Skip to main content Accessibility help

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

  • Yong-Jiang Li (a1), Xiaojie Zhang (a2) and Ya-Min Li (a3)


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.


Corresponding author

*Ya-Min Li, PhD, Email:


Hide All
1.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):146148.
2.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):123.
3.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):17731783.
4.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):15331540.
5.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:S124S135.
6.Lord, C, Elsabbagh, M, Baird, G, Veenstra-Vanderweele, J. Autism spectrum disorder. Lancet. 2018;392(10146):508520.
7.Buescher, AVS, Cidav, Z, Knapp, M, Mandell, DS Costs of autism spectrum disorders in the United Kingdom and the United States. JAMA Pediatr. 2014;168(8):721728.
8.Jarbrink, K. The economic consequences of autistic spectrum disorder among children in a Swedish municipality. Autism. 2007;11(5):453463.
9.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):395402.
10.Cidav, Z, Marcus, SC, Mandell, DS Implications of childhood autism for parental employment and earnings. Pediatrics. 2012;129(4):617623.
11.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):533549.
12.Knapp, M, Romeo, R, Beecham, J. Economic cost of autism in the UK. Autism. 2009;13(3):317336.
13.Peacock, G, Amendah, D, Ouyang, LJ, Grosse, SD Autism spectrum disorders and health care expenditures: the effects of co-occurring conditions. J Dev Behav Pediatr. 2012;33(1):28.
14.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.
15.Liu, H, Talalay, P, Fahey, JW Biomarker-guided strategy for treatment of autism spectrum disorder (ASD). CNS Neurol Disord Drug Targets. 2016;15(5):602613.
16.Petrelli, F, Pucci, L, Bezzi, P. Astrocytes and microglia and their potential link with autism spectrum disorders. Front Cell Neurosci. 2016;10:21.
17.Neniskyte, U, Gross, CT Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci. 2017;18(11):658670.
18.Schafer, DP, Stevens, B. Microglia function in central nervous system development and plasticity. CSH Perspect Biol. 2015;7(10):a020545.
19.Clarke, LE, Barres, BA Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci. 2013;14(5):311321.
20.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):1089610901.
21.Wu, Y, Dissing-Olesen, L, MacVicar, BA, Stevens, B. Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol. 2015;36(10):605613.
22.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):316329.
23.Stevens, B, Allen, NJ, Vazquez, LE, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131(6):11641178.
24.Hong, S, Beja-Glasser, VF, Nfonoyim, BM, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352(6286):712716.
25.Halassa, MM, Fellin, T, Takano, H, Dong, JH, Haydon, PG Synaptic islands defined by the territory of a single astrocyte. J Neurosci. 2007;27(24):64736477.
26.Bushong, EA, Martone, ME, Jones, YZ, Ellisman, MH Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002;22(1):183192.
27.Chung, WS, Clarke, LE, Wang, GX, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013;504(7480):394400.
28.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):1018610191.
29.Bialas, AR, Stevens, B. TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013;16(12):17731782.
30.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.
31.Sipe, GO, Lowery, RL, Tremblay, ME, Kelly, EA, Lamantia, CE, Majewska, AK Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat Commun. 2016;7:10905.
32.Voineagu, I, Wang, XC, Johnston, P, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. 2011;474(7351):380.
33.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.
34.Schafer, DP, Lehrman, EK, Kautzman, AG, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74(4):691705.
35.Gehrmann, J, Matsumoto, Y, Kreutzberg, GW Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev. 1995;20(3):269287.
36.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):420433.
37.Lenz, KM, Nelson, LH Microglia and beyond: innate immune cells as regulators of brain development and behavioral function. Front Immunol. 2018;9:698.
38.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):608618.
39.Kofler, J, Wiley, CA Microglia: key innate immune cells of the brain. Toxicol Pathol. 2011;39(1):103114.
40.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.
41.Vargas, DL, Nascimbene, C, Krishnan, C, Zimmerman, AW, Pardo, CA Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57(1):6781.
42.Morgan, JT, Chana, G, Abramson, I, Semendeferi, K, Courchesne, E, Everall, IP Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism. Brain Res. 2012;1456:7281.
43.Tetreault, NA, Hakeem, AY, Jiang, S, et al. Microglia in the cerebral cortex in autism. J Autism Dev Disord. 2012;42(12):25692584.
44.Edmonson, C, Ziats, MN, Rennert, OM Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum. Mol Autism. 2014;5(1):3.
45.Suzuki, K, Sugihara, G, Ouchi, Y, et al. Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry. 2013;70(1):4958.
46.Li, X, Chauhan, A, Sheikh, AM, et al. Elevated immune response in the brain of autistic patients. J Neuroimmunol. 2009;207(1–2):111116.
47.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.
48.Estes, ML, McAllister, AK Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015;16(8):469486.
49.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.
50.Ricci, S, Businaro, R, Ippoliti, F, et al. Altered cytokine and BDNF levels in autism spectrum disorder. Neurotox Res. 2013;24(4):491501.
51.Molloy, CA, Morrow, AL, Meinzen-Derr, J, et al. Elevated cytokine levels in children with autism spectrum disorder. J Neuroimmunol. 2006;172(1–2):198205.
52.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.
53.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;58:165172.
54.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):142147.
55.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):766775.
56.Li, YM, Ou, JJ, Liu, L, Zhang, D, Zhao, JP, Tang, SY Association between maternal obesity and autism spectrum disorder in offspring: a meta-analysis. J Autism Dev Disord. 2016;46(1):95102.
57.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;296:6169.
58.Marques, AH, O’Connor, TG, Roth, C, Susser, E, Bjorke-Monsen, AL The 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.
59.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):207243.
60.Knuesel, I, Chicha, L, Britschgi, M, et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat Rev Neurol. 2014;10(11):643660.
61.Estes, ML, McAllister, AK Maternal immune activation: implications for neuropsychiatric disorders. Science. 2016;353(6301):772777.
62.Smith, SE, Li, J, Garbett, K, Mirnics, K, Patterson, PH Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007;27(40):1069510702.
63.Hsiao, EY, Patterson, PH Activation of the maternal immune system induces endocrine changes in the placenta via IL-6. Brain Behav Immunity. 2011;25(4):604615.
64.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):109119.
65.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):14051409.
66.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):649658.
67.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):11421161.
68.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):481496.
69.Riccomagno, MM, Kolodkin, AL Sculpting neural circuits by axon and dendrite pruning. Annu Rev Cell Dev Biol. 2015;31:779805.
70.Darabid, H, Arbour, D, Robitaille, R. Glial cells decipher synaptic competition at the mammalian neuromuscular junction. J Neurosci. 2013;33(4):12971313.
71.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):400406.
72.Dinstein, I, Pierce, K, Eyler, L, et al. Disrupted neural synchronization in toddlers with autism. Neuron. 2011;70(6):12181225.
73.Dichter, GS Functional magnetic resonance imaging of autism spectrum disorders. Dialog Clin Neurosci. 2012;14(3):319351.
74.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):254263.
75.Tang, GM, Gudsnuk, K, Kuo, SH, et al. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014;83(5):11311143.
76.Hutsler, JJ, Zhang, H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 2010;1309:8394.
77.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.
78.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):15761584.
79.Paolicelli, RC, Bolasco, G, Pagani, F, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333(6048):14561458.
80.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):7686.
81.Ma, Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401426.
82.Shih, RH, Wang, CY, Yang, CM NF-kappaB signaling pathways in neurological inflammation: a mini review. Front Mol Neurosci. 2015;8:77.
83.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):631636.
84.Gupta, SC, Sundaram, C, Reuter, S, Aggarwal, BB Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta. 2010;1799(10–12):775787.
85.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):20702082.
86.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):713727.
87.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):883892.
88.Kim, JE, You, DJ, Lee, C, Ahn, C, Seong, JY, Hwang, JI Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation. Cell Signal. 2010;22(11):16451654.
89.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):680689.
90.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):298308.
91.Lee, HJ, Macbeth, AH, Pagani, JH, Young, WS Oxytocin: the great facilitator of life. Prog Neurobiol. 2009;88(2):127151.
92.Guastella, AJ, Hickie, IB Oxytocin Treatment, circuitry, and autism: a critical review of the literature placing oxytocin into the autism context. Biol Psychiatry. 2016;79(3):234242.
93.Wagner, S, Harony-Nicolas, H. Oxytocin and animal models for autism spectrum disorder. Curr Top Behav Neurosci. 2018;35:213237.
94.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.
95.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):43894394.
96.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.
97.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):521531.
98.Domes, G, Heinrichs, M, Kumbier, E, Grossmann, A, Hauenstein, K, Herpertz, SC Effects of intranasal oxytocin on the neural basis of face processing in autism spectrum disorder. Biol Psychiatry. 2013;74(3):164171.
99.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):166175.
100.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):2095320958.
101.Guastella, AJ, Einfeld, SL, Gray, KM, et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry. 2010;67(7):692694.
102.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):444452.
103.Yatawara, CJ, Einfeld, SL, Hickie, IB, Davenport, TA, Guastella, AJ The 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):12251231.
104.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.
105.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.
106.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.
107.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.
108.Bakos, J, Srancikova, A, Havranek, T, Bacova, Z. Molecular mechanisms of oxytocin signaling at the synaptic connection. Neural Plasticity. 2018;2018:4864107.
109.van den Pol, AN. Neuropeptide transmission in brain circuits. Neuron. 2012;76(1):98115.
110.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.
111.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;107:262269.
112.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):341350.
113.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.
114.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):10301036.
115.Bent, S, Ailarov, A, Dang, KT, Widjaja, F, Lawton, BL, Hendren, RL Open-label trial of vitamin D3 supplementation in children with autism spectrum disorder. J Alternat Complement Med. 2017;23(5):394395.
116.Feng, J, Shan, L, Du, L, et al. Clinical improvement following vitamin D3 supplementation in autism spectrum disorder. Nutr Neurosci. 2017;20(5):284290.
117.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. 2018:14. doi: 10.1080/1028415X.2018.1458421
118.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):e196e198.
119.Cannell, JJ Vitamin D and autism, what’s new? Rev Endocr Metab Disord. 2017;18(2):183193.
120.Huang, YN, Ho, YJ, Lai, CC, Chiu, CT, Wang, JY 1,25-Dihydroxyvitamin D3 attenuates endotoxin-induced production of inflammatory mediators by inhibiting MAPK activation in primary cortical neuron-glia cultures. J Neuroinflam. 2015;12:147.
121.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):586595.
122.Eyles, DW, Burne, TH, McGrath, JJ Vitamin 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):4764.
123.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):S258S264.
124.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):E4359E4366.
125.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):603608.
126.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.
127.Benedict, AL, Mountney, A, Hurtado, A, et al. Neuroprotective effects of sulforaphane after contusive spinal cord injury. J Neurotr. 2012;29(16):25762586.
128.Carrasco-Pozo, C, Tan, KN, Borges, K. Sulforaphane is anticonvulsant and improves mitochondrial function. J Neurochem. 2015;135(5):932942.
129.Singh, K, Connors, SL, Macklin, EA, et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci USA. 2014;111(43):1555015555.
130.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.
131.Jang, M, Cho, IH Sulforaphane 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):26192635.
132.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):23472360.
133.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):1592615931.
134.Jeong, WS, Kim, IW, Hu, R, Kong, AN Modulatory properties of various natural chemopreventive agents on the activation of NF-kappaB signaling pathway. Pharm Res. 2004;21(4):661670.
135.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):3200832015.
136.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;85:2938.
137.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):19491958.
138.Jo, C, Kim, S, Cho, SJ, et al. Sulforaphane induces autophagy through ERK activation in neuronal cells. FEBS Lett. 2014;588(17):30813088.
139.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):539547.
140.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.
141.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;21:115.
142.Bhandari, R, Kuhad, A. Resveratrol suppresses neuroinflammation in the experimental paradigm of autism spectrum disorders. Neurochem Int. 2017;103:823.
143.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;583:176181.
144de Sa Coutinho, D, Pacheco, MT, Frozza, RL, Bernardi, A. Anti-inflammatory effects of resveratrol: mechanistic insights. Int J Mol Sci. 2018;19(6):e1812.
145.Elshaer, M, Chen, Y, Wang, XJ, Tang, X. Resveratrol: an overview of its anti-cancer mechanisms. Life Sci. 2018;207:340349.
146.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;64:162172.
147.Truong, VL, Jun, M, Jeong, WS Role of resveratrol in regulation of cellular defense systems against oxidative stress. BioFactors. 2018;44(1):3649.
148.Cianciulli, A, Calvello, R, Cavallo, P, Dragone, T, Carofiglio, V, Panaro, MA Modulation 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):11221128.
149.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):122128.
150.Quincozes-Santos, A, Gottfried, C. Resveratrol modulates astroglial functions: neuroprotective hypothesis. Ann NY Acad Sci. 2011;1215:7278.


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

  • Yong-Jiang Li (a1), Xiaojie Zhang (a2) and Ya-Min Li (a3)


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.