Functional Correlates and Impact of Dietary Lactoferrin Intervention and its Concentration‐dependence on Neurodevelopment and Cognition in Neonatal Piglets

Abstract

Scope: Lactoferrin (Lf ), a sialylated milk glycoprotein, promotes early neurodevelopment and cognition. Functional concentrations of Lf, however, remain unknown. Our objective is to determine the concentration-dependency of Lf on genes associated with neurodevelopment and cognition in neonatal piglets. Methods and results: Piglets are given milk replacer with Lf at concentrations of 155 (low) or 285 mg kg -1 day -1 (high) from postnatal days 3 to 38. Gene expression associated with neurodevelopment, cognition, and cognate proteins were quantitated. This study found 1) The rate of learning and long-term memory was higher with 155 mg kg -1 day -1 assessed in an eight-arm radial maze; 2) Global gene transcription profiling showed this lower concentration upregulated genes and functions correlated with neurodevelopment and cognition, while the higher concentration regulated cellular processes for neuroprotection; 3) Expression of BDNF genes and proteins were higher with both concentrations, while genes regulating BDNF signaling, including SLC6A3, IGF-1 responded more to the lower concentration; 4) The lower concentration modulated genes in the five highest networks associated with cellularity and neurocognition, while the prevention of neurodevelopmental and neurological pathologies was associated with the higher concentration. Conclusion: The lower concentrations of Lf enhanced neurodevelopment and cognition, while higher concentrations are greater neuroprotective, findings of potential novel clinical relevance.

Dose-Dependent Neuroprotective Effects of Bovine Lactoferrin Following Neonatal Hypoxia–Ischemia in the Immature Rat Brain

“…In agreement, Chen and colleagues showed that Lf modulates genes in a dose-dependent manner during early development of piglets in the absence of injury. Chen et al showed that, when administered at low doses (i.e., 15 mg/kg/day), Lf modulated genes (associated) related to brain development, whereas higher doses (2 g/kg) should be used for neuroprotection [50]. Interestingly, our study shows that despite the molecular neuroprotection using the highest dose of Lf (10 g/kg), tissue damage was not reversed.…”

“…The neuroprotective effects of Lactoferrin have been attracting widespread attention among clinical and preclinical researchers in the last years [50,83]. Kaufman and colleagues administered up to 300 mg/day of enteral bovine Lf and reported no adverse effects in preterm babies [83].…”

“…Lf supplementation through lactation was able to partially reverse most of the alterations induced by HI insult. Importantly, although all three doses reduced metabolite alterations induced by HI, the effects in Cr and PCr, as well as in Glu + Gln and Glu/Gln were clearly dependent of the Lf dosage, which may infer that the mechanisms of Lf neuroprotection could be distinct depending on the dose used [50]. HILf0.1 had the best performance, decreasing alterations induced by HI in the Cr + PCr and Glu/Gln ratio.…”

A Review on Lactoferrin and Central Nervous System Diseases

“…Thus, the increase in the BDNF-polySia complex levels in the brain might be considered to be the main mechanism by which Lf affects neurodevelopment and cognitive formation [ 45 ]. In fact, an extended study by Chen et al provided new evidence supporting the regulation of BDNF signaling by exogenous Lf intervention and elucidated the molecular mechanisms underlying the concentration-dependent effect of Lf supplementation on promoting neurodevelopment and cognition in neonatal piglets [ 148 ].…”

“…Moreover, BDNF, which is mainly released by astrocytes, is known to contribute to several aspects of neuronal development and function, such as synaptic plasticity, neuronal survival and differentiation, neuronal process growth, and neuronal repair following injury [ 178 ]. Interestingly, BDNF expression is up-regulated after Lf treatment [ 45 , 64 , 88 , 89 , 148 , 153 ], suggesting that some functions of astrocytes may be activated.…”