Iron supplementation dose for perinatal iron deficiency differentially alters the neurochemistry of the frontal cortex and hippocampus in adult rats

Abstract

Background Long-term prefrontal cortex and hippocampus-based cognitive deficits are the sequelae of perinatal iron deficiency, despite iron supplementation starting in the newborn period. Whether high dose iron supplementation prevents these deficits is not known. Methods Perinatal iron deficiency was induced in rat pups using low-iron (3 mg/kg diet) diet during gestation until postnatal day (P) 8. Iron was supplemented using standard (40 mg/kg diet) or 10-fold higher (400 mg/kg diet) iron-containing diet until P21. Prefrontal cortex and hippocampal neurochemistry was determined using in vivo 1H nuclear magnetic resonance spectroscopy at 9.4 tesla on P90. Results Both iron supplementation doses corrected anemia and brain iron deficiency by P21. The neurochemical profile of the prefrontal cortex in both supplementation groups was comparable to the control group. In the hippocampus, standard-dose iron supplementation resulted in lower N-acetylaspartate and phosphoethanolamine, and higher N-acetylaspartylglutamate and glycerophosphocholine + phosphocholine concentrations. High-dose iron supplementation resulted in lower phosphoethanolamine and higher glycerophosphocholine + phosphocholine concentrations. Conclusions The iron supplementation dose for perinatal iron deficiency differentially alters the neurochemical profile of the prefrontal cortex and hippocampus in adulthood. The neurochemical changes suggest altered glutamatergic neurotransmission, hypomyelination and abnormal phospholipid metabolism in the formerly iron-deficient hippocampus.

Is early-life iron exposure critical in neurodegeneration?

“…20 Furthermore, high iron supplementation in rats with simulated iron deficiency anaemia failed to prevent neurochemical deficits. 56 One curiosity among the literature is why lower levels of iron fortification that more closely resemble the levels in breast milk have not been included in clinical studies of the possible health benefits of iron supplementation, particularly when some evidence suggests that moderate iron supplementation is sufficient (and even preferable) for the correction of behavioural deficits that arise from iron deficiency. 57 If, as the ESPGHAN reported, iron fortification is only beneficial to infants who are preterm and have anaemia, the lack of acute health effects that arise from overexposure to iron should not exclude modest supplementation from further study.…”

Region-specific aging of the human brain as evidenced by neurochemical profiles measured noninvasively in the posterior cingulate cortex and the occipital lobe using 1 H magnetic resonance spectroscopy at 7 T

“…Each observable neurochemical can provide distinctive information because neurochemical levels are sensitive to different in vivo processes. In particular, N -acetylaspartate (NAA) is a putative marker of neuronal viability (Brand et al, 1993, Urenjak et al, 1993, Mountford et al, 2010, Duarte et al, 2012, Rae, 2014), creatine (Cr) and phosphocreatine (PCr) are neuronal energy substrates, glycerophosphorylcholine (GPC), phosphorylcholine (PCho), phosphorylethanolamine (PE), and myo -inositol (mIns) are associated with membrane turnover (Michaelis et al, 1993, Boulanger et al, 2000, Duarte et al, 2012, Rae, 2014), PE is also associated with myelination (Rao et al, 2013), N -acetylaspartylglutamate (NAAG) is a neuromodulatory peptide (Moffett et al, 2007, Duarte et al, 2012), ascorbate (Asc) is an antioxidant (Rice and Russo-Menna, 1998), and glutamate (Glu) is a neurotransmitter. Also, some neurochemicals are preferentially concentrated in certain cell types.…”

Fetal iron deficiency alters the proteome of adult rat hippocampal synaptosomes

“…While it is likely that the long-term abnormalities are due to early-life iron deficiency anemia, an alternate possibility is that iron treatment may have led to the increased risk of these neuropathologies. A recent study utilized various doses of iron supplementation to treat early iron deficiency in the rat model suggests adverse effects associated with a high iron dose (58,71). It is possible that the dose of iron supplementation used in this study could be too high and thus had negatively contributed to the risk of neuropathologies.…”