Abstract

Introduction: Intrauterine Growth Restriction (IUGR) refers to an impaired development of the fetus and hence results in adverse neurodevelopmental and psychiatric consequences later in life. Lactoferrin (Lf) is a glycoprotein present in milk that has already shown neuroprotective effects through its anti-inflammatory and antioxidant properties on impaired developing brains. The aim of this study was to characterize a rat model of IUGR and assess the neuroprotective effect of a nutritional supplementation with bovine Lf during pregnancy and lactation on this model.Methods: A model of 50% gestational caloric restriction (CR) was used. Three groups were designed, and pregnant rats had either ad libitum access to food (control group, CTL) or 50% of the controls' intake (restricted group, IUGR). The diet was isocaloric and supplemented with bovine Lf for the caloric restricted dams (restricted-Lf, IUGR_Lf). At postnatal day 7 and 21, advanced ex-vivo diffusion MRI techniques at 9.4T were used to investigate brain cortical and white matter microstructure. Further, genes and proteins involved in structure (synaptophysin, MBP), microglia (Iba-1), metabolism (MCT2, βCaMKII) and apoptosis (Bcl-2) were analyzed in the cortex and striatum. In the cortex, the number of parvalbumin immunoreactive interneurons and their perineuronal nets were quantified. Behavioral tests were performed at P31.Results: Effects of the CR were significant in the cortex and striatum with reduction of synaptophysin (marker of synaptogenesis) at P7 and MBP (marker of myelin) at P21 in the cortex. Indeed, MCT2 (energy metabolism), Bcl-2 (anti-apoptotic protein) and βCaMKII (synapse activity) expressions were reduced in IUGR groups at P7. In the striatum NG2 (marker of oligodendrocyte precursor cells) and Bcl-2 at P7 as well as βCaMKII at P21 were decreased following IUGR and restored by Lf. Cortical microstructure was impaired following CR with partial effect of Lf. Lf prevented oxidative stress induced parvalbumin interneurons impairments whereas striatum and external capsule showed alterations in microstructure depicted by diffusion MRI, which were also partially reversed by Lf.Discussion and Conclusion: The model of 50% caloric restriction induced mild impairment partially reversed by nutritional intervention using Lf during pregnancy and lactation.

Highlights

  • Intrauterine Growth Restriction (IUGR) refers to an impaired development of the fetus and results in adverse neurodevelopmental and psychiatric consequences later in life

  • Effects of the caloric restriction (CR) were significant in the cortex and striatum with reduction of synaptophysin at postnatal day 7 (P7) and Myelin basic protein (MBP) at P21 in the cortex

  • Lf prevented oxidative stress induced parvalbumin interneurons impairments whereas striatum and external capsule showed alterations in microstructure depicted by diffusion MRI, which were partially reversed by Lf

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Summary

Introduction

Intrauterine Growth Restriction (IUGR) refers to an impaired development of the fetus and results in adverse neurodevelopmental and psychiatric consequences later in life. The definition of intrauterine growth retardation (IUGR) given by world health organization in 1995 was “An infant suffering from IUGR is defined as being below the 10% percentile of the recommended gender-specific birthweight for gestational age reference curves.”. It is one of the main causes of developmental brain damage with possible long life neurodevelopmental disabilities. The often-associated morbidities of IUGR, prematurity and poor postnatal growth represent a major risk for poor development of affective cognition and psychiatric disorders [1,2,3]

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