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Review
. 2022 Jul 17;14(14):2923.
doi: 10.3390/nu14142923.

Neuroprotective Role of Lactoferrin during Early Brain Development and Injury through Lifespan

Gabriel Henrique Schirmbeck  1 , Stéphane Sizonenko  2 , Eduardo Farias Sanches  2
Affiliations
Review

Neuroprotective Role of Lactoferrin during Early Brain Development and Injury through Lifespan

Gabriel Henrique Schirmbeck et al. Nutrients. .

Abstract

Early adverse fetal environments can significantly disturb central nervous system (CNS) development and subsequently alter brain maturation. Nutritional status is a major variable to be considered during development and increasing evidence links neonate and preterm infant impaired brain growth with neurological and psychiatric diseases in adulthood. Breastfeeding is one of the main components required for healthy newborn development due to the many "constitutive" elements breastmilk contains. Maternal intake of specific nutrients during lactation may alter milk composition, thus affecting newborn nutrition and, potentially, brain development. Lactoferrin (Lf) is a major protein present in colostrum and the main protein in human milk, which plays an important role in the benefits of breastfeeding during postnatal development. It has been demonstrated that Lf has antimicrobial, as well as anti-inflammatory properties, and is potentially able to reduce the incidence of sepsis and necrotizing enterocolitis (NEC), which are particularly frequent in premature births. The anti-inflammatory effects of Lf can reduce birth-related pathologies by decreasing the release of pro-inflammatory factors and inhibiting premature cervix maturation (also related to commensal microbiome abnormalities) that could contribute to disrupting brain development. Pre-clinical evidence shows that Lf protects the developing brain from neuronal injury, enhances brain connectivity and neurotrophin production, and decreases inflammation in models of perinatal inflammatory challenge, intrauterine growth restriction (IUGR) and neonatal hypoxia-ischemia (HI). In this context, Lf can provide nutritional support for brain development and cognition and prevent the origin of neuropsychiatric diseases later in life. In this narrative review, we consider the role of certain nutrients during neurodevelopment linking to the latest research on lactoferrin with respect to neonatology. We also discuss new evidence indicating that early neuroprotective pathways modulated by Lf could prevent neurodegeneration through anti-inflammatory and immunomodulatory processes.

Keywords: brain development; lactoferrin; neurodegenerative diseases; neuroprotection; prematurity.

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Conflict of interest statement

The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1
Figure 1
Schematic representation of the CNS development in the first 1000 days period. Infant’s brain undergoes major hallmarks of neurodevelopment during this period and can be affected by poor nutrition, infectious pathogens and pollutants with life lasting consequences. Common neurodevelopmental disorders involve myelination disturbances (IUGR, prematurity) or synaptic pruning failure such as Autism Spectrum Disorder and Schizophrenia and can be triggered by early life events during brain maturation. Nutritional policies can be adopted to improve outcomes, with proper macro and micronutrient adequacy. Specific macronutrients such as Lactoferrin and n-3 polyunsaturated fatty acids have promising benefits for neurodevelopment and should be further explored in clinical trials.
Figure 2
Figure 2
Maternal milk is the optimal source of nutrients for newborns, even in the absence of consensus about its ideal composition. Dietary interventions during pregnancy can alter maternal milk composition and alter the infant’s immune system, playing a major role during brain development. The best understanding of molecules present in maternal milk is important not only for improving recommendation directives, but also for defining better formulas to be administered for infants at risk.
Figure 3
Figure 3
Protective effects of lactoferrin through the lifespan. Lf has been shown to prevent disturbances during pregnancy, decreasing the incidence of NEC, sepsis and prematurity among other complications. Allied to this, clinical and preclinical data have indicated that Lf modulates several pathways (ion scavenger, anti-inflammatory, anti-apoptotic and improving microbiome) protecting the developing brain. Lf has also been considered a potential biomarker of neurodegeneration and its mechanisms of action make it a good candidate to be tested for the prevention of neurodegenerative diseases.
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Grants and funding

The manuscript was supported by the Brazilian Agencies CAPES and CNPq, the Bill and Melinda Gates Foundation and the Fondation pour Recherches Médicales, Geneva, Swiss National Fund, Fondation Paralysie Cérébrale, France.