Hostname: page-component-78c5997874-m6dg7 Total loading time: 0 Render date: 2024-11-10T15:52:14.951Z Has data issue: false hasContentIssue false
  • English
  • Français

Antineuroinflammatory therapy: potential treatment for autism spectrum disorder by inhibiting glial activation and restoring synaptic function

Published online by Cambridge University Press:  29 October 2019

Yong-Jiang Li ,
Xiaojie Zhang  and
Ya-Min Li Open the ORCID record for Ya-Min Li [Opens in a new window]
Yong-Jiang Li
Affiliation:
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Xiaojie Zhang
Affiliation:
Mental Health Institute of The Second Xiangya Hospital, Central South University, The China National Clinical Research Center for Mental Health Disorders, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Changsha, Hunan, People’s Republic of China
Ya-Min Li*
Affiliation:
Clinical Nursing Teaching and Research Section, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
*
*Ya-Min Li, PhD, Email: aminny@csu.edu.cn
Get access Rights & Permissions [Opens in a new window]

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by deficits in social interactions and perseverative and stereotypical behavior. Growing evidence points toward a critical role for synaptic dysfunction in the onset of ASD, and synaptic function is influenced by glial cells. Considering the evidence that neuroinflammation in ASD is mediated by glial cells, one hypothesis is that reactive glial cells, under inflammatory conditions, contribute to the loss of synaptic functions and trigger ASD. Ongoing pharmacological treatments for ASD, including oxytocin, vitamin D, sulforaphane, and resveratrol, are promising and are shown to lead to improvements in behavioral performance in ASD. More importantly, their pharmacological mechanisms are closely related to anti-inflammation and synaptic protection. We focus this review on the hypothesis that synaptic dysfunction caused by reactive glial cells would lead to ASD, and discuss the potentials of antineuroinflammatory therapy for ASD.

Keywords

Autism spectrum disordersynaptic dysfunctionmicrogliaastrocyteneuroinflammationtherapy
Type
Review
Information
CNS Spectrums , Volume 25 , Issue 4 , August 2020 , pp. 493 - 501
Copyright
© Cambridge University Press 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Posar, A, Resca, F, Visconti, P.Autism according to diagnostic and statistical manual of mental disorders 5(th) edition: the need for further improvements. J Pediatr Neurosci. 2015;10(2):146–148.Google Scholar
Baio, J, Wiggins, L, Christensen, DL, et al.Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ. 2018;67(6):1–23.Google Scholar
Kent, JM, Kushner, S, Ning, XP, et al.Risperidone dosing in children and adolescents with autistic disorder: a double-blind, placebo-controlled study. J Autism Dev Disord. 2013;43(8):1773–1783.Google Scholar
Owen, R, Sikich, L, Marcus, RN, et al.Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics. 2009;124(6):1533–1540.Google Scholar
Fung, LK, Mahajan, R, Nozzolillo, A, et al.Pharmacologic treatment of severe irritability and problem behaviors in autism: a systematic review and meta-analysis . Pediatrics. 2016;137:S124–S135.Google Scholar
Lord, C, Elsabbagh, M, Baird, G, Veenstra-Vanderweele , J.Autism spectrum disorder. Lancet. 2018;392(10146):508–520.Google Scholar
Buescher, AVS, Cidav, Z, Knapp, M, Mandell, DSCosts of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr. 2014;168(8):721–728.Google Scholar
Jarbrink, K.The economic consequences of autistic spectrum disorder among children in a Swedish municipality. Autism. 2007;11(5):453–463.Google Scholar
Jarbrink, K, Fombonne, E, Knapp, M.Measuring the parental, service and cost impacts of children with autistic spectrum disorder: a pilot study. J Autism Dev Disord. 2003;33(4):395–402.Google Scholar
Cidav, Z, Marcus, SC, Mandell, DSImplications of childhood autism for parental employment and earnings. Pediatrics. 2012;129(4):617–623.Google Scholar
Howlin, P, Alcock, J, An, Burkin C.8 year follow-up of a specialist supported employment service for high-ability adults with autism or Asperger syndrome. Autism. 2005;9(5):533–549.Google Scholar
Knapp, M, Romeo, R, Beecham, J.Economic cost of autism in the UK. Autism. 2009;13(3):317–336.Google Scholar
Peacock, G, Amendah, D, Ouyang, LJ, Grosse, SDAutism spectrum disorders and health care expenditures: the effects of co-occurring conditions. J Dev Behav Pediatr. 2012;33(1):2–8.Google Scholar
Modabbernia, A, Velthorst, E, Reichenberg, A.Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses . Mol Autism. 2017;8:13.Google Scholar
Liu, H, Talalay, P, Fahey, JWBiomarker-guided strategy for treatment of autism spectrum disorder (ASD). CNS Neurol Disord Drug Targets. 2016;15(5):602–613.Google Scholar
Petrelli, F, Pucci, L, Bezzi, P.Astrocytes and microglia and their potential link with autism spectrum disorders. Front Cell Neurosci. 2016;10:21.Google Scholar
Neniskyte, U, Gross, CTErrant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci. 2017;18(11):658–670.Google Scholar
Schafer, DP, Stevens, B.Microglia function in central nervous system development and plasticity. CSH Perspect Biol. 2015;7(10):a020545.Google Scholar
Clarke, LE, Barres, BAEmerging roles of astrocytes in neural circuit development. Nat Rev Neurosci. 2013;14(5):311–321.Google Scholar
Harrison, JK, Jiang, Y, Chen, S, et al.Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA. 1998;95(18):10896–10901.Google Scholar
Wu, Y, Dissing-Olesen , L, MacVicar, BA, Stevens, B.Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol. 2015;36(10):605–613.Google Scholar
Kakegawa, W, Mitakidis, N, Miura, E, et al.Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum. Neuron. 2015;85(2):316–329.Google Scholar
Stevens, B, Allen, NJ, Vazquez, LE, et al.The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):1164–1178.Google Scholar
Hong, S, Beja-Glasser , VF, Nfonoyim, BM, et al.Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352(6286):712–716.Google Scholar
Halassa, MM, Fellin, T, Takano, H, Dong, JH, Haydon, PGSynaptic islands defined by the territory of a single astrocyte. J Neurosci. 2007;27(24):6473–6477.Google Scholar
Bushong, EA, Martone, ME, Jones, YZ, Ellisman, MHProtoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002;22(1):183–192.Google Scholar
Chung, WS, Clarke, LE, Wang, GX, et al.Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013;504(7480):394–400.Google Scholar
Chung, WS, Verghese, PB, Chakraborty, C, et al.Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci USA. 2016;113(36):10186–10191.Google Scholar
Bialas, AR, Stevens, B.TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013;16(12):1773–1782.Google Scholar
Yang, J, Yang, H, Liu, Y, et al.Astrocytes contribute to synapse elimination via type 2 inositol 1,4,5-trisphosphate receptor-dependent release of ATP. eLife. 2016;5:e15043.Google Scholar
Sipe, GO, Lowery, RL, Tremblay, ME, Kelly, EA, Lamantia, CE, Majewska, AKMicroglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun. 2016;7:10905.Google Scholar
Voineagu, I, Wang, XC, Johnston, P, et al.Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474(7351):380.Google Scholar
Nardone, S, Sams, DS, Reuveni, E, et al.DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl Psychiatry. 2014;4:e433.Google Scholar
Schafer, DP, Lehrman, EK, Kautzman, AG, et al.Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691–705.Google Scholar
Gehrmann, J, Matsumoto, Y, Kreutzberg, GWMicroglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev. 1995;20(3):269–287.Google Scholar
Lan, X, Han, X, Li, Q, Yang, QW, Wang, J.Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol. 2017;13(7):420–433.Google Scholar
Lenz, KM, Nelson, LHMicroglia and beyond: innate immune cells as regulators of brain development and behavioral function. Front Immunol. 2018;9:698.Google Scholar
Barbierato, M, Facci, L, Argentini, C, Marinelli, C, Skaper, SD, Giusti, P.Astrocyte-microglia cooperation in the expression of a pro-inflammatory phenotype. CNS Neurol Disord Drug Targets. 2013;12(5):608–618.Google Scholar
Kofler, J, Wiley, CAMicroglia: key innate immune cells of the brain. Toxicol Pathol. 2011;39(1):103–114.Google Scholar
Young, AM, Chakrabarti, B, Roberts, D, Lai, MC, Suckling, J, Baron-Cohen , S.From molecules to neural morphology: understanding neuroinflammation in autism spectrum condition. Mol Autism. 2016;7:9.Google Scholar
Vargas, DL, Nascimbene, C, Krishnan, C, Zimmerman, AW, Pardo, CANeuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):67–81.Google Scholar
Morgan, JT, Chana, G, Abramson, I, Semendeferi, K, Courchesne, E, Everall, IPAbnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res. 2012;1456:72–81.Google Scholar
Tetreault, NA, Hakeem, AY, Jiang, S, et al.Microglia in the cerebral cortex in autism. J Autism Dev Disord. 2012;42(12):2569–2584.Google Scholar
Edmonson, C, Ziats, MN, Rennert, OMAltered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum. Mol Autism. 2014;5(1):3.Google Scholar
Suzuki, K, Sugihara, G, Ouchi, Y, et al.Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry. 2013;70(1):49–58.Google Scholar
Li, X, Chauhan, A, Sheikh, AM, et al.Elevated immune response in the brain of autistic patients. J Neuroimmunol. 2009;207(1–2):111–116.Google Scholar
Wei, H, Zou, H, Sheikh, AM, et al.IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflam. 2011;8:52.Google Scholar
Estes, ML, McAllister, AKImmune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015;16(8):469– 486.Google Scholar
Masi, A, Breen, EJ, Alvares, GA, et al.Cytokine levels and associations with symptom severity in male and female children with autism spectrum disorder. Mol Autism. 2017;8:63.Google Scholar
Ricci, S, Businaro, R, Ippoliti, F, et al.Altered cytokine and BDNF levels in autism spectrum disorder. Neurotox Res. 2013;24(4):491–501.Google Scholar
Molloy, CA, Morrow, AL, Meinzen-Derr , J, et al.Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol. 2006;172(1–2):198–205.Google Scholar
Suzuki, K, Matsuzaki, H, Iwata, K, et al.Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS One. 2011;6(5):e20470.Google Scholar
Jiang, HY, Xu, LL, Shao, L, et al.Maternal infection during pregnancy and risk of autism spectrum disorders: a systematic review and meta-analysis . Brain Behav Immunity. 2016;58:165–172.Google Scholar
Dachew, BA, Mamun, A, Maravilla, JC, Alati, R.Pre-eclampsia and the risk of autism-spectrum disorder in offspring: meta-analysis . Br J Psychiatry. 2018;212(3):142–147.Google Scholar
Xu, G, Jing, J, Bowers, K, Liu, B, Bao, W.Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis . J Autism Dev Disord. 2014;44(4):766–775.Google Scholar
Li, YM, Ou, JJ, Liu, L, Zhang, D, Zhao, JP, Tang, SYAssociation between maternal obesity and autism spectrum disorder in offspring: a meta-analysis . J Autism Dev Disord. 2016;46(1):95–102.Google Scholar
Chen, SW, Zhong, XS, Jiang, LN, et al.Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: a systematic review and meta-analysis . Behav Brain Res. 2016;296:61–69.Google Scholar
Marques, AH, O’Connor, TG, Roth, C, Susser, E, Bjorke-Monsen , ALThe influence of maternal prenatal and early childhood nutrition and maternal prenatal stress on offspring immune system development and neurodevelopmental disorders. Front Neurosci. 2013;7:120.Google Scholar
Kim, KC, Gonzales, EL, Lazaro, MT, et al.Clinical and neurobiological relevance of current animal models of autism spectrum disorders. Biomol Therap. 2016;24(3):207–243.Google Scholar
Knuesel, I, Chicha, L, Britschgi, M, et al.Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014;10(11):643–660.Google Scholar
Estes, ML, McAllister, AKMaternal immune activation: implications for neuropsychiatric disorders. Science. 2016;353(6301):772–777.Google Scholar
Smith, SE, Li, J, Garbett, K, Mirnics, K, Patterson, PHMaternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27(40):10695–10702.Google Scholar
Hsiao, EY, Patterson, PHActivation of the maternal immune system induces endocrine changes in the placenta via IL-6. Brain Behav Immunity. 2011;25(4):604–615.Google Scholar
Graham, AM, Rasmussen, JM, Rudolph, MD, et al.Maternal systemic interleukin-6 during pregnancy is associated with newborn amygdala phenotypes and subsequent behavior at 2 years of age. Biol Psychiatry. 2018;83(2):109–119.Google Scholar
Magni, P, Ruscica, M, Dozio, E, Rizzi, E, Beretta, G, Maffei Facino, R.Parthenolide inhibits the LPS-induced secretion of IL-6 and TNF-alpha and NF-kappaB nuclear translocation in BV-2 microglia. Phytother Res. 2012;26(9):1405–1409.Google Scholar
Nakanishi, M, Niidome, T, Matsuda, S, Akaike, A, Kihara, T, Sugimoto, H.Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur J Neurosci. 2007;25(3):649–658.Google Scholar
Almolda, B, Villacampa, N, Manders, P, et al.Effects of astrocyte-targeted production of interleukin-6 in the mouse on the host response to nerve injury. Glia. 2014;62(7):1142–1161.Google Scholar
Penkowa, M, Camats, J, Hadberg, H, et al.Astrocyte-targeted expression of interleukin-6 protects the central nervous system during neuroglial degeneration induced by 6-aminonicotinamide. J Neurosci Res. 2003;73(4):481–496.Google Scholar
Riccomagno, MM, Kolodkin, ALSculpting neural circuits by axon and dendrite pruning. Annu Rev Cell Dev Biol. 2015;31:779–805.Google Scholar
Darabid, H, Arbour, D, Robitaille, R.Glial cells decipher synaptic competition at the mammalian neuromuscular junction. J Neurosci. 2013;33(4):1297–1313.Google Scholar
Zhan, Y, Paolicelli, RC, Sforazzini, F, et al.Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci. 2014;17(3):400–406.Google Scholar
Dinstein, I, Pierce, K, Eyler, L, et al.Disrupted neural synchronization in toddlers with autism. Neuron. 2011;70(6):1218–1225.Google Scholar
Dichter, GSFunctional magnetic resonance imaging of autism spectrum disorders. Dialog Clin Neurosci. 2012;14(3):319–351.Google Scholar
Barttfeld, P, Wicker, B, Cukier, S, Navarta, S, Lew, S, Sigman, M.A big-world network in ASD: dynamical connectivity analysis reflects a deficit in long-range connections and an excess of short-range connections. Neuropsychologia. 2011;49(2):254–263.Google Scholar
Tang, GM, Gudsnuk, K, Kuo, SH, et al.Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014;83(5):1131–1143.Google Scholar
Hutsler, JJ, Zhang, H.Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 2010;1309:83–94.Google Scholar
Piochon, C, Kloth, AD, Grasselli, G, et al.Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat Commun. 2015;5:5586.Google Scholar
Kim, HJ, Cho, MH, Shim, WH, et al.Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol Psychiatry. 2017;22(11):1576–1584.Google Scholar
Paolicelli, RC, Bolasco, G, Pagani, F, et al.Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):1456– 1458.Google Scholar
Itoh, K, Wakabayashi, N, Katoh, Y, et al.Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13(1):76–86.Google Scholar
Ma, Q.Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401–426.Google Scholar
Shih, RH, Wang, CY, Yang, CMNF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci. 2015;8:77.Google Scholar
Matsushima, A, Kaisho, T, Rennert, PD, et al.Essential role of nuclear factor (NF)-kappaB-inducing kinase and inhibitor of kappaB (IkappaB) kinase alpha in NF-kappaB activation through lymphotoxin beta receptor, but not through tumor necrosis factor receptor I. J Exp Med. 2001;193(5):631– 636.Google Scholar
Gupta, SC, Sundaram, C, Reuter, S, Aggarwal, BBInhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta. 2010;1799(10–12):775–787.Google Scholar
Nair, S, Doh, ST, Chan, JY, Kong, AN, Cai, L.Regulatory potential for concerted modulation of Nrf2- and Nfkb1-mediated gene expression in inflammation and carcinogenesis. Br J Cancer. 2008;99(12):2070–2082.Google Scholar
Liu, GH, Qu, J, Shen, X.NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochim Biophys Acta. 2008;1783(5):713–727.Google Scholar
Yu, MA, Li, H, Liu, QM, et al.Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. Cell Signal. 2011;23(5):883–892.Google Scholar
Kim, JE, You, DJ, Lee, C, Ahn, C, Seong, JY, Hwang, JISuppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation. Cell Signal. 2010;22(11):1645–1654.Google Scholar
Innamorato, NG, Rojo, AI, Garcia-Yague , AJ, Yamamoto, M, de Ceballos, ML, Cuadrado, A.The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol. 2008;181(1):680–689.Google Scholar
Ho, FM, Kang, HC, Lee, ST, et al.The anti-inflammatory actions of LCY-2-CHO, a carbazole analogue, in vascular smooth muscle cells. Biochem Pharmacol. 2007;74(2):298–308.Google Scholar
Lee, HJ, Macbeth, AH, Pagani, JH, Young, WSOxytocin: the great facilitator of life. Prog Neurobiol. 2009;88(2):127–151.Google Scholar
Guastella, AJ, Hickie, IBOxytocin Treatment, circuitry, and autism: a critical review of the literature placing oxytocin into the autism context. Biol Psychiatry. 2016;79(3):234–242.Google Scholar
Wagner, S, Harony-Nicolas , H.Oxytocin and animal models for autism spectrum disorder. Curr Top Behav Neurosci. 2018;35:213–237.Google Scholar
Anagnostou, E, Soorya, L, Chaplin, W, et al.Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism. 2012;3(1):16.Google Scholar
Andari, E, Duhamel, JR, Zalla, T, Herbrecht, E, Leboyer, M, Sirigu, A.Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA. 2010;107(9):4389–4394.Google Scholar
Auyeung, B, Lombardo, MV, Heinrichs, M, et al.Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism. Transl Psychiatry. 2015;5:e507.Google Scholar
Dadds, MR, MacDonald, E, Cauchi, A, Williams, K, Levy, F, Brennan, J.Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. J Autism Dev Disord. 2014;44(3):521–531.Google Scholar
Domes, G, Heinrichs, M, Kumbier, E, Grossmann, A, Hauenstein, K, Herpertz, SCEffects of intranasal oxytocin on the neural basis of face processing in autism spectrum disorder. Biol Psychiatry. 2013;74(3):164–171.Google Scholar
Watanabe, T, Abe, O, Kuwabara, H, et al.Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: a randomized trial. JAMA Psychiatry. 2014;71(2):166– 175.Google Scholar
Gordon, I, Vander Wyk, BC, Bennett, RH, et al.Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci USA. 2013;110(52):20953–20958.Google Scholar
Guastella, AJ, Einfeld, SL, Gray, KM, et al.Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry. 2010;67(7):692–694.Google Scholar
Guastella, AJ, Gray, KM, Rinehart, NJ, et al.The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J Child Psychol Psychiatry Allied Disc. 2015;56(4):444–452.Google Scholar
Yatawara, CJ, Einfeld, SL, Hickie, IB, Davenport, TA, Guastella, AJThe effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry. 2016;21(9):1225–1231.Google Scholar
Yamasue , H, Okada, T, Munesue, T, et al.Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial. Mol Psychiatry. 2018. doi: 10.1038/s41380-018-0097-2.Google Scholar
Munesue, T, Nakamura, H, Kikuchi, M, et al.Oxytocin for male subjects with autism spectrum disorder and comorbid intellectual disabilities: a randomized pilot study. Front Psychiatry. 2016;7:2.Google Scholar
Kosaka, H, Okamoto, Y, Munesue, T, et al.Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial. Transl Psychiatry. 2016;6(8):e872.Google Scholar
Rajamani, KT, Wagner, S, Grinevich, V, Harony-Nicolas , H.Oxytocin as a modulator of synaptic plasticity: implications for neurodevelopmental disorders. Front Synaptic Neurosci. 2018;10:17.Google Scholar
Bakos, J, Srancikova, A, Havranek, T, Bacova, Z.Molecular mechanisms of oxytocin signaling at the synaptic connection. Neural Plasticity. 2018;2018:4864107.Google Scholar
van den Pol, AN. Neuropeptide transmission in brain circuits. Neuron. 2012;76(1):98–115.Google Scholar
Yuan, L, Liu, S, Bai, X, et al.Oxytocin inhibits lipopolysaccharide-induced inflammation in microglial cells and attenuates microglial activation in lipopolysaccharide-treated mice. J Neuroinflam. 2016;13(1):77.Google Scholar
Wang, Y, Zhao, S, Liu, X, Zheng, Y, Li, L, Meng, S.Oxytocin improves animal behaviors and ameliorates oxidative stress and inflammation in autistic mice. Biomed Pharmacother. 2018;107:262–269.Google Scholar
Wang, T, Shan, L, Du, L, et al.Serum concentration of 25-hydroxyvitamin D in autism spectrum disorder: a systematic review and meta-analysis . Eur Child Adolesc Psychiatry. 2016;25(4):341–350.Google Scholar
Fernell, E, Bejerot, S, Westerlund, J, et al.Autism spectrum disorder and low vitamin D at birth: a sibling control study. Mol Autism. 2015;6:3.Google Scholar
Kerley, CP, Power, C, Gallagher, L, Coghlan, D.Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT. Arch Dis Childh. 2017;102(11):1030–1036.Google Scholar
Bent, S, Ailarov, A, Dang, KT, Widjaja, F, Lawton, BL, Hendren, RLOpen-label trial of vitamin D3 supplementation in children with autism spectrum disorder. J Alternat Complement Med. 2017;23(5):394–395.Google Scholar
Feng, J, Shan, L, Du, L, et al.Clinical improvement following vitamin D3 supplementation in autism spectrum disorder. Nutr Neurosci. 2017;20(5):284–290.Google Scholar
Jia , F, Shan, L, Wang, B, et al.Fluctuations in clinical symptoms with changes in serum 25(OH) vitamin D levels in autistic children: three cases report. Nutr Neurosci. 2018:1–4. doi: 10.1080/1028415X.2018.1458421Google Scholar
Jia, F, Wang, B, Shan, L, Xu, Z, Staal, WG, Du, L.Core symptoms of autism improved after vitamin D supplementation. Pediatrics. 2015;135(1):e196 – e198.Google Scholar
Cannell, JJVitamin D and autism, what’s new? Rev Endocr Metab Disord. 2017;18(2):183–193.Google Scholar
Huang, YN, Ho, YJ, Lai, CC, Chiu, CT, Wang, JY1,25-Dihydroxyvitamin D3 attenuates endotoxin-induced production of inflammatory mediators by inhibiting MAPK activation in primary cortical neuron-glia cultures. J Neuroinflam. 2015;12:147.Google Scholar
Nakai, K, Fujii, H, Kono, K, et al.Vitamin D activates the Nrf2-Keap1 antioxidant pathway and ameliorates nephropathy in diabetic rats. Am J Hypertens. 2014;27(4):586–595.Google Scholar
Eyles, DW, Burne, TH, McGrath, JJVitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol. 2013;34(1):47–64.Google Scholar
Grecksch, G, Ruthrich, H, Hollt, V, Becker, A.Transient prenatal vitamin D deficiency is associated with changes of synaptic plasticity in the dentate gyrus in adult rats. Psychoneuroendocrinology. 2009;34(Suppl 1):S258–S264.Google Scholar
Latimer, CS, Brewer, LD, Searcy, JL, et al.Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci USA. 2014;111(41):E4359–E4366.Google Scholar
Fernandes de Abreu, DA, Nivet, E, Baril, N, Khrestchatisky, M, Roman, F, Feron, F. Developmental vitamin D deficiency alters learning in C57Bl/6J mice. Behav Brain Res. 2010;208(2):603–608.Google Scholar
Tarozzi, A, Angeloni, C, Malaguti, M, Morroni, F, Hrelia, S, Hrelia, P.ulforaphane as a potential protective phytochemical against neurodegenerative diseases. Oxidat Med Cell Long. 2013;2013:415078.Google Scholar
Benedict, AL, Mountney, A, Hurtado, A, et al.Neuroprotective effects of sulforaphane after contusive spinal cord injury. J Neurotr. 2012;29(16):2576–2586.Google Scholar
Carrasco-Pozo , C, Tan, KN, Borges, K.Sulforaphane is anticonvulsant and improves mitochondrial function. J Neurochem. 2015;135(5):932–942.Google Scholar
Singh, K, Connors, SL, Macklin, EA, et al.Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci USA. 2014;111(43):15550–15555.Google Scholar
Bent, S, Lawton, B, Warren, T, et al.Identification of urinary metabolites that correlate with clinical improvements in children with autism treated with sulforaphane from broccoli. Mol Autism. 2018;9:35.Google Scholar
Jang, M, Cho, IHSulforaphane ameliorates 3-nitropropionic acid-induced striatal toxicity by activating the Keap1-Nrf2-ARE pathway and inhibiting the MAPKs and NF-kappaB pathways. Mol Neurobiol. 2016;53(4):2619–2635.Google Scholar
Jazwa, A, Rojo, AI, Innamorato, NG, Hesse, M, Fernandez-Ruiz , J, Cuadrado, A.Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal. 2011;14(12):2347–2360.Google Scholar
Liu, H, Dinkova-Kostova , AT, Talalay, P.Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles. Proc Natl Acad Sci USA. 2008;105(41):15926–15931.Google Scholar
Jeong, WS, Kim, IW, Hu, R, Kong, ANModulatory properties of various natural chemopreventive agents on the activation of NF-kappaB signaling pathway. Pharm Res. 2004;21(4):661–670.Google Scholar
Heiss, E, Herhaus, C, Klimo, K, Bartsch, H, Gerhauser, C.Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J Biol Chem. 2001;276(34):32008–32015.Google Scholar
Holloway, PM, Gillespie, S, Becker, F, et al.Sulforaphane induces neurovascular protection against a systemic inflammatory challenge via both Nrf2-dependent and independent pathways. Vasc Pharmacol. 2016;85:29–38.Google Scholar
Pawlik, A, Wiczk, A, Kaczynska, A, Antosiewicz, J, Herman-Antosiewicz , A.Sulforaphane inhibits growth of phenotypically different breast cancer cells. Eur J Nutr. 2013;52(8):1949–1958.Google Scholar
Jo, C, Kim, S, Cho, SJ, et al.Sulforaphane induces autophagy through ERK activation in neuronal cells. FEBS Lett. 2014;588(17):3081–3088.Google Scholar
Liu, Y, Hettinger, CL, Zhang, D, Rezvani, K, Wang, X, Wang, H.Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington’s disease. J Neurochem. 2014;129(3):539–547.Google Scholar
Gambini, J, Ingles, M, Olaso, G, et al.Properties of resveratrol: in vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxid Med Cell Long. 2015;2015:837042.Google Scholar
Novelle, MG, Wahl, D, Dieguez, C, Bernier, M, de Cabo, R.Resveratrol supplementation: where are we now and where should we go? Ageing Res Rev. 2015;21:1–15.Google Scholar
Bhandari, R, Kuhad, A.Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochem Int. 2017;103:8–23.Google Scholar
Bambini-Junior , V, Zanatta, G, Della Flora Nunes, G, et al.Resveratrol prevents social deficits in animal model of autism induced by valproic acid. Neurosci Lett. 2014;583:176–181.Google Scholar
de Sa Coutinho, D, Pacheco, MT, Frozza, RL, Bernardi, A. Anti-inflammatory effects of resveratrol: mechanistic insights. Int J Mol Sci. 2018;19(6):e1812.Google Scholar
Elshaer, M, Chen, Y, Wang, XJ, Tang, X.Resveratrol: an overview of its anti-cancer mechanisms. Life Sci. 2018;207:340–349.Google Scholar
Yang, X, Xu, S, Qian, Y, Xiao, Q.Resveratrol regulates microglia M1/M2 polarization via PGC-1alpha in conditions of neuroinflammatory injury. Brain Behav Immun. 2017;64:162–172.Google Scholar
Truong, VL, Jun, M, Jeong, WSRole of resveratrol in regulation of cellular defense systems against oxidative stress. BioFactors. 2018;44(1):36–49.Google Scholar
Cianciulli, A, Calvello, R, Cavallo, P, Dragone, T, Carofiglio, V, Panaro, MAModulation of NF-kappaB activation by resveratrol in LPS treated human intestinal cells results in downregulation of PGE2 production and COX-2 expression. Toxicol In Vitro. 2012;26(7):1122–1128.Google Scholar
Li, H, Wang, J, Wang, P, Rao, Y, Chen, L.Resveratrol reverses the synaptic plasticity deficits in a chronic cerebral hypoperfusion rat model. J Stroke Cerebrovasc Dis. 2016;25(1):122–128.Google Scholar
Quincozes-Santos , A, Gottfried, C.Resveratrol modulates astroglial functions: neuroprotective hypothesis. Ann NY Acad Sci. 2011;1215:72–78.Google Scholar