Nuclear Factor-Kappa B and Other Oxidative Stress Biomarkers in Serum of Autistic Children

DOI: 10.4236/ojmip.2015.51002   PDF   HTML   XML   4,488 Downloads   5,207 Views   Citations


The aim of the present study was to investigate the status of oxidative stress in the serum of children affected with autism spectrum disorder. Twenty autistic children aged 3 to 12 years, were gender and age-matched with 20 typically developing children. Changes in the levels of the redox-sensing transcription factor nuclear factor-kappa B (NF-κB) was measured in serum of autistic children and controls. Other oxidative stress biomarkers such as malondialdehyde, reduced glutathione, total antioxidant capacity, catalase activity, and paraoxonase 1 activity were determined in serum as well. Significant increase was observed in serum NF-κB of autistic children compared to that in controls (by 138.6%). There was also marked increase in malondialdehyde level by 87.3% in autistic patients. Meanwhile, there were significant decreases in reduced glutathione (by 24%), catalase activity (by 40.8%), paraoxonase 1 activity (by 36.6%), and total antioxidant capacity (by 36.5%) compared to the control group. These data clearly demonstrate increased oxidative stress in serum of autistic children and suggest that the NF-κB signaling pathway is activated in autism, possibly due to increased oxidative burden.

Share and Cite:

E. Abdel-Salam, O. , Youness, E. , Mohammed, N. and Elhamed, W. (2015) Nuclear Factor-Kappa B and Other Oxidative Stress Biomarkers in Serum of Autistic Children. Open Journal of Molecular and Integrative Physiology, 5, 18-27. doi: 10.4236/ojmip.2015.51002.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders. DSM-IV. 4th Edition, American Psychiatric Association, Washington DC.
[2] Baird, G., Cass, H. and Slonims, V. (2003) Diagnosis of Autism. BMJ, 327, 488-493.
[3] Fombonne, E., Zakarian, R., Bennett, A., Meng, L. and McLean-Heywood, D. (2006) Pervasive Developmental Disorders in Montreal, Quebec, Canada: Prevalence and Links with Immunizations. Pediatrics, 118, e139-e150.
[4] Napoli, E., Wong, S. and Giulivi, C. (2013) Evidence of Reactive Oxygen Species-Mediated Damage to Mitochondrial DNA in Children with Typical Autism. Molecular Autism, 4, 2.
[5] Gargus, J.J. and Imtiaz, F. (2008) Mitochondrial Energy-Deficient Endophenotype in Autism. American Journal of Biochemistry and Biotechnology. Special Issue on Autism Spectrum Disorders, 4, 198-207.
[6] Cohly, H.H. and Panja, A. (2005) Immunological Findings in Autism. International Review of Neurobiology, 71, 317-341.
[7] Theoharides, T.C., Asadi, S. and Patel, A.B. (2013) Focal Brain Inflammation and Autism. Journal of Neuroinflammation, 10, 46.
[8] De Rubeis, S., He, X., Goldberg, A.P., Poultney, C.S., Samocha, K., Ercument Cicek, A., Kou, Y., Liu, L. et al. (2014) Synaptic, Transcriptional and Chromatin Genes Disrupted in Autism. Nature, 515, 209-215.
[9] Edelson, S.B. and Cantor, D.S. (2000) The Neurotoxic Etiology of the Autistic Spectrum Disorder: A Replicative Study. Toxicology and Industrial Health, 16, 239-247.
[10] Vojdani, A., Campbell, A.W., Anyanwu, E., Kashanian, A., Bock, K. and Vojdani, E. (2002) Antibodies to Neuron-Specific Antigens in Children with Autism: Possible Cross Reaction with Encephalitogenic Proteins from Milk, Chlamydia Pneumoniae and Stretoccoccus Group A. Journal of Neuroimmunology, 129, 168-177.
[11] Vojdani, A., Mumper, E., Granpeesheh, D., Mielke, L., Traver, D., Bock, K., Hirani, K., Neubrander, J., Woeller, K.N., O’Hara, N., Usman, A., Schneider, C., Hebroni, F., Berookhim, J. and McCandless, J. (2008) Low Natural Killer Cell Cytotoxic Activity in Autism: The Role of Glutathione, IL-2 and IL-15. Journal of Neuroimmunology, 205, 148-154.
[12] Halliwell, B. (2001) Role of Free Radicals in the Neurodegenerative Diseases. Drugs & Aging, 18, 685-716.
[13] Hirsch, E.C. and Hunot, S. (2009) Neuroin-flammation in Parkinson’s Disease: A Target for Neuroprotection? The Lancet Neurology, 8, 382-397.
[14] Dasuri, K., Zhang, L. and Keller, J.N. (2013) Oxidative Stress, Neurodegeneration, and the Balance of Protein Degradation and Protein Synthesis. Free Radical Biology and Medicine, 62, 170-185.
[15] Yao, J.K. and Reddy, R. (2011) Oxidative Stress in Schizophrenia: Pathogenetic and Therapeutic Implications. Antioxidants & Redox Signaling, 15, 1999-2002.
[16] Haider, L., Fischer, M.T., Frischer, J.M., Bauer, J., Hoftberger, R., Botond, G., Esterbauer, H., Binder, C.J., Witztum, J.L. and Lassmann, H. (2011) Oxidative Damage in Multiple Sclerosis Lesions. Brain, 134, 1914-1924.
[17] Sies, H. (1997) Oxidative Stress: Oxidants and Antioxidants. Experimental Physiology, 82, 291-295.
[18] Bains, J.S. and Shaw, C.A. (1997) Neurodegenerative Disorders in Humans: The Role of Glutathione in Oxidative Stress-Mediated Neuronal Death. Brain Research Reviews, 25, 335-358.
[19] Sian, J., Dexter, D.T., Lees, A.J., Daniel, S., Agid, Y., Javoy-Agid, F., Jenner, P. and Marsden, C.D. (1994) Alterations in Glutathione Levels in Parkinson’s Disease and Other Neurodegenerative Disorders Affecting Basal Ganglia. Annals of Neurology, 36, 348-355.
[20] Dickinson, D.A. and Forman, H.J. (2002) Cellular Glutathione and Thiols Metabolism. Biochemical Pharmacology, 64, 1019-1026.
[21] Li, N. and Karin, M. (1999) Is NF-κB the Sensor of Oxidative Stress? The FASEB Journal, 13, 1137-1143.
[22] Sen, R. and Baltimore, D. (1986) Indicibility of κ Immunoglobulin Enhancer-Binding Protein NF-κB by a Posttranslational Mechanism. Cell, 47, 921-928.
[23] Christman, J.W., Blackwell, T.S. and Juurlink, B.H.J. (2000) Redox Regulation of Nuclear Factor Kappa B: Therapeutic Potential for Attenuating Inflammatory Responses. Brain Pathology, 10, 153-162.
[24] Haddad, J.J. (2002) Redox Regulation of Pro-Inflammatory Cytokines and IκB-α/NF-κB Nuclear Translocation and Activation. Biochemical and Biophysical Research Communications, 296, 847-856.
[25] Celec, P. (2004) Nuclear Factor Kappa B—Molecular Biomedicine: The Next Generation. Biomedicine & Pharmacotherapy, 58, 365-371.
[26] Gutteridge, J.M. (1995) Lipid Peroxidation and Antioxidants as Biomarkers of Tissue Damage. Clinical Chemistry, 41, 1819-1828.
[27] Furlong, C.E. (2008) Paraoxonases: An Historical Perspective. In: Mackness, B., Mackness, M., Aviram, M. and Paragh, G., Eds., The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism, Springer, Dordrecht, 3-31.
[28] Menini, T. and Gugliucci, A. (2014) Paraoxonase 1 in Neurological Disorders. Redox Report, 19, 49-58.
[29] Ruiz-Larrea, M.B., Leal, A.M., Liza, M., Lacort, M. and de Groot, H. (1994) Antioxidant Effects of Estradiol and 2-Hydroxyestradiol on Iron-Induced Lipid Peroxidation of Rat Liver Microsomes. Steroids, 59, 383-388.
[30] Beutler, M., Duron, O. and Kelly, B.M. (1963) Improved Method for the Determination of Blood Glutathione. Journal of Laboratory and Clinical Medicine, 61, 882-888.
[31] Koracevic, D., Koracevic, G. and Djordjevic, V. (2001) Method for the Measurement of Antioxidant Activity in Human Fluids. Journal of Clinical Pathology, 54, 356-361.
[32] Aebi, H. (1984) Catalase in Vitro. Methods in Enzymology, 105, 121-126.
[33] Higashino, K., Takahashi, Y. and Yamamura, Y. (1972) Release of Phenyl Acetate Esterase from Liver Microsomes by Carbon Tetrachloride. Clinica Chimica Acta, 41, 313-320.
[34] Watson, A.D., Berliner, J.A., Hama, S.Y., La Du, B.N., Faull, K.F., Fogelman, A.M. and Navab, M. (1995) Protective Effect of High Density Lipoprotein Associated Paraoxonase. Inhibition of the Biological Activity of Minimally Oxidized Low Density Lipoprotein. The Journal of Clinical Investigation, 96, 2882-2891.
[35] Van den Berg, R., Haenen, G.R.M.M., Van den Berg, H. and Bast, A. (2001) Transcription Factor NF-κB as a Potential Biomarker for Oxidative Stress. British Journal of Nutrition, 86, 121-127.
[36] Naik, U.S., Gangadharan, C., Abbagani, K., Nagalla, B., Dasari, N. and Manna, S.K. (2011) A Study of Nuclear Transcription Factor-Kappa B in Childhood Autism. PLoS ONE, 6, e19488.
[37] Young, A.M., Campbell, E., Lynch, S., Suckling, J. and Powis, S.J. (2011) Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation. Frontiers in Psychiatry, 2, 27.
[38] Malik, M., Tauqeer, Z., Sheikh, A.M., Wen, G., Nagori, A., Yang, K., Brown, W.T. and Li, X. (2011) NF-κB Signaling in the Brain of Autistic Subjects. Mediators of Inflammation, 2011, Article ID: 785265.
[39] Halliwell, B. and Gutteridge, J.M.C. (1989) Free Radicals in Biology and Medicine. 2nd Edition, Clarendon Press, Oxford, 22-85.
[40] Sies, H. (1991) Role of Reactive Oxygen Species in Biological Processes. Klinische Wochenschrift, 69, 965-968.
[41] Halliwell, B. and Whiteman, M. (2004) Measuring Reactive Species and Oxidative Damage in Vivo and in Cell Culture: How Should You Do It and What Do the Results Mean? British Journal of Pharmacology, 142, 231-255.
[42] Halliwell, B. and Cross, C.E. (1994) Oxygen-Derived Species: Their Relation to Human Disease and Environmental Stress. Environmental Health Perspectives, 102, 5-12.
[43] Halliwell, B. (2007) Biochemistry of Oxidative Stress. Biochemical Society Transactions, 35, 1147-1150.
[44] Martin, H.L. and Teismann, P. (2009) Glutathione—A Review on Its Role and Significance in Parkinson’s Disease. The FASEB Journal, 23, 3263-3272.
[45] Aoyama, K., Watabe, M. and Nakaki, T. (2008) Regulation of Neuronal Glutathione Synthesis. Journal of Pharmacological Sciences, 108, 227-238.
[46] González-Fraguela, M.E., Hung, M.-L.D., Vera, H., Maragoto, C., Noris, E., Blanco, L., Galvizu, R. and Robinson, M. (2013) Oxidative Stress Markers in Children with Autism Spectrum Disorders. British Journal of Medicine and Medical Research, 3, 307-317.
[47] Pecorelli, A., Leoncini, S., De Felice, C., Signorini, C., Cerrone, C., Valacchi, G., Ciccoli, L. and Hayek, J. (2013) Non-Protein-Bound Iron and 4-Hydroxynonenal Protein Adducts in Classic Autism. Brain & Development, 35, 146-154.
[48] James, S.J., Rose, S., Melnyk, S., Jernigan, S., Blossom, S., Pavliv, O. and Gaylor, D.W. (2009) Cellular and Mitochondrial Glutathione Redox Imbalance in Lymphoblastoid Cells Derived from Children with Autism. The FASEB Joural, 23, 2374-2383.
[49] Chauhan, A., Audhya, T. and Chauhan, V. (2012) Brain Region-Specific Glutathione Redox Imbalance in Autism. Neurochemical Researchs, 37, 1681-1689.
[50] Gu, F., Chauhan, V. and Chauhan, A. (2013) Impaired Synthesis and Antioxidant Defense of Glutathione in the Cerebellum of Autistic Subjects: Alterations in the Activities and Protein Expression of Glutathione-Related Enzymes. Free Radical Biology and Medicine, 65, 488-496.
[51] Hauser, R.A., Lyons, K.E., McClain, T., Carter, S. and Perlmutter, D. (2009) Randomized, Double-Blind, Pilot Evaluation of Intravenous Glutathione in Parkinson’s Disease. Movement Disorders, 24, 979-983.
[52] Do, K.Q., Bovet, P. and Cuenod, M. (2004) Schizophrenia: Glutathione Deficit as a New Vulnerability Factor for Disconnectivity Syndrome. Schweizer Archiv für Neurologie, Neurochirurgie und Psychiatrie, 155, 375-385.
[53] Prior, R.L. and Cao, G. (1999) In Vivo Total Antioxidant Capacity: Comparison of Different Analytical Methods. Free Radical Biology and Medicine, 27, 1173-1181.
[54] Vassalle, C., Masini, S., Carpeggiani, C., L’Abbate, A., Boni, C. and Zucchelli, G.C. (2004) In Vivo Total Antioxidant Capacity: Comparison of Two Different Analytical Methods. Clinical Chemistry and Laboratory Medicine, 42, 84-89.
[55] Ziyatdinova, G.K., Budnikov, H.C., Pogoreltzev, V.I. and Ganeev, T.S. (2006) The Application of Coulometry for Total Antioxidant Capacity Determination of Human Blood. Talanta, 68, 800-805.
[56] Suresh, D.R., Annam, V., Pratibha, K. and Prasad, M.B.V. (2009) Total Antioxidant Capacity—A Novel Early Bio-Chemical Marker of Oxidative Stress in HIV Infected Individuals. Journal of Biomedical Science, 16, 61.
[57] Papageorgiou, M., Stiakaki, E., Dimitriou, H., Malliaraki, N., Notas, G., Castanas, E. and Kalmanti, M. (2005) Cancer Chemotherapy Reduces Plasma Total Antioxidant Capacity in Children with Malignancies. Leukemia Research, 29, 11-16.
[58] Abdel-Salam, O.M.E., Youness, E.R. and Hafez, H.F. (2011) The Antioxidant Status of the Plasma in Patients with Breast Cancer Undergoing Chemotherapy. Open Journal of Molecular and Integrative Physiology, 1, 29-35.
[59] Primo-Parmo, S.L., Sorenson, R.C., Teiber, J. and La Du, B.N. (1996) The Human Serum Paraoxonase/Arylesterase Gene (PON1) Is One Member of a Multigene Family. Genomics, 33, 498-507.
[60] Mackness, B., Quarck, R., Verreth, W., Mackness, M. and Holvoet, P. (2006) Human Paraoxonase-1 Overexpression Inhibits Atherosclerosis in a Mouse Model of Metabolic Syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 1545-1550.
[61] Jamroz-Wisniewska, A., Beltowski, J., Stelmasiak, Z. and Bartosik-Psujek, H. (2009) Paraoxonase 1 Activity in Different Types of Multiple Sclerosis. Multiple Sclerosis Journal, 15, 399-402.
[62] Kotan, V.O., Sarandol, E., Kirhan, E., Ozkaya, G. and Kirli, S. (2011) Effects of Long-Term Antidepressant Treatment on Oxidative Status in Major Depressive Disorder: A 24-Week Follow-Up Study. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 35, 1284-1290.
[63] Zengi, O., Karakas, A., Ergun, U., Senes, M., Inan, L. and Yucel, D. (2011) Urinary 8-Hydroxy-2’-Deoxyguanosine Level and Plasma Paraoxonase 1 Activity with Alzheimer’s Disease. Clinical Chemistry and Laboratory Medicine, 50, 529-534.
[64] Wehr, H., Bednarska-Makaruk, M., Graban, A., Lipczyńska-Lojkowska, W., Rodo, M., Bochyńska, A. and Ryglewicz, D. (2009) Paraoxonase Activity and Dementia. Journal of the Neurological Sciences, 283, 107-108.
[65] Gaita, L., Manzi, B., Sacco, R., Lintas, C., Altieri, L., Lombardi, F., Pawlowski, T.L., Redman, M., Craig, D.W., Huentelman, M.J., Ober-Reynolds, S., Brautigam, S., Melmed, R., Smith, C.J., Marsillach, J., Camps, J., Curatolo, P. and Persico, A.M. (2010) Decreased Serum Arylesterase Activity in Autism Spectrum Disorders. Psychiatry Research, 180, 105-113.
[66] Aviram, M., Rosenblat, M., Billecke, S., Erogul, J., Sorenson, R., Bisgaier, C.L., Newton, R.S. and La Du, B. (1999) Human Serum Paraoxonase (PON 1) Is Inactivated by Oxidized Low Density Lipoprotein and Preserved by Antioxidants. Free Radical Biology and Medicine, 26, 892-904.
[67] Seres, I., Fulop, T., Paragh, G. and Khalil, A. (2008) Age-Related Alterations in PON1. In: Mackness, B., Mackness, M., Aviram, M. and Paragh, G., Eds., The Paraoxonases: Their Role in Disease Development and Xenobiotic Metabolism, Springer, Dordrecht, 199-206.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.