sexes, ii) growth, metabolic, hormonal developmental steps of maturation and, iii) biochemical and NB patterns of concentration at the stage under investigation [2,3,4, 6,7,8].

Finally, we recognize that the present study has several limitations, such as: i) the small population recruited, ii) the need of an empowerment in LT measurement technique in terms of reproducibility, and iii) longitudinal NB monitoring. Further investigations aimed at addressing the aforementioned issues are eagerly awaited.


In conclusion, the present results showing a correlation between LT and S100B support the notion of a potential LT neurotrophic role and open the way to further investigations aimed at promoting LT in a panel of trustable biomarkers of CNS development/damage.

Availability of data and materials

The deidentified individual participant data will not be made available.



Central nervous System


Food and Drug Administration


European Medicine Agency


National Institute of Health






Gestational age


Birth Weight


High Performance liquid Cromatography


Atmospheric Pressure Chemical Ionization


Cerebral Ultrasound

SaO2 :

Pulsed Arterial Oxygen Saturation


Red Blood Cell Count


Hemoglobin Blood Concentration


Hematocrit Rate

pCO2 :

Partial Venous Carbon Dioxide Pressure

pO2 :

Partial Venous Oxygen Pressure


Base Excess


Standard Deviation


Glial fibrillary acidic protein


Magnetic Resonance Imaging


  1. Heizmann CW. Ca2+−binding S100 proteins in the central nervous system. Neurochem Res. 1999;24:1097–100.

    Article  CAS  PubMed  Google Scholar 

  2. Abella R, Varrica A, Satriano A, Tettamanti G, Pelissero G, Gavilanes ADW, et al. Biochemical markers for brain injury monitoring in children with or without congenital heart diseases. CNS Neurol Disord Drug Targets. 2015;14:12–23.

    Article  CAS  PubMed  Google Scholar 

  3. Michetti F, Gazzolo D. S100B testing in pregnancy. Clin Chim Acta. 2003;335(1-2):1–7.

    Article  CAS  PubMed  Google Scholar 

  4. Satriano A, Pluchinotta F, Gazzolo F, Serpero L, Gazzolo D. The potentials and limitations of neuro-biomarkers as predictors of outcome in neonates with birth asphyxia. Early Hum Dev. 2017;105:63–7.

    Article  PubMed  Google Scholar 

  5. Gazzolo D, Bruschettini M, Corvino V, Oliva R, Sarli R, Lituania M, et al. S100B protein concentrations in amniotic fluid correlate with gestational age and with cerebral ultrasound scanning results in healthy fetuses. Clin Chem. 2001;47:954–6.

    Article  CAS  Google Scholar 

  6. Gazzolo D, Vinesi P, Marinoni E, Di lorio R, Marras M, Lituania M, et al. S100B protein concentrations in cord blood: correlations with gestational age in term and preterm deliveries. Clin Chem. 2000;46:998–1000.

    Article  CAS  Google Scholar 

  7. Gazzolo D, Bruschettini M, Lituania M, Serra G, Gandullia E, Michetti F. S100B protein concentrations in urine are correlated with gestational age in healthy preterm and term newborns. Clin Chem. 2001;47:1132–3.

    Article  CAS  Google Scholar 

  8. Gazzolo D, Lituania M, Bruschettini M, Ciotti S, Sacchi R, Serra G, et al. S100B protein levels in saliva: correlation with gestational age in normal term and preterm newborns. Clin Biochem. 2005;38:229–33.

    Article  CAS  PubMed  Google Scholar 

  9. Gazzolo D, Monego G, Corvino V, Bruschettini M, Bruschettini P, Zelano G, et al. Human milk contains S100B protein. Biochim Biophys Acta. 2003;1619:209–12.

    Article  CAS  PubMed  Google Scholar 

  10. Serpero LD, Bellissima V, Colivicchi M, Sabatini M, Frigiola A, Ricotti A, et al. Next generation biomarkers for brain injury. J Matern Fetal Neonatal Med. 2013;26(Suppl):44–9.

    Article  CAS  PubMed  Google Scholar 

  11. Dwyer JH, Navab M, Dwyer KM, Hassan K, Sun P, Shircore A, et al. Oxygenated carotenoid lutein and progression of early atherosclerosis: the Los Angeles atherosclerosis study. Circulation. 2001;103:2922–7.

    Article  CAS  PubMed  Google Scholar 

  12. González S, Astner S, An W, Goukassian D, Pathak MA. Dietary lutein/zeaxanthin decreases ultraviolet B-induced epidermal hyperproliferation and acute inflammation in hairless mice. J Invest Dermatol. 2003;121:399–405.

    Article  PubMed  Google Scholar 

  13. Schweigert FJ, Bathe K, Chen F, Büscher U, Dudenhausen JW. Effect of the stage of lactation in humans on carotenoid levels in milk, blood plasma and plasma lipoprotein fractions. Eur J Nutr. 2004;43:39–44.

    Article  CAS  PubMed  Google Scholar 

  14. Gossage CP, Deyhim M, Yamini S, Douglass LW, Moser-Veillon PB. Carotenoid composition of human milk during the first month postpartum and the response to beta-carotene supplementation. Am J Clin Nutr. 2002;76(1):193–7.

    Article  CAS  PubMed  Google Scholar 

  15. Rubin LP, Chan GM, Barrett-Reis BM, Fulton AB, Hansen RM, Ashmeade TL, et al. Effect of carotenoid supplementation on plasma carotenoids, inflammation and visual development in preterm infants. J Perinatol. 2012;32:418–24.

    Article  CAS  PubMed  Google Scholar 

  16. Vishwanathan R, Kuchan MJ, Sen S, Johnson EJ. Lutein and preterm infants with decreased concentrations of brain carotenoids. J Pediatr Gastroenterol Nutr. 2014;59:659–65.

    Article  CAS  PubMed  Google Scholar 

  17. Lieblein-Boff JC, Johnson EJ, Kennedy AD, Lai CS, Kuchan MJ. Exploratory Metabolomic analyses reveal compounds correlated with lutein concentration in frontal cortex, Hippocampus, and occipital cortex of human infant brain. PLoS One. 2015;10:e0136904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Picone S, Ritieni A, Fabiano A, Troise AD, Graziani G, Paolillo P, et al. Arterial cord blood lutein levels in preterm and term healthy newborns are sex and gestational age dependent. Clin Biochem. 2012;45:1558–63.

    Article  CAS  PubMed  Google Scholar 

  19. Gasparroni G, Graziosi A, Bersani I, Caulo M, Moataza B, Aboulgar A, et al. S100B protein, cerebral ultrasound and magnetic resonance imaging patterns in brain injured preterm infants. Clin Chem Lab Med. 2021;59:1527–34.

    Article  CAS  PubMed  Google Scholar 

  20. Picone S, Ritieni A, Fabiano A, Graziani G, Paolillo P, Livolti G, et al. Lutein levels in arterial cord blood correlate with neuroprotein activin a in healthy preterm and term newborns: a trophic role for lutein? Clin Biochem. 2018;52:80–4.

    Article  CAS  PubMed  Google Scholar 

  21. Campbell S, Thoms A. Ultrasound measurement of the fetal head to abdomen circumference ratio in the assessment of growth retardation. Br J Obstet Gynaecol. 1977;84:165–74.

    Article  CAS  PubMed  Google Scholar 

  22. Villar J, Cheikh Ismail L, Victora CG, Ohuma EO, Bertino E, Altman DG, et al. International standards for newborn weight, length, and head circumference by gestational age and sex: the newborn cross-sectional study of the INTERGROWTH-21st project. Lancet. 2014;384:857–68.

    Article  PubMed  Google Scholar 

  23. Prechtl HFR. Assessment methods for the newborn infant: a critical evaluation. In: Stratton D, editor. Psychobiology of the human newborn. Chichester: Wiley; 1982. p. 21–52.

    Google Scholar 

  24. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92:529–34.

    Article  CAS  PubMed  Google Scholar 

  25. Bellissima V, Visser GH, Ververs TF, Van Bel F, Termote JUM, van der Heide M, et al. Antenatal maternal antidepressants drugs affect S100B concentrations in fetal-maternal biological fluids. CNS Neurol Disord Drug Targets. 2015;14:49–54.

    Article  CAS  PubMed  Google Scholar 

  26. Undén L, Calcagnile O, Undén J, Reinstrup P, Bazarian J. Validation of the Scandinavian guidelines for initial management of minimal, mild and moderate traumatic brain injury in adults. BMC Med. 2015;13:292.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bersani I, Pluchinotta F, Dotta A, Savarese I, Campi F, Auriti C, et al. Early predictors of perinatal brain damage: the role of neurobiomarkers. Clin Chem Lab Med. 2020;58:471–86.

    Article  CAS  PubMed  Google Scholar 

  28. Guihard-Costa AM, Larroche JC. Differential growth between the fetal brain and its infratentorial part. Early Hum Dev. 1990;23:27–40.

    Article  CAS  PubMed  Google Scholar 

  29. Back SA, Luo NL, Borenstein NS, Levine JM, Volpe JJ, Kinney HC. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci. 2001;21:1302–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hüppi PS, Warfield S, Kikinis R, Barnes PD, Zientara GP, Jolesz FA, et al. Quantitative magnetic resonance imaging of brain development in premature and mature newborns. Ann Neurol. 1998;43:224–35.

    Article  PubMed  Google Scholar 

  31. Florio P, Abella R, Marinoni E, Di Iorio R, Livolti G, Galvano F, et al. Biochemical markers of perinatal brain damage. Front Biosci (Schol Ed). 2010;2:47–72.

    Article  Google Scholar 

  32. Tina LG, Frigiola A, Abella R, Tagliabue P, Ventura L, Paterlini G, et al. S100B protein and near infrared spectroscopy in preterm and term newborns. Front Biosci (Elite Ed). 2010;2:159–64.

    Article  Google Scholar 

  33. Tina LG, Frigiola A, Abella R, Artale B, Puleo G, D’Angelo S, et al. Near infrared spectroscopy in healthy preterm and term newborns: correlation with gestational age and standard monitoring parameters. Curr Neurovasc Res. 2009;6:148–54.

    Article  PubMed  Google Scholar 

  34. Grometto A, Pizzo B, Strozzi MC, Gazzolo F, Gazzolo D. Cerebral NIRS patterns in late preterm and very preterm infants becoming late preterm. J Matern Fetal Neonatal Med. 2019;32:1124–9.

    Article  PubMed  Google Scholar 

  35. Kingsbury MA, Rehen SK, Contos JJ, Higgins CM, Chun J. Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding. Nat Neurosci. 2003;6:1292–9.

    Article  CAS  PubMed  Google Scholar 

  36. Nogaroli L, Yuelling LM, Dennis J, Gorse K, Payne SG, Fuss B. Lysophosphatidic acid can support the formation of membranous structures and an increase in MBP mRNA levels in differentiating oligodendrocytes. Neurochem Res. 2009;34:182–93.

    Article  CAS  PubMed  Google Scholar 

  37. Bourre JM, Daudu O. Stearyl-alcohol biosynthesis from stearyl-CoA in mouse brain microsomes in normal and dysmyelinating mutants (quaking and jimpy). Neurosci Lett. 1978;7:225–30.

    Article  CAS  PubMed  Google Scholar 

  38. Bradl M, Lassmann H. Oligodendrocytes: biology and pathology. Acta Neuropathol. 2010;119:37–53.

    Article  PubMed  Google Scholar 

  39. Ben-Ari Y, Gaiarsa JL, Tyzio R, Khazipov R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007;87:1215–84.

    Article  CAS  PubMed  Google Scholar 

  40. Barbin G, Pollard H, Gaïarsa JL, Ben-Ari Y. Involvement of GABAA receptors in the outgrowth of cultured hippocampal neurons. Neurosci Lett. 1993;152:150–4.

    Article  CAS  PubMed  Google Scholar 

  41. Represa A, Ben-Ari Y. Trophic actions of GABA on neuronal development. Trends Neurosci. 2005;28:278–83.

    Article  CAS  PubMed  Google Scholar 

  42. Dingledine R, Mc Bain CJ. Glutamate and aspartate are the major excitatory transmitters in the brain. Philadelphia: Lippincott-Raven; 1999. p. 89–267.

    Google Scholar 

  43. Li SY, Fu ZJ, Lo AC. Hypoxia-induced oxidative stress in ischemic retinopathy. Oxidative Med Cell Longev. 2012;2012:426769.

    Article  CAS  Google Scholar 

  44. Moritz AE, Free RB, Sibley DR. Advances and challenges in the search for D2 and D3 dopamine receptor-selective compounds. Cell Signal. 2018;41:75–81.

    Article  CAS  PubMed  Google Scholar 

  45. Ostendorp T, Leclerc E, Galichet A, Koch M, Demling N, Weigle B, et al. Structural and functional insights into RAGE activation by multimeric S100B. EMBO J. 2007;26:3868–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Santamaria-Kisiel L, Rintala-Dempsey AC, Shaw GS. Calcium-dependent and -independent interactions of the S100 protein family. Biochem J. 2006;396:201–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


This work is part of the I.O. PhD International Program under the auspices of the Italian Society of Neonatology and was partially supported by grants to DG from “I Colori della Vita Foundation” and “Associazione Gruppo l’Insieme”, Italy. We thank Diasorin, Saluggia, Italy, for supporting analysis kits.

Informed consent statement

Informed consent was obtained from all subjects involved in the study.


This work is part of the I.O. PhD International Program under the auspices of the Italian Society of Neonatology and was partially supported by grants to DG from “I Colori della Vita Foundation”, Italy. We thank Diasorin, Saluggia, Italy, for supporting analysis kits.

Author information

Authors and Affiliations



SP, AR, GG, PP, ED’A, VB, DP, ST, DD, ADL and FC contributed to the conceptualization, investigation and writing of the original draft. DG contributed to the project administration, conceptualization, investigation, supervision and writing – review and editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Diego Gazzolo.

Ethics declarations

Ethics approval and consent to participate

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of ASO SS Antonio, Biagio and C. Arrigo, Alessandria, Italy (CoMBINeASO.Neonat17.01).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Picone, S., Ritieni, A., Graziani, G. et al. Lutein levels in arterial cord blood correlate with neurotrophic calcium binding S100B protein in healthy preterm and term newborns. Ital J Pediatr 48, 80 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


  • Newborns
  • Cord blood
  • Lutein
  • S100B
  • Biomarkers
  • Brain development