Biological Activities of Omega-3 Fatty Acids in the Developing Brain
In parallel to the interest in omega-3 fatty acids for maternal mental health, there has been growing work exploring the role of these lipids in the optimization of fetal and postnatal mental development. Significant DHA accumulation occurs in the developing brain during the third intrauterine trimester and the first year of life.[55,56] DHA is an important ingredient in the synthesis of membrane phospholipids that occurs with neurogenesis. During pregnancy, most DHA supplied to the fetus originates from maternal sources, either from diet or mobilization of fat stores, and is transferred across the placenta. ALA transferred across the placenta may also be converted, to a limited degree, to DHA in the fetal compartment. Postpartum, the infant receives DHA through breast milk as well as from PUFA-fortified formula. In a study of human mother–infant dyads, maternal red blood cell omega-6:omega-3 ratios increased during the course of lactation, while DHA content of milk over a similar time scale did not show a decrease, suggesting that DHA continues to be transferred through breast milk to the infant to support the needs of ongoing brain development.
Although an optimal level of dietary DHA for fetal development has not been established, there is some evidence that the developing fetus may be vulnerable to the effects of low maternal DHA supply. Studies carried out in the rat model have shown that maternal diets deficient in omega-3 fatty acid during gestation may alter neurogenesis and the morphology of telencephalic structures in the embryo. In a study comparing brain development of rat embryos, pregnant rats were fed a diet deficient in ALA, with a high omega-6:omega-3 ratio, or an ALA-adequate control diet. The respective diets were initiated 2 weeks prior to mating and continued through embryonic day 19. The investigators noted that brains of the embryonic pups of mothers eating the deficient diet had a 55–65% reduction in DHA content. There was a compensatory increase in ARA noted. The cerebral hemispheres of the omega-3 fatty acid-deficient rat embryos were noticeably smaller than that of controls due to a decrease in size of their cortical plate, primordial hippocampus and dentate gyrus.
Another study compared neurons of embryonic rat hippocampi under conditions of maternal dietary deficiency of omega-3 fatty acids (fed with 0.09 wt% of LA) versus an omega-3 fatty acid adequate diet (2.5 wt% LA plus 0.9 wt% DHA). Hippocampal neurons from the omega-3 fatty acid-deficient embryos showed inhibited neurite growth and synaptogenesis, a decrease in synapsins and glutamate receptor subunits and impairment of long-term potentiation. By contrast, the brains of 18-day-old embryos from dams that had received a DHA- and LA-adequate diet manifested increased neurite growth and synapsin formation as well as increased levels of pre- and postsynaptic proteins, including glutamate receptors. This potentiation of neural growth by DHA has also been demonstrated in vitro with neural stem cells of 15.5-day-old rat embryos cultured with or without DHA. Those cultured with DHA showed more morphologically mature neurons an increased number of Tuj1-positive neurons and an increased incorporation ratio of 5-bromo-2'-deoxyuridine – a mitotic division marker. DHA also appeared to accelerate the transition of neural stem cells from undifferentiated to differentiated by promoting cell-cycle exit. The number of pyknotic cells was also decreased on day 7 in DHA-supplemented cultures, suggesting that DHA may suppress apoptotic cell death and increase the viability of young neurons.
In a later study, in a rat model of hypothyroidism-induced neuronal apoptosis, omega-3 fatty acid (EPA-rich marine oil) supplementation of pregnant and lactating hypothyroid maternal rats significantly decreased DNA fragmentation and caspase-3 activation in the cerebellums of the hypothyroid pups whose mothers had been supplemented, compared with cerebellums of pups born to hypothyroid dams that had not been supplemented. Additionally, supplementation decreased the levels of proapoptotic proteins Bcl-2 and Bax, and increased the levels of antiapoptotic proteins Bcl-2 and Bcl-xL in the developing cerebellum.
The rat model has also been used to demonstrate the detrimental effects of maternal omega-3 fatty acid deficiency on dopaminergic regulatory proteins in the developing brain. Kuperstein et al. fed dams either a LA adequate or deficient diet from the second postconception day through lactation. Neonatal rats were weaned on the 21st postnatal day, then sacrificed on the 28th postnatal day. Decreased levels of tyrosine hydroxylase (the rate-limiting enzyme in dopamine synthesis), the vesicular monoamine transporter (VMAT-2) and VMAT-associated vesicles in the hippocampus were seen in omega-3 fatty acid-deficient offspring. Dopamine receptors DAR1 and DAR2 were markedly increased in the cortex and striatum. This study also found that omega-3 fatty acid deficiency in the developing brain increased microglia activation and NF-κB levels, suggesting that there may be a correlation between omega-3 fatty acid deficiency, oxidative stress and dysregulation of dopaminergic components.
Although DHA is critical for optimal development of the fetal nervous system and its deficiency may result in adverse effects on neurodevelopment, excess levels of DHA during fetal life may also have undesired consequences.[7,63] Davis-Bruno et al. recently conducted a comprehensive review of the literature surrounding DHA, EPA and ARA in pregnancy and lactation in animal models. Based on their review of animal studies, they note that deficiencies of DHA and/or EPA may result in neuronal arborization deficits. They hypothesized that preterm infants are particularly vulnerable to the effects of DHA deficiency and that this deficiency may underlie the vascular fragility leading to intraventricular hemorrhage. Their review of the animal literature also suggested that although adequacy of DHA is necessary for optimal neurodevelopment, DHA excess may be detrimental, by increasing oxidative stress and apoptosis. The authors concluded that although balancing the ratio of DHA:ARA is necessary for optimal neurodevelopment, it is unclear whether maternal omega-3 fatty acid supplementation during pregnancy and lactation or fortification of infant formula is beneficial.
Recent research in animal models has also explored a possible role for DHA supplementation for neuroprotection, with a view toward the potential use of DHA to prevent childhood disability resulting from intrapartum hypoxia–ischemia.[64–66] Indeed, in a study in which intra-amniotic DHA was administered to maternal rats whose fetuses were experiencing global ischemic stress during intrauterine life, DHA was shown to confer neuroprotection through its free radical scavenging abilities. Fetal rats that experienced ischemic stress during gestations in which their mothers had been fed a diet deficient in omega-3 fatty acids (LA) were observed to have an overexpression of a multitude of genes coding for receptors for neurotransmitters, especially DAR1 and DAR2. Likewise, in a series of experiments in neonatal rats (postnatal day 7), DHA–albumin administered before or after experimental hypoxia ischemia was shown to improve forepaw placement scores compared with control animals who received albumin alone.[65,66] Similarly, in a study in which 7-day-old rat pups underwent hypoxia–ischemia potentiated by lipopolysaccharide-induced brain inflammation, pretreatment with DHA conferred neuroprotection and resulted in improved function after brain insult. To date, any preventive or therapeutic role for DHA awaits further translational investigation and clinical trials.
Clin Lipidology. 2012;7(1):93-109. © 2012 Future Medicine Ltd.