- Email: [email protected]
Nutritional factors in the pathobiology of autism
Nutrition 29 (2013) 1066–1069
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Editorial
Nutritional factors in the pathobiology of autism
Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication, and restricted and repetitive behavior. Its symptoms become apparent before a child is age 3 y [1]. Autism affects information processing in the brain by altering how nerve cells and their synapses connect and organize; although how this occurs is not well understood [2]. Autism has a strong genetic basis, although the genetics of autism are complex. The prevalence of autism is about 1 to 2 per 1000 people worldwide [3]. Synaptic dysfunction in autism Several lines of evidence suggest that synaptic dysfunction may cause autism [4–6]. Some rare mutations may lead to autism by disrupting synaptic pathways, such as those involved with cell adhesion [7]. For example, neuroligin-3 knockout mice (a model for nonsyndromic autism and neuroligin is a postsynaptic adhesion molecules involved in synapse assembly) exhibited disrupted heterosynaptic competition and perturbed metabotropic glutamate receptor–dependent synaptic plasticity. These phenotypes could be rescued by reexpression of neuroligin-3 in juvenile mice, highlighting the possibility of reverting neuronal circuit alterations in autism after the completion of development [4]. This implies that interventions employed even in adult life (much after neurodevelopment is over) can restore normalcy in those having autism. Cholinergic and cytokine abnormalities in autism Patients with autism have neuropathologic abnormalities in cholinergic nuclei in the basal forebrain [8]. Because abnormal galvanic skin responses have been observed in individuals with autism, and such responses depend on the integrity of sympathetic cholinergic neural pathways [9], it suggests that the central nervous system cholinergic abnormalities and peripheral nervous system dysfunction could coexist in this population. Acetylcholine, the principal vagal neurotransmitter, has potent anti-inflammatory actions and suppresses the production of interleukin (IL)-6, tumor necrosis factor (TNF)-a, and highmobility group box-1 (HMGB1) [10], suggesting a role for inflammatory pathways in the pathobiology of autism. Patients with autism have increased plasma-circulating levels of proinflammatory cytokines [11,12]. These results imply that maternal (clinical or subclinical) infection-induced elevation in IL-6 and 0899-9007/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nut.2012.11.013
TNF-a evoke fetal brain injuries that could lead to changes in gene-expression patterns during the neonatal period. These changes may lead to fetal brain injury and mechanistically to long-term adverse outcomes for exposed offspring, including development of autism [13,14]. Polyunsaturated fatty acid deficiency may occur in autism Despite several studies and advances, it is not clear what factors control brain growth and development, synapse formation, and interconnectivity among various neurons that could be extrapolated to understand the pathophysiology of autism. In this context, it is noteworthy that polyunsaturated fatty acids (PUFAs) seem to play a significant role in brain growth and development, synapse and memory formation, and cognitive function development. Several studies revealed that arachidonic acid (AA; 20:4 u-6), eicosapentaenoic acid (EPA; 20:5 u-3) and docosahexaenoic acid (DHA; 22:6 u-3) are essential for normal development and growth of brain and memory formation and consolidation [15–21]. This implies that a PUFA deficiency may have a role in the pathobiology of autism. Studies showed that both plasma and red blood cell (RBC) phospholipid fatty-acid composition are altered in subjects with autism. Fatty-acid compositions of RBC phospholipids from a patient with autistic spectrum disorder (ASD) showed reduced percentages of highly unsaturated fatty acids compared with control samples. The percentage of unsaturated fatty acids in the RBC from the patient with autism was dramatically reduced (70%) when the sample was stored for 6 wk at 20 C, implying instability of RBC unsaturated fatty acids [22]. Vancassel et al. [23] reported that the phospholipid fatty acids in the plasma of patients with autism had a marked reduction in the levels of 22: 6u-3 (23%). Several other investigators reported similar deficiency of EPA/DHA/AA in children with autism and intervention studies showed that supplementation of EPA/DHA could significantly benefit them [24–27], although some studies did not support these claims. The discrepancy in these studies could be attributed to the different doses employed, duration of PUFA supplementation, the enormous differences in the clinical spectrum of autism studied, and failure to use adequate amounts of AA in some of the studies because addition of high amounts of AA can produce a significant benefit in autism [28]. The beneficial action of AA can be attributed to its ability to stimulate syntaxin 3 to form the ternary SNARE complex (soluble N-ethylmaleimide-sensitive
Editorial / Nutrition 29 (2013) 1066–1069
1067
factor attachment protein receptor), which is needed for the fusion of plasmalemmal precursor vesicles into the cell surface membrane that leads to membrane fusion that facilitates neurite outgrowth [29,30].
with development [31]. Several studies [31–34] indicated that BDNF plays a significant role in the pathobiology of autism.
Deficiency of BDNF occurs in autism
The description of abnormalities in PUFAs and BDNF in autism suggests that these two endogenous molecules may interact with each other and thus, modulate brain growth and development and improve cognitive function. PUFAs are known to augment the levels of BDNF in the brain [35,36]. Prostaglandin E2 (PGE2), derived from AA, induced release of BDNF from glial cells and astrocytes through a G-protein– related signaling pathway [37]. Both PGE2 analog 16,16 dimethyl PGE2 (dmPGE2) or the agonists of EP1 and EP4 (prostaglandin) receptors significantly increased BDNF levels. It has been suggested that nerve-derived PGE2 contributes to BDNF upregulation
Additionally, patients with autism showed altered plasma levels of brain-derived neurotrophic factor (BDNF), which is involved in the regulation of neuronal development and plasticity and has a role in learning and memory. In healthy controls, serum BDNF concentrations increased over the first several years, then slightly decreased after reaching the adult level. In the patients with autism, mean levels were significantly lower in children ages 0 to 9 y compared with teenagers or adults, or to agematched healthy controls, indicating a delayed BDNF increase
PUFAs and BDNF interact with each other
Fig. 1. Metabolism of essential fatty acids: LA (linoleic acid) and ALA (a-linolenic acid), their conversion to AA, EPA, and DHA, role of cofactors in their metabolism, BDNF, neurotransmitters such as acetylcholine, cytokines, NO, and their role in autism. LA, Linoleic acid; ALA, Alph-linolenic acid; GLA, Gamma-linolenic acid; DGLA, Dihomogamma-linolenic acid; AA, Arachdonic acid; PGE1, Prostaglandin E1; Zn, Zinc; Mg, Magnesium; EPA, Eicosapentaenoic acid; DHA, Docosahexaenoic acid; PGs, Prostaglandins; TXA, Thromboxane A; LT, Leukotriene; LXs, Lipoxins; EETs, Epoxyeicosatrienoic acids; HETEs, Hydroxyeicosatetraenoic acids; BDNF, Brain-derived neurotrophic factor; IL, Interleukin; TNF, Tumor necrosis factor; SNAP25, Synaptosomal-associated protein 25.
1068
Editorial / Nutrition 29 (2013) 1066–1069
in dorsal root ganglion neurons following nerve injury [38], which facilitates the synthesis of BDNF in primary sensory neurons to initiate repair of damaged neurons and neuronal regeneration. In a recent study using bioinformatics approach, we showed that lipoxin A4 (LXA4), a known anti-inflammatory bioactive metabolite derived from AA, showed highest binding affinity for BDNF compared with other PUFAs and metabolites, suggesting those PUFAs and their metabolites especially, LXA4 physically interact with BDNF. Similar interactions were noted between BDNF and resolvins and protectins, which are anti-inflammatory metabolites formed from EPA and DHA, respectively, but were of lesser intensity compared with LXA4 [39]. Vitamins and micronutrients in autism The current author has reported previously that altered maternal micronutrients (folic acid and vitamin B12), increased homocysteine and oxidative stress that could lead to epigenetic modifications contributing to preterm birth and poor fetal outcome. This could increase the risk for behavioral disorders, such as autism, in children [40,41]. These results showed that antioxidants, minerals, trace elements, and various vitamins function as cofactors in the metabolism of PUFAs. For instance, folic acid, vitamins C and B6, and zinc serve as cofactors in the metabolism of essential fatty acids and in the formation of various eicosanoids [15,42] (Fig. 1). Furthermore, AA, EPA, and DHA form precursors to anti-inflammatory bioactive lipids such as lipoxins, resolvins, and protectins that are essential for wound healing, protecting neurons from various endogenous and exogenous insults, including free radicals and proinflammatory prostaglandins [42–45]. Thus, it is likely that in some patients with autism, the metabolism of PUFAs is deficient or abnormal such that adequate amounts of lipoxins, resolvins, and protectins are not formed, which could lead to enhanced production of proinflammatory cytokines and oxidative stress (in the form of enhanced lipid peroxidation process and increased formation of proinflammatory eicosanoids); imbalance in the formation and action of various neurotransmitters such as dopamine, serotonin, catecholamines, and BDNF, which could result in inappropriate neuronal damage leading to the onset and progression of autism and poor response to the administered PUFAs. This is supported by the work of Al-Farsi et al. [46], who reported that low folate and vitamin B12 nourishment is common among Omani children newly diagnosed with autism. Although this finding in itself is interesting, it is not clear from their study whether low folate and vitamin B12 levels seen in the study population is the cause or effect of the disease. It remains to be determined whether folate and vitamin B12 supplementation would decrease the manifestations of autism or halt its progress. Additionally, it may prove interesting to estimate the plasma levels of PUFAs and lipoxins and correlate those levels with those of vitamins, minerals, and trace elements and with severity of clinical manifestations of autism. Such a comprehensive study is needed. Acknowledgments The author was a recipient of the Ramalingaswami Fellowship of the Department of Biotechnology, India during the tenure of this study. This study was supported in particular by a grant to the author from the Department of Defense and Research Organisation (DRDO), New Delhi.
References [1] Caronna EB, Milunsky JM, Tager-Flusberg H. Autism spectrum disorders: clinical and research frontiers. Arch Dis Child 2008;93:518–23. [2] Levy SE, Mandell DS, Schultz RT. Autism. Lancet 2009;374:1627–38. [3] Prevalence of autism spectrum disorders dautism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill Summ 2012;61:1–19. [4] Baudouin SJ, Gaudias J, Gerharz S, Hatstatt L, Zhou K, Punnakkal P, et al. Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism. Science 2012;338:128–32. [5] Garber K. Autism’s cause may reside in abnormalities at the synapse. Science 2007;317:190–1. [6] Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 2007;318:71–6. [7] Betancur C, Sakurai T, Buxbaum JD. The emerging role of synaptic celladhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci 2009;32:402–12. [8] Perry EK, Lee MLW, Martin-Ruiz CM, Court JA, Volsen SG, Merrit J, et al. Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am J Psychiatry 2001;158:1058–66. [9] Tordjman S, Antoine C, Cohen DJ, Gauvain-Piquard A, Carlier M, Roubertoux P, et al. Study of the relationships between self-injurious behavior and pain reactivity in infantile autism. Encephale 1999;25:122–34. [10] Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic antiinflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 2003;9:125–34. [11] Suzuki K, Matsuzaki H, Iwata K, Kameno Y, Shimmura C, Kawai S, et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS One 2011;6:e20470. [12] Wei H, Zou H, Sheikh AM, Malik M, Dobkin C, Brown WT, et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflammation 2011;8:52. [13] Elovitz MA, Brown AG, Breen K, Anton L, Maubert M, Burd I. Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury. Int J Dev Neurosci 2011;29:663–71. [14] Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J. Altered T cell responses in children with autism. Brain Behav Immun 2011;25:840–9. [15] Das UN. A perinatal strategy for preventing adult diseases: the role of longchain polyunsaturated fatty acids. Boston: Kluwer Academic Publishers; 2002. [16] Das UN. Long-chain polyunsaturated fatty acids in growth and development of brain and memory. Nutrition 2003;19:62–5. [17] Das UN. Can memory be improved? A discussion on the role of ras, GABA, acetylcholine, NO, insulin, TNF-a, and long-chain polyunsaturated fatty acids in memory formation and consolidation. Brain and Development 2003;25:251–61. [18] Das UN. Long-chain polyunsaturated fatty acids in memory formation and consolidation: Further evidence and discussion. Nutrition 2003; 19:988–93. [19] Hajjar T, Meng GY, Rajion MA, et al. Omega 3 polyunsaturated fatty acid improves spatial learning and hippocampal peroxisome proliferator activated receptors (PPARa and PPARg) gene expression in rats. BMC Neuroscience 2012;13:109. [20] Kotani S, Sakaguchi E, Warashina S, Matsukawa N, Ishikura Y, Kiso Y, et al. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res 2006;56:159–64. [21] Kavraal S, Oncu SK, Bitiktas S, Artis AS, Dolu N, Gunes T, et al. Maternal intake of Omega-3 essential fatty acids improves long term potentiation in the dentate gyrus and Morris water maze performance in rats. Brain Res 2012;1482:32–9. [22] Bell JG, Sargent JR, Tocher DR, Dick JR. Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders? Prostaglandins Leukot Essent Fatty Acids 2000;63:21–5. le my C, Lejeune B, Martineau J, Guilloteau D, [23] Vancassel S, Durand G, Barthe et al. Plasma fatty acid levels in autistic children. Prostaglandins Leukot Essent Fatty Acids 2001;65:1–7. €fer MR, Klier C, Friedrich MH, Feucht M. [24] Amminger GP, Berger GE, Scha Omega-3 fatty acids supplementation in children with autism: a doubleblind randomized, placebo-controlled pilot study. Biol Psychiatry 2007; 61:551–3. [25] Bent S, Bertoglio K, Hendren RL. Omega- 3 fatty acids for autistic spectrum disorder: a systematic review. J Autism Dev Disord 2009;39:1145–54. [26] Meguid NA, Atta HM, Gouda AS, Khalil RO. Role of polyunsaturated fatty acids in the management of Egyptian children with autism. Clin Biochem 2008;41:1044–8. [27] El-Ansary AK, Bacha AG, Al-Ayahdi LY. Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia. Lipids Health Dis 2011;10:63. [28] Yui K, Koshiba M, Nakamura S, Kobayashi Y. Effects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in
Editorial / Nutrition 29 (2013) 1066–1069
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
individuals with autism spectrum disorders: a double-blind, placebocontrolled, randomized trial. J Clin Psychopharmacol 2012;32:200–6. Connell E, Darios F, Broersen K, Gatsby N, Peak-Chew S-Y, Rickman C, et al. Mechanism of arachidonic acid action on syntaxin–Munc18. EMBO Rep 2007;8:414–9. Latham CF, Osborne SL, Cryle MJ, Meunier FA. Arachidonic acid potentiates exocytosis and allows neuronal SNARE complex to interact with Munc18a. J Neurochem 2007;100:1543–54. Katoh-Semba R, Wakako R, Komori T, Shigemi H, Miyazaki N, Ito H, et al. Agerelated changes in BDNF protein levels in human serum: differences between autism cases and normal controls. Int J Dev Neurosci 2007;25:367–72. Sheikh AM, Malik M, Wen G, Chauhan A, Chauhan V, Gong CX, et al. BDNFAkt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. J Neurosci Res 2010;88:2641–7. Chapleau CA, Larimore JL, Theibert A, Pozzo-Miller L. Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism. J Neurodev Disord 2009;1:185–96. Raznahan A, Toro R, Proitsi P, Powell J, Paus T, Bolton PF, et al. A functional polymorphism of the brain derived neurotrophic factor gene and cortical anatomy in autism spectrum disorder. J Neurodev Disord 2009;1:215–23. Bousquet M, Gibrat C, Saint-Pierre M, Julien C, Calon F, Cicchetti F. Modulation of brain-derived neurotrophic factor as a potential neuroprotective mechanism of action of omega-3 fatty acids in a parkinsonian animal model. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1401–8. Wu A, Ying Z, Gomez-Pinilla F. Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma 2004;21:1457–67. Hutchinson AJ, Chou CL, Israel DD, Xu W, Regan JW. Activation of EP2 prostanoid receptors in human glial cell lines stimulates the secretion of BDNF. Neurochem Int 2009;54:439–46. Cruz Duarte P, St-Jacques B, Ma W. Prostaglandin E2 contributes to the synthesis of brain-derived neurotrophic factor in primary sensory neuron in ganglion explant cultures and in a neuropathic pain model. Exp Neurol 2012;234:466–81. Vetrivel U, Ravichandran SB, Kuppan K, Mohanlal J, Das UN, Narayanasamy A. Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on
[40]
[41]
[42] [43]
[44]
[45]
[46]
1069
brain-derived neurotrophic factor (BDNF) through molecular docking simulation. Lipids Health Dis 2012;11:109. Dhobale M, Joshi S. Altered maternal micronutrients (folic acid, vitamin B(12)) and omega 3 fatty acids through oxidative stress may reduce neurotrophic factors in preterm pregnancy. J Matern Fetal Neonatal Med 2012; 25:317–23. Kulkarni A, Dangat K, Kale A, Sable P, Chavan-Gautam P, Joshi S. Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats. PLoS One 2011; 6:e17706. Das UN. Molecular basis of health and disease. New York: Springer; 2011. Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest 2005;115: 2774–83. Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 2003;278: 43807–17. Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci U S A 2004;101:8491–6. Al-Farsi YM, Waly MI, Deth RC, Al-Sharbati MM, Al-Shafaee M, Al-Farsi O, et al. Low folate and vitamin B12 nourishment is common among Omani children newly diagnosed with autism. Nutrition 2013;29:537–41.
Undurti N. Das, M.D., F.A.M.S., F.R.S.C. UND Life Sciences 13800 Fairhill Road, #321 Shaker Heights, OH 44120, USA Department of Biotechnology Jawaharlal Nehru Technological University Kakinada-533 003, India
Contents lists available at ScienceDirect
Nutrition journal homepage: www.nutritionjrnl.com
Editorial
Nutritional factors in the pathobiology of autism
Autism is a neurodevelopmental disorder characterized by impaired social interaction and communication, and restricted and repetitive behavior. Its symptoms become apparent before a child is age 3 y [1]. Autism affects information processing in the brain by altering how nerve cells and their synapses connect and organize; although how this occurs is not well understood [2]. Autism has a strong genetic basis, although the genetics of autism are complex. The prevalence of autism is about 1 to 2 per 1000 people worldwide [3]. Synaptic dysfunction in autism Several lines of evidence suggest that synaptic dysfunction may cause autism [4–6]. Some rare mutations may lead to autism by disrupting synaptic pathways, such as those involved with cell adhesion [7]. For example, neuroligin-3 knockout mice (a model for nonsyndromic autism and neuroligin is a postsynaptic adhesion molecules involved in synapse assembly) exhibited disrupted heterosynaptic competition and perturbed metabotropic glutamate receptor–dependent synaptic plasticity. These phenotypes could be rescued by reexpression of neuroligin-3 in juvenile mice, highlighting the possibility of reverting neuronal circuit alterations in autism after the completion of development [4]. This implies that interventions employed even in adult life (much after neurodevelopment is over) can restore normalcy in those having autism. Cholinergic and cytokine abnormalities in autism Patients with autism have neuropathologic abnormalities in cholinergic nuclei in the basal forebrain [8]. Because abnormal galvanic skin responses have been observed in individuals with autism, and such responses depend on the integrity of sympathetic cholinergic neural pathways [9], it suggests that the central nervous system cholinergic abnormalities and peripheral nervous system dysfunction could coexist in this population. Acetylcholine, the principal vagal neurotransmitter, has potent anti-inflammatory actions and suppresses the production of interleukin (IL)-6, tumor necrosis factor (TNF)-a, and highmobility group box-1 (HMGB1) [10], suggesting a role for inflammatory pathways in the pathobiology of autism. Patients with autism have increased plasma-circulating levels of proinflammatory cytokines [11,12]. These results imply that maternal (clinical or subclinical) infection-induced elevation in IL-6 and 0899-9007/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nut.2012.11.013
TNF-a evoke fetal brain injuries that could lead to changes in gene-expression patterns during the neonatal period. These changes may lead to fetal brain injury and mechanistically to long-term adverse outcomes for exposed offspring, including development of autism [13,14]. Polyunsaturated fatty acid deficiency may occur in autism Despite several studies and advances, it is not clear what factors control brain growth and development, synapse formation, and interconnectivity among various neurons that could be extrapolated to understand the pathophysiology of autism. In this context, it is noteworthy that polyunsaturated fatty acids (PUFAs) seem to play a significant role in brain growth and development, synapse and memory formation, and cognitive function development. Several studies revealed that arachidonic acid (AA; 20:4 u-6), eicosapentaenoic acid (EPA; 20:5 u-3) and docosahexaenoic acid (DHA; 22:6 u-3) are essential for normal development and growth of brain and memory formation and consolidation [15–21]. This implies that a PUFA deficiency may have a role in the pathobiology of autism. Studies showed that both plasma and red blood cell (RBC) phospholipid fatty-acid composition are altered in subjects with autism. Fatty-acid compositions of RBC phospholipids from a patient with autistic spectrum disorder (ASD) showed reduced percentages of highly unsaturated fatty acids compared with control samples. The percentage of unsaturated fatty acids in the RBC from the patient with autism was dramatically reduced (70%) when the sample was stored for 6 wk at 20 C, implying instability of RBC unsaturated fatty acids [22]. Vancassel et al. [23] reported that the phospholipid fatty acids in the plasma of patients with autism had a marked reduction in the levels of 22: 6u-3 (23%). Several other investigators reported similar deficiency of EPA/DHA/AA in children with autism and intervention studies showed that supplementation of EPA/DHA could significantly benefit them [24–27], although some studies did not support these claims. The discrepancy in these studies could be attributed to the different doses employed, duration of PUFA supplementation, the enormous differences in the clinical spectrum of autism studied, and failure to use adequate amounts of AA in some of the studies because addition of high amounts of AA can produce a significant benefit in autism [28]. The beneficial action of AA can be attributed to its ability to stimulate syntaxin 3 to form the ternary SNARE complex (soluble N-ethylmaleimide-sensitive
Editorial / Nutrition 29 (2013) 1066–1069
1067
factor attachment protein receptor), which is needed for the fusion of plasmalemmal precursor vesicles into the cell surface membrane that leads to membrane fusion that facilitates neurite outgrowth [29,30].
with development [31]. Several studies [31–34] indicated that BDNF plays a significant role in the pathobiology of autism.
Deficiency of BDNF occurs in autism
The description of abnormalities in PUFAs and BDNF in autism suggests that these two endogenous molecules may interact with each other and thus, modulate brain growth and development and improve cognitive function. PUFAs are known to augment the levels of BDNF in the brain [35,36]. Prostaglandin E2 (PGE2), derived from AA, induced release of BDNF from glial cells and astrocytes through a G-protein– related signaling pathway [37]. Both PGE2 analog 16,16 dimethyl PGE2 (dmPGE2) or the agonists of EP1 and EP4 (prostaglandin) receptors significantly increased BDNF levels. It has been suggested that nerve-derived PGE2 contributes to BDNF upregulation
Additionally, patients with autism showed altered plasma levels of brain-derived neurotrophic factor (BDNF), which is involved in the regulation of neuronal development and plasticity and has a role in learning and memory. In healthy controls, serum BDNF concentrations increased over the first several years, then slightly decreased after reaching the adult level. In the patients with autism, mean levels were significantly lower in children ages 0 to 9 y compared with teenagers or adults, or to agematched healthy controls, indicating a delayed BDNF increase
PUFAs and BDNF interact with each other
Fig. 1. Metabolism of essential fatty acids: LA (linoleic acid) and ALA (a-linolenic acid), their conversion to AA, EPA, and DHA, role of cofactors in their metabolism, BDNF, neurotransmitters such as acetylcholine, cytokines, NO, and their role in autism. LA, Linoleic acid; ALA, Alph-linolenic acid; GLA, Gamma-linolenic acid; DGLA, Dihomogamma-linolenic acid; AA, Arachdonic acid; PGE1, Prostaglandin E1; Zn, Zinc; Mg, Magnesium; EPA, Eicosapentaenoic acid; DHA, Docosahexaenoic acid; PGs, Prostaglandins; TXA, Thromboxane A; LT, Leukotriene; LXs, Lipoxins; EETs, Epoxyeicosatrienoic acids; HETEs, Hydroxyeicosatetraenoic acids; BDNF, Brain-derived neurotrophic factor; IL, Interleukin; TNF, Tumor necrosis factor; SNAP25, Synaptosomal-associated protein 25.
1068
Editorial / Nutrition 29 (2013) 1066–1069
in dorsal root ganglion neurons following nerve injury [38], which facilitates the synthesis of BDNF in primary sensory neurons to initiate repair of damaged neurons and neuronal regeneration. In a recent study using bioinformatics approach, we showed that lipoxin A4 (LXA4), a known anti-inflammatory bioactive metabolite derived from AA, showed highest binding affinity for BDNF compared with other PUFAs and metabolites, suggesting those PUFAs and their metabolites especially, LXA4 physically interact with BDNF. Similar interactions were noted between BDNF and resolvins and protectins, which are anti-inflammatory metabolites formed from EPA and DHA, respectively, but were of lesser intensity compared with LXA4 [39]. Vitamins and micronutrients in autism The current author has reported previously that altered maternal micronutrients (folic acid and vitamin B12), increased homocysteine and oxidative stress that could lead to epigenetic modifications contributing to preterm birth and poor fetal outcome. This could increase the risk for behavioral disorders, such as autism, in children [40,41]. These results showed that antioxidants, minerals, trace elements, and various vitamins function as cofactors in the metabolism of PUFAs. For instance, folic acid, vitamins C and B6, and zinc serve as cofactors in the metabolism of essential fatty acids and in the formation of various eicosanoids [15,42] (Fig. 1). Furthermore, AA, EPA, and DHA form precursors to anti-inflammatory bioactive lipids such as lipoxins, resolvins, and protectins that are essential for wound healing, protecting neurons from various endogenous and exogenous insults, including free radicals and proinflammatory prostaglandins [42–45]. Thus, it is likely that in some patients with autism, the metabolism of PUFAs is deficient or abnormal such that adequate amounts of lipoxins, resolvins, and protectins are not formed, which could lead to enhanced production of proinflammatory cytokines and oxidative stress (in the form of enhanced lipid peroxidation process and increased formation of proinflammatory eicosanoids); imbalance in the formation and action of various neurotransmitters such as dopamine, serotonin, catecholamines, and BDNF, which could result in inappropriate neuronal damage leading to the onset and progression of autism and poor response to the administered PUFAs. This is supported by the work of Al-Farsi et al. [46], who reported that low folate and vitamin B12 nourishment is common among Omani children newly diagnosed with autism. Although this finding in itself is interesting, it is not clear from their study whether low folate and vitamin B12 levels seen in the study population is the cause or effect of the disease. It remains to be determined whether folate and vitamin B12 supplementation would decrease the manifestations of autism or halt its progress. Additionally, it may prove interesting to estimate the plasma levels of PUFAs and lipoxins and correlate those levels with those of vitamins, minerals, and trace elements and with severity of clinical manifestations of autism. Such a comprehensive study is needed. Acknowledgments The author was a recipient of the Ramalingaswami Fellowship of the Department of Biotechnology, India during the tenure of this study. This study was supported in particular by a grant to the author from the Department of Defense and Research Organisation (DRDO), New Delhi.
References [1] Caronna EB, Milunsky JM, Tager-Flusberg H. Autism spectrum disorders: clinical and research frontiers. Arch Dis Child 2008;93:518–23. [2] Levy SE, Mandell DS, Schultz RT. Autism. Lancet 2009;374:1627–38. [3] Prevalence of autism spectrum disorders dautism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill Summ 2012;61:1–19. [4] Baudouin SJ, Gaudias J, Gerharz S, Hatstatt L, Zhou K, Punnakkal P, et al. Shared synaptic pathophysiology in syndromic and nonsyndromic rodent models of autism. Science 2012;338:128–32. [5] Garber K. Autism’s cause may reside in abnormalities at the synapse. Science 2007;317:190–1. [6] Tabuchi K, Blundell J, Etherton MR, Hammer RE, Liu X, Powell CM, et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 2007;318:71–6. [7] Betancur C, Sakurai T, Buxbaum JD. The emerging role of synaptic celladhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci 2009;32:402–12. [8] Perry EK, Lee MLW, Martin-Ruiz CM, Court JA, Volsen SG, Merrit J, et al. Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am J Psychiatry 2001;158:1058–66. [9] Tordjman S, Antoine C, Cohen DJ, Gauvain-Piquard A, Carlier M, Roubertoux P, et al. Study of the relationships between self-injurious behavior and pain reactivity in infantile autism. Encephale 1999;25:122–34. [10] Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic antiinflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 2003;9:125–34. [11] Suzuki K, Matsuzaki H, Iwata K, Kameno Y, Shimmura C, Kawai S, et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS One 2011;6:e20470. [12] Wei H, Zou H, Sheikh AM, Malik M, Dobkin C, Brown WT, et al. IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflammation 2011;8:52. [13] Elovitz MA, Brown AG, Breen K, Anton L, Maubert M, Burd I. Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury. Int J Dev Neurosci 2011;29:663–71. [14] Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J. Altered T cell responses in children with autism. Brain Behav Immun 2011;25:840–9. [15] Das UN. A perinatal strategy for preventing adult diseases: the role of longchain polyunsaturated fatty acids. Boston: Kluwer Academic Publishers; 2002. [16] Das UN. Long-chain polyunsaturated fatty acids in growth and development of brain and memory. Nutrition 2003;19:62–5. [17] Das UN. Can memory be improved? A discussion on the role of ras, GABA, acetylcholine, NO, insulin, TNF-a, and long-chain polyunsaturated fatty acids in memory formation and consolidation. Brain and Development 2003;25:251–61. [18] Das UN. Long-chain polyunsaturated fatty acids in memory formation and consolidation: Further evidence and discussion. Nutrition 2003; 19:988–93. [19] Hajjar T, Meng GY, Rajion MA, et al. Omega 3 polyunsaturated fatty acid improves spatial learning and hippocampal peroxisome proliferator activated receptors (PPARa and PPARg) gene expression in rats. BMC Neuroscience 2012;13:109. [20] Kotani S, Sakaguchi E, Warashina S, Matsukawa N, Ishikura Y, Kiso Y, et al. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res 2006;56:159–64. [21] Kavraal S, Oncu SK, Bitiktas S, Artis AS, Dolu N, Gunes T, et al. Maternal intake of Omega-3 essential fatty acids improves long term potentiation in the dentate gyrus and Morris water maze performance in rats. Brain Res 2012;1482:32–9. [22] Bell JG, Sargent JR, Tocher DR, Dick JR. Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders? Prostaglandins Leukot Essent Fatty Acids 2000;63:21–5. le my C, Lejeune B, Martineau J, Guilloteau D, [23] Vancassel S, Durand G, Barthe et al. Plasma fatty acid levels in autistic children. Prostaglandins Leukot Essent Fatty Acids 2001;65:1–7. €fer MR, Klier C, Friedrich MH, Feucht M. [24] Amminger GP, Berger GE, Scha Omega-3 fatty acids supplementation in children with autism: a doubleblind randomized, placebo-controlled pilot study. Biol Psychiatry 2007; 61:551–3. [25] Bent S, Bertoglio K, Hendren RL. Omega- 3 fatty acids for autistic spectrum disorder: a systematic review. J Autism Dev Disord 2009;39:1145–54. [26] Meguid NA, Atta HM, Gouda AS, Khalil RO. Role of polyunsaturated fatty acids in the management of Egyptian children with autism. Clin Biochem 2008;41:1044–8. [27] El-Ansary AK, Bacha AG, Al-Ayahdi LY. Impaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi Arabia. Lipids Health Dis 2011;10:63. [28] Yui K, Koshiba M, Nakamura S, Kobayashi Y. Effects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in
Editorial / Nutrition 29 (2013) 1066–1069
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
individuals with autism spectrum disorders: a double-blind, placebocontrolled, randomized trial. J Clin Psychopharmacol 2012;32:200–6. Connell E, Darios F, Broersen K, Gatsby N, Peak-Chew S-Y, Rickman C, et al. Mechanism of arachidonic acid action on syntaxin–Munc18. EMBO Rep 2007;8:414–9. Latham CF, Osborne SL, Cryle MJ, Meunier FA. Arachidonic acid potentiates exocytosis and allows neuronal SNARE complex to interact with Munc18a. J Neurochem 2007;100:1543–54. Katoh-Semba R, Wakako R, Komori T, Shigemi H, Miyazaki N, Ito H, et al. Agerelated changes in BDNF protein levels in human serum: differences between autism cases and normal controls. Int J Dev Neurosci 2007;25:367–72. Sheikh AM, Malik M, Wen G, Chauhan A, Chauhan V, Gong CX, et al. BDNFAkt-Bcl2 antiapoptotic signaling pathway is compromised in the brain of autistic subjects. J Neurosci Res 2010;88:2641–7. Chapleau CA, Larimore JL, Theibert A, Pozzo-Miller L. Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism. J Neurodev Disord 2009;1:185–96. Raznahan A, Toro R, Proitsi P, Powell J, Paus T, Bolton PF, et al. A functional polymorphism of the brain derived neurotrophic factor gene and cortical anatomy in autism spectrum disorder. J Neurodev Disord 2009;1:215–23. Bousquet M, Gibrat C, Saint-Pierre M, Julien C, Calon F, Cicchetti F. Modulation of brain-derived neurotrophic factor as a potential neuroprotective mechanism of action of omega-3 fatty acids in a parkinsonian animal model. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1401–8. Wu A, Ying Z, Gomez-Pinilla F. Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma 2004;21:1457–67. Hutchinson AJ, Chou CL, Israel DD, Xu W, Regan JW. Activation of EP2 prostanoid receptors in human glial cell lines stimulates the secretion of BDNF. Neurochem Int 2009;54:439–46. Cruz Duarte P, St-Jacques B, Ma W. Prostaglandin E2 contributes to the synthesis of brain-derived neurotrophic factor in primary sensory neuron in ganglion explant cultures and in a neuropathic pain model. Exp Neurol 2012;234:466–81. Vetrivel U, Ravichandran SB, Kuppan K, Mohanlal J, Das UN, Narayanasamy A. Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on
[40]
[41]
[42] [43]
[44]
[45]
[46]
1069
brain-derived neurotrophic factor (BDNF) through molecular docking simulation. Lipids Health Dis 2012;11:109. Dhobale M, Joshi S. Altered maternal micronutrients (folic acid, vitamin B(12)) and omega 3 fatty acids through oxidative stress may reduce neurotrophic factors in preterm pregnancy. J Matern Fetal Neonatal Med 2012; 25:317–23. Kulkarni A, Dangat K, Kale A, Sable P, Chavan-Gautam P, Joshi S. Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats. PLoS One 2011; 6:e17706. Das UN. Molecular basis of health and disease. New York: Springer; 2011. Lukiw WJ, Cui JG, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest 2005;115: 2774–83. Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 2003;278: 43807–17. Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci U S A 2004;101:8491–6. Al-Farsi YM, Waly MI, Deth RC, Al-Sharbati MM, Al-Shafaee M, Al-Farsi O, et al. Low folate and vitamin B12 nourishment is common among Omani children newly diagnosed with autism. Nutrition 2013;29:537–41.
Undurti N. Das, M.D., F.A.M.S., F.R.S.C. UND Life Sciences 13800 Fairhill Road, #321 Shaker Heights, OH 44120, USA Department of Biotechnology Jawaharlal Nehru Technological University Kakinada-533 003, India