Introduction
Folate is an essential micronutrient and one of the B vitamins. Folates are vital for one-carbon metabolism pathways which are involved in methylation, biosynthesis of DNA and production of purines, nucleotides, neurotransmitters and amino acids (Budni et al., 2018). In the methylation cycle the active form of folate, 5-Methyltetrahydrofolate (5-MTHF), donates its methyl group to homocysteine (Hcy) for the formation of methionine (McGarel et al., 2015). Methionine is the precursor for synthesis of S-adenosine methionine (SAMe) which is needed for methylation of DNA, proteins, chromosomes, phospholipids, myelin production and neurotransmitters (McGarel et al., 2015). Folate is crucial for the balance between Hcy and methionine, maintaining optimum methylation levels and avoiding high homocysteine (HHcy) (Kalani et al., 2014, Kaye et al., 2020).
Folate and Brain Development
Folate is needed for cell proliferation, tissue growth and cognitive development during foetal growth and is vital for the prevention of neural tube defects (McGarel et al., 2015). In human studies, maternal FA supp has been associated with increased methylation of inulin-like growth factor 2 (IGF-2), which is involved in placental and foetal development (McGarel et al., 2015). It is widely accepted that increased maternal folate intake is needed during pre-conception and during the early stages of pregnancy. Observational and animal research suggests that folate intake during the later stages of pregnancy is also important and may be associated with increased cognitive performance post-birth (McGarel et al., 2015).
Research suggests that folate may have a beneficial influence on neurotrophins such as brain derived neurotropic factor (BDNF) and nerve growth factor (NGF). BDNF is crucial for brain homeostasis and neurogenesis as it regulates neural circuit development, neuronal growth and synaptic plasticity and NGF, amongst other things, is essential for the survival of cholinergic neurons in the CNS (Sahay, Kale and Joshi, 2020). Changes in levels of BDNF and NGF are known to be involved in brain and psychiatric disorders (Sahay, Kale and Joshi, 2020). Neurotrophins are vital during pre and post-natal brain development and maternal low levels of folate (and imbalances between folate and vitamin B12) have been associated with low levels of BDNF and NGF (Sahay, Kale and Joshi, 2020). Low neurotrophin levels are suggested to increase the risk of preeclampsia which has been shown to increase the risk of neurodevelopmental disorders such as ADHD as well increased risk of epilepsy, lower cognitive ability and greater cognitive decline in older age (Sahay, Kale and Joshi, 2020). In animal research, FA supplementation has been shown to increase BDNF serum levels (Zhou, Cong and Liu, 2020).
Folate and Neurotransmitters
Folate is essential for the biosynthesis of neurotransmitters associated with mood, stress, motivation and cognitive performance, such as serotonin (5-HT), noradrenaline (NA) and dopamine (DA) (Zhou, Cong and Liu, 2020). Research suggests that individuals suffering from depression may have decreased levels of dopamine, serotonin and BDNF and that low folate status is associated with depression (Zhou, Cong and Liu, 2020). This may be due to low folate resulting in elevated Hcy as Hcy has been found to be toxic to the dopaminergic system and has been associated with low levels of 5-HIAA, a 5-HT metabolite (Zhou, Cong and Liu, 2020). Depressed patients with low folate levels have been found to have reduced cognitive performance and to respond less well to anti-depressant treatment (Zhou, Cong and Liu, 2020). In an animal model of depression Zhou, Cong and Liu (2020) demonstrated that therapeutic levels of FA supplementation resulted in higher levels of DA and NA whilst significantly suppressing Hcy and IL-6. Inflammatory cytokine IL-6 is able to reduce levels of BH4 which is a cofactor for DA synthesis (Zhou, Cong and Liu, 2020). FA supplementation also increased serum BDNF levels, BDNF is thought to play a protective role in the regulation of the dopaminergic system as well as stimulating 5-HT neuron growth (Zhou, Cong and Liu, 2020). Calderon Guzmán et al. (2018) found that FA supplementation, in rats with neurodegeneration, increased the levels of 5-HT metabolite 5-HIAA.
Excitotoxicity through elevated glutamate has been associated with neurodegenerative diseases and in-vitro research suggests FA may be protective against glutamate toxicity in the brain. FA was found to activate the PI3K signaling cascade which was shown to be protective against the effects of glutamate (Budni et al., 2018). FA has also been shown to prevent glutamate inducing iNOS expression which is a driver of inflammation and neuronal death (Budni et al., 2018).
Anti-Oxidant Properties of Folate
Oxidative damage is implicated in the pathology of various neurodegenerative diseases and it has been suggested that folate has anti-oxidative properties outside of its influence on Hcy. The exact mechanisms are unclear however, research suggests increased FA intake is associated with increases in total anti-oxidant capacity (TAC) and glutathione (GSH), as well as reductions in inflammatory markers (CRP and IL-6) and peroxidation by-products (Asbaghi et al., 2021). In-vitro research also suggests FA and active forms of folate are able to scavenge reactive oxygen species (ROS) (Jones et al., 2019). Calderon Guzmán et al. (2018) showed that FA increased GSH in the cortex of rats with induced neurodegeneration and also reduced levels of TBARS, a by-product of lipid peroxidation. Decreased TBARS were also seen by Novochadlo et al. (2021) within the hippocampus of sepsis-surviving rats, who found that FA also decreased neuroinflammation by decreasing MPO, a peroxidase enzyme that indicates the presence of neutrophils in damaged tissues and is involved in ROS production. FA has been associated with reducing BBB permeability, seen with HHcy, through the recovery of tight junction proteins (Kalani et al., 2014, Novochadlo et al., 2021).
Folate and Methylation
Folate influences DNA methylation and repair through its involvement in nucleotide synthesis (McGarel et al., 2015). Folate is a cofactor for the synthesis of thymidine used in DNA. Lack of folate can result in uracil accumulation in DNA, in place of thymidine, leading to DNA damage and apoptosis of neurocytes which can result in cognitive dysfunction (Zhou et al., 2021). Animal research suggests folic acid (FA) can inhibit apoptosis of astrocytes and delay neurodegeneration (Zhou et al., 2021). Folate’s role in the methylation of DNA is also important as hypomethylation of inflammation-related genes may increase the risk of diseases impacted by inflammation (Jones et al., 2019). Folate also has an impact on nitric oxide (NO) production which helps to maintain healthy endothelial function, an important contributor to brain health (Jones et al., 2019). Elevated Hcy can reduce NO by increasing levels of ROS and decreasing Tetrahydrobiopterin (BH4), an eNOS cofactor (Jones et al., 2019). Reduced levels of BH4 can result in the uncoupling of eNOS and superoxide production instead of NO (Jones et al., 2019). BH4 deficiency can also result in elevated levels of phenylalanine which can damage brains cells (Kaye et al., 2020). Folate increases bioavailability of BH4 as well as mimicking its action due to structural similarities that allow folate to bind to eNOS, stimulating NO production whilst reducing ROS (Jones et al., 2019)
Folate Deficiency & Homocysteine
Low folate levels can result in hyperhomocysteinaemia (HHcy), which can cause oxidative damage and blood brain barrier (BBB) permeability (Kalani et al., 2014). HHcy has been associated with greater hippocampal atrophy and impaired cognition pathways and has been implicated in neurodegenerative diseases, cognitive dysfunction, depression and psychiatric disorders (McGarel et al., 2015). Research suggests that supplementation with FA can result in a decrease in Hcy levels and may protect against Hcy induced neurotoxicity (Kalani et al., 2014).
Researcher: Lucy Richards BSc (Hons) Nutritional Science, CNELM
References
Asbaghi, O., Ghanavati, M., Ashtary-Larky, D., Bagheri, R., Rezaei Kelishadi, M., Nazarian, B., Nordvall, M., Wong, A., Dutheil, F., Suzuki, K. and Alavi Naeini, A., 2021. Effects of folic acid supplementation on oxidative stress markers: a systematic review and meta-analysis of randomized controlled trials. Antioxidants, 10(6), p.871.
Budni, J., Molz, S., Dal-Cim, T., Martín-de-Saavedra, M.D., Egea, J., Lopéz, M.G., Tasca, C.I. and Rodrigues, A.L.S., 2018. Folic acid protects against glutamate-induced excitotoxicity in hippocampal slices through a mechanism that implicates inhibition of GSK-3β and iNOS. Molecular Neurobiology, 55(2), pp.1580-1589.
Calderon Guzman, D., Osnaya Brizuela, N., Ortiz Herrera, M., Juárez Olguín, H., Valenzuela Peraza, A., Hernandez Garcia, E. and Barragán Mejía, G., 2020. Folic acid increases levels of GHS in brain of rats with oxidative stress induced with 3-nitropropionic acid. Archives of Physiology and Biochemistry, 126(1), pp.1-6.
Jones, P., Lucock, M., Scarlett, C.J., Veysey, M. and Beckett, E.L., 2019. Folate and Inflammation–links between folate and features of inflammatory conditions. Journal of nutrition & intermediary metabolism, 18, p.100104.
Kaye, A.D., Jeha, G.M., Pham, A.D., Fuller, M.C., Lerner, Z.I., Sibley, G.T., Cornett, E.M., Urits, I., Viswanath, O. and Kevil, C.G., 2020. Folic acid supplementation in patients with elevated homocysteine levels. Advances in Therapy, 37(10), pp.4149-4164.
Kalani, A., Kamat, P.K., Givvimani, S., Brown, K., Metreveli, N., Tyagi, S.C. and Tyagi, N., 2014. Nutri-epigenetics ameliorates blood–brain barrier damage and neurodegeneration in hyperhomocysteinemia: role of folic acid. Journal of Molecular Neuroscience, 52(2), pp.202-215.
McGarel, C., Pentieva, K., Strain, J.J. and McNulty, H., 2015. Emerging roles for folate and related B-vitamins in brain health across the lifecycle. Proceedings of the Nutrition Society, 74(1), pp.46-55.
Novochadlo, M., Goldim, M.P., Bonfante, S., Joaquim, L., Mathias, K., Metzker, K., Machado, R.S., Lanzzarin, E., Bernades, G., Bagio, E. and Garbossa, L., 2021. Folic acid alleviates the blood brain barrier permeability and oxidative stress and prevents cognitive decline in sepsis-surviving rats. Microvascular Research, 137, p.104193.
Sahay, A., Kale, A. and Joshi, S., 2020. Role of neurotrophins in pregnancy and offspring brain development. Neuropeptides, 83, p.102075.
Zhou, Y., Cong, Y. and Liu, H., 2020. Folic acid ameliorates depression-like behaviour in a rat model of chronic unpredictable mild stress. BMC neuroscience, 21(1), pp.1-8.
Zhou, D., Lv, X., Wang, Y., Liu, H., Luo, S., Li, W. and Huang, G., 2021. Folic acid alleviates age-related cognitive decline and inhibits apoptosis of neurocytes in senescence-accelerated mouse prone 8: deoxythymidine triphosphate biosynthesis as a potential mechanism. The Journal of Nutritional Biochemistry, 97, p.108796.
