An explanation of the pathophysiology of adverse neurodevelopmental outcomes in iron deficiency

Bakoyiannis, Ioannis; Gkioka, Eleana; Daskalopoulou, Afrodite; Κορού, Λασκαρίνα-Μαρία; Perrea, Despina; Pergialiotis, Vasilios

doi:10.1515/revneuro-2015-0012

Cited by 28 publications

(20 citation statements)

References 112 publications

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“…More recently, Galler et al (2011) reported that early childhood malnutrition was linked to problems in executive functioning in later childhood and adolescence, as well as increased levels of aggression (Galler et al 2013). Furthermore, iron deficiency in children has been linked to adverse social-emotional behavioral outcomes (Lozoff et al 2007;Lozoff et al 2008;Corapci et al 2010;Chang et al 2011;Lozoff et al 2014;Bakoyiannis et al 2015). Conversely, nutritional supplements of omega-3 fatty acids reduced behavioral problems among children aged 8 to 16 years old (Raine et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Nutritional status and social behavior in preschool children: the mediating effects of neurocognitive functioning

Liu

Raine

2016

Maternal & Child Nutrition

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Early malnutritional status has been associated with reduced cognitive ability in childhood. However, there are almost no studies on the effect of malnutrition on positive social behavior, and no tests of possible mediating mechanisms. This study tests the hypothesis that poor nutritional status is associated with impaired social functioning in childhood, and that neurocognitive ability mediates this relationship. We assessed 1553 male and female 3-year-olds from a birth cohort on measures of malnutrition, social behavior and verbal and spatial neurocognitive functions. Children with indicators of malnutrition showed impaired social behavior (p <.0001) as compared with children in the control group with adequate nutritional status. These associations even persisted after controlling for social adversity and parental education. Findings were not moderated by gender or ethnicity, and there was no interaction effect with parental education. A dose–response relationship was observed between degree of malnutrition and degree of social behavior, with increased malnutrition associated with more impaired social behavior. Neurocognitive ability was found to mediate the nutrition–social behavior relationship. The mediation effect of neurocognitive functioning suggests that poor nutrition negatively impacts brain areas that play important roles in developing positive social behavior. Findings suggest that reducing poor nutrition, alternatively promoting good nutrition, may help promote positive social behavior in early childhood during a critical period for social and neurocognitive development, with implications for improving positive health in adulthood.

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Section: Discussionmentioning

confidence: 99%

Nutritional status and social behavior in preschool children: the mediating effects of neurocognitive functioning

Liu

Raine

2016

Maternal & Child Nutrition

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“…Children with iron deficiency face the risk of anemia and neurological disorders [35]. Iron supplements are generally given orally, intravenously or intramuscularly, but these common administration routes are often problematic for children.…”

Section: Discussionmentioning

confidence: 99%

Nasal delivery of nanoliposome-encapsulated ferric ammonium citrate can increase the iron content of rat brain

et al. 2017

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BackgroundIron deficiency in children can have significant neurological consequences, and iron supplementation is an effective treatment of choice. However, traditional routes of iron supplementation do not allow efficient iron delivery to the brain due to the presence of the blood–brain barrier. So an easily delivered iron formulation with high absorption efficiency potentially could find widespread application in iron deficient infants.ResultsIn this study, we have developed and characterized a nanovesicular formulation of ferric ammonium citrate (ferric ammonium citrate nanoliposomes, FAC-LIP) and have shown that it can increase brain iron levels in rats following nasal administration. FAC was incorporated into liposomes with high efficiency (97%) and the liposomes were small (40 nm) and stable. Following intranasal delivery in rats, FAC-LIP significantly increased the iron content in the olfactory bulb, cerebral cortex, striatum, cerebellum and hippocampus, and was more efficient at doing so than FAC alone. No signs of apoptosis or abnormal cell morphology were observed in the brain following FAC-LIP administration, and there were no significant changes in the levels of SOD and MDA, except in the cerebellum and hippocampus. No obvious morphological changes were observed in lung epithelial cells or tracheal mucosa after nasal delivery, suggesting that the formulation was not overtly toxic.ConclusionsIn this study, nanoscale FAC-LIP proved an effective system delivering iron to the brain, with high encapsulation efficiency and low toxicity in rats. Our studies provide the foundation for more detailed investigations into the applications of niosomal nasal delivery of liposomal formulations of iron as a simple and safe therapy for iron deficiency anemia.Graphical abstractThe diagrammatic sketch of “Nasal delivery of nanoliposome-encapsulated ferric ammonium citrate can increase the iron content of rat brain”. Nanoliposome-encapsulated ferric ammonium citrate (FAC-LIP) was successfully prepared and intranasal administration of FAC-LIP increased both the total iron contents and iron storage protein (FTL) expression in rat olfactory bulb, cerebral cortex, striatum and hippocampus, compared with those of FAC groups. Moreover, there was not overtly toxic affects to brain, lung epithelial cells and tracheal mucosa. Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-017-0277-2) contains supplementary material, which is available to authorized users.

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“…C-WT, WT mice on a control diet; dID-WT, WT mice on an iron-deficient diet [Color figure can be viewed at wileyonlinelibrary.com] ID is one of the most important nutritional deficits, affecting almost 2 billion people worldwide. Maternal ID during gestation has been associated with important offspring neurological impairment, including motor and social neurological dysfunction (Bakoyiannis et al, 2015;Farrelly et al, 2017). When acquired during development, ID impacts OL maturation, which causes long-lasting hypomyelination in adulthood even after an iron-sufficient diet has been reinstated (Badaracco et al, 2008;Ortiz et al, 2004).…”

Section: Behavioral Correlation With Didmentioning

confidence: 99%

Ontogenetic oligodendrocyte maturation through gestational iron deprivation: The road not taken

Guitart

Vence

Correale

et al. 2019

Glia

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Developmental iron deficiency (dID) models facilitate the study of specific oligodendrocyte (OL) requirements for their progression to a mature state and subsequent contribution to myelination. In the current work, we used the dID model in transgenic mice expressing green fluorescence protein under the CNPase promoter allowing the identification of cells belonging to the oligodendroglial lineage, and the visualization of the entire myelin structure and single OL morphology. The present work evaluates dID effects on OL complexity in different brain areas. Control animals showed an increase in OL complexity both during development and along the anterior–posterior axis. In contrast, dID animals exhibited an initial increase in CNPase+ cells with prevalence of immature‐OL (i‐OL), an effect later compensated during development by selective death of those i‐OL. As a consequence, developmental behavior was impaired in terms of body balance, muscle response, and sensorimotor functions. To explore why i‐OL fail to mature in dID, expression levels of transcriptional factors involved in the maturation of the OL lineage were studied. In nuclear fractions, dID animals showed an increase in Hes5, which prevents the maturation of i‐OL, and a decrease in Sox10, a positive regulator of OL maturation. The cytoplasmic fractions showed a decrease in Olig1, which is critical for precursor cell differentiation into premyelinating OL. Overall, the expression levels of Hes5, Sox10, and Olig1 in dID conditions correlated with an unfavorable OL maturation profile. In sum, the current results provide further evidence of dID impact on myelination, keeping OL away from the maturational path.

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An explanation of the pathophysiology of adverse neurodevelopmental outcomes in iron deficiency

Cited by 28 publications

References 112 publications

Nutritional status and social behavior in preschool children: the mediating effects of neurocognitive functioning

Nutritional status and social behavior in preschool children: the mediating effects of neurocognitive functioning

Nasal delivery of nanoliposome-encapsulated ferric ammonium citrate can increase the iron content of rat brain

Ontogenetic oligodendrocyte maturation through gestational iron deprivation: The road not taken

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