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

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.

Astrocyte‐derived lactoferrin reduces β‐amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP/PS1 transgenic mice

“…Astrocytic Lf knockout impaired neuronal dendritic complexity and cognitive ability, by decreasing cholesterol production during early life in mice (Xu et al, 2022), suggesting important roles for astrocytic Lf in regulating neuronal functions. In this study, human Lf overexpression in astrocytes improved the cognitive capacity of APP/PS1 mice and also improved the vision of WT mice, possibly via enhanced brain development caused by Lf‐induced up‐regulation of neuronal connectivity and neurotrophin production (Chen et al, 2015; Schirmbeck et al, 2022). Vision is important for MWM behavioural tests.…”

Versatile Nanoparticulate Systems as a Prosperous Platform for Targeted Nose–Brain Drug Delivery

“…For example, targeting specific receptors that are expressed in different CNS regions can facilitate the passage of different molecules into the CNS bypassing the BBB. Lactoferrin (LF) receptors are robustly expressed in BBB endothelial cells, so surface decoration of certain drugs with LF (a physiological iron-binding glycoprotein) can successfully results in efficient brain targeting. − Likewise, transferrin (TF) is a glycoprotein that controls extracellular iron levels within body fluids. Transferrin receptors are highly expressed by brain capillary endothelial cells; thus, TF is considered as an excellent ligand for brain targeting bypassing the rigid selective composition of BBB.…”

Characterization of Recombinant Human Lactoferrin Expressed inKomagataella Phaffii

“…Human lactoferrin (hLF) is an iron-binding glycoprotein found in high concentrations in human milk and to a lesser degree in tears, saliva, intestinal secretions, and neutrophils [1]. Human milk LF (hmLF) is a bioactive protein that nourishes newborns and supports optimal growth and development [2, 3]. Lactoferrin (LF) also supports immune health at every life stage [4, 5].…”