Hamza AYAYDIN, İsmail KOYUNCU, Hakim ÇELİK, Adnan KİRMİT, İsmail AKALTUN, Hatice TAKATAK

Low HO-1 and High KEAP1 Serum Levels in Children with Attention Deficit Hyperactivity Disorder: The First Clinical Study

Objective: The purpose of this study was therefore to evaluate serum heme oxygenase-1 (HO-1), kelch-like ECHassociated protein 1 (KEAP1), and nuclear factor erythroid 2 related factor 2 (NRF2) levels in children with attention deficit hyperactivity disorder (ADHD) and to reveal their association with the severity of ADHD. Methods: The patient group consisted of 41 children aged 6–12 years, first diagnosed with ADHD and the control group consisted of 34 age- and gender- matched children. ADHD was diagnosed by child psychiatrists during clinical interviews based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The parents of the children in the ADHD group were also given the Turgay DSM-IV-based Disruptive Behavior Disorders Child and Adolescent Rating and Screening Scale (T-DSM-IV-S). Serum HO-1, KEAP1, and NRF2 levels were determined in the biochemistry laboratory using the ELISA technique. Results: HO-1 levels in the patient group were significantly lower than in the control group, while KEAP1 levels were significantly higher, but no significant difference was observed between the groups in terms of NRF2 (p=0.041, p

Dikkat Eksikliği Hiperaktivite Bozukluğu Olan Çocuklarda Düşük HO-1 ve Yüksek KEAP1 Serum Düzeyleri

Amaç: Bu çalışmanın amacı, dikkat eksikliği hiperaktivite bozukluğu (DEHB) olan çocuklarda serum heme oksijenaz-1 (HO-1), kelch benzeri ECH ile ilişkili protein 1 (KEAP1) ve nükleer faktör eritroid 2 ile ilişkili faktör 2 (NRF2) düzeylerini değerlendirip, bozukluğun şiddeti ile ilişkilerini ortaya koymaktır. Yöntem: Hasta grubu 6-12 yaşları arasında 41 DEHB’li çocuktan, kontrol grubu ise yaş ve cinsiyet açısından eşleştirilmiş 34 çocuktan oluşmaktadır. Zihinsel Bozuklukların Tanısal ve İstatistiksel El Kitabı, Beşinci Baskı (DSM-5) temel alınarak yapılan klinik görüşmeler sırasında DEHB tanısı çocuk psikiyatristleri tarafından konmuştur. DEHB’li çocukların ailelerine de Turgay DSM-IV Tabanlı Yıkıcı Davranış Bozuklukları Çocuk ve Ergen Derecelendirme ve Tarama Ölçeği (T-DSM-IV-Ö) verilmiştir. ELISA tekniği kullanılarak biyokimya laboratuvarında serum HO-1, KEAP1 ve NRF2 düzeyleri belirlendi. Bulgular: Hasta grubundaki HO-1 düzeyleri kontrol grubuna göre anlamlı derecede düşükken, KEAP1 düzeyleri anlamlı derecede yüksek bulundu, ancak NRF2 açısından gruplar arasında anlamlı fark gözlenmedi (p=0.041, p

PDF

___

Ercan ES, Suren S, Bacanlı A, et al. Decreasing ADHD phenotypic heterogeneity: searching for neurobiological underpinnings of the restrictive inattentive phenotype. Eur Child Adolesc Psychiatry 2016; 25(3):273-282.

Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007; 39(1):44-84.

Gutteridge JM, Halliwell B. Antioxidant Protection and Oxygen Radical Signaling. Reactive oxygen Species in Biological Systems. Springer, 2002, pp.189-218.

Ceballos-Picot I, Trivier J, Nicole A, Sinet P, Thevenin M. Age-correlated modifications of copper-zinc superoxide dismutase and glutathione-related enzyme activities in human erythrocytes. Clin Chem 1992; 38(1):66-70.

Dvořáková M, Sivoňová M, Trebatická J, Škodáček I, Waczuliková I, Muchová J, et al. The effect of polyphenolic extract from pine bark, Pycnogenol® on the level of glutathione in children suffering from attention deficit hyperactivity disorder (ADHD). Redox Rep 2006; 11(4):163-172.

Sezen H, Kandemir H, Savik E, Basmaci Kandemir S, Kilicaslan F, Bilinc H, Aksoy N. Increased oxidative stress in children with attention deficit hyperactivity disorder. Redox Rep 2016; 21(6): 248-253.

Kul M, Unal F, Kandemir H, Sarkarati B, Kilinc K, Kandemir SB. Evaluation of oxidative metabolism in child and adolescent patients with attention deficit hyperactivity disorder. Psychiatry Investig 2015; 12(3):361.

Ceylan M, Sener S, Bayraktar AC, Kavutcu M. Oxidative imbalance in child and adolescent patients with attention-deficit/hyperactivity disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 2010; 34(8):1491-1494.

Ceylan MF, Sener S, Bayraktar AC, Kavutcu M. Changes in oxidative stress and cellular immunity serum markers in attention‐deficit/hyperactivity disorder. Psychiatry Clin Neurosci 2012; 66(3): 220-226.

Simsek S, Gencoglan S, Ozaner S, Kaplan I, Kaya MC. Antioxidant status and DNA damage in children with attention deficit hyperactivity disorder with or without comorbid disruptive behavioral disorders. Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychopharmacology 2016; 26(2):119-125.

Guney E, Cetin FH, Alisik M. Attention deficit hyperactivity disorder and oxidative stress: A short term follow up study. Psychiatry Res 2015; 229(1- 2):310-317.

Prawan A, Kundu JK, Surh Y-J. Molecular basis of heme oxygenase-1 induction: implications for chemoprevention and chemoprotection. Antioxid Redox Signal 2005;7(11-12):1688-1703.

Ewing JF, Maines MD. Immunohistochemical localization of biliverdin reductase in rat brain: age related expression of protein and transcript. Brain Res 1995; 672(1-2):29-41.

Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 2016; 73(17):3221-3247.

Zhuang H, Littleton-Kearney MT, Doré S. Characterization of heme oxygenase in adult rodent platelets. Curr Neurovasc Res 2005; 2(2):163-168.

Levonen A-L, Hill BG, Kansanen E, Zhang J, Darley-Usmar VM. Redox regulation of antioxidants, autophagy, and the response to stress: implications for electrophile therapeutics. Free Radic Biol Med 2014; 71:196-207.

Sihvola V, Levonen A-L. Keap1 as the redox sensor of the antioxidant response. Arch Biochem Biophys 2017; 617:94-100.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). Fifth ed., Arlington, VA: American Psychiatric Pub., 2013.

Gokler B, Ünal F, Pehlivantürk B, Çengel-Kültür E, Akdemir D, Taner Y. Reliability and validity of Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version-Turkish Version (K-SADS-PL-T). Turk J Child Adolesc Mental Health 2004; 11:109-116. (in Turkish)

Ercan E, Amado S, Somer O, Çıkoğlu S. Development of a test battery for the assessment of attention deficit hyperactivity disorder. Turk J Child Adolesc Psychiatry 2001; 8:132-144.

Oztop D, Altun H, Baskol G, Ozsoy S. Oxidative stress in children with attention deficit hyperactivity disorder. Clin Biochem 2012; 45(10-11):745-748.

Görmez V, Örengül AC, Özer ÖF, Uzuner S, Selek Ş. Thiol/disulphide homeostasis and oxida-tive stress parameters in children and adolescents with attention deficit/hyperactivity disorder. Anatol Clin 2016; 21(3):179-186.

Bulut M, Selek S, Bez Y, Kaya MC, Gunes M, Karababa F, Celik H, Savas HA. Lipid peroxidation markers in adult attention deficit hyperactivity disorder: new findings for oxidative stress. Psychiatry Res 2013; 209(3):638-642.

Selek S, Savas HA, Gergerlioglu HS, Bulut M, Yilmaz HR. Oxidative imbalance in adult attention deficit/hyperactivity disorder. Biol Psychol 2008; 79(2):256-259.

Avcil S, Uysal P, Avcil M, Alışık M, Biçer C. Dynamic thiol/disulfide homeostasis in children with attention deficit hyperactivity disorder and its relation with disease subtypes. Compr Psychiatry 2017; 73:53-60.

Tas FV, Guvenir T, Tas G, Cakaloz B, Ormen M. Nitric oxide levels in disruptive behavioral disorder. Neuropsychobiology 2006; 53(4):176-180.

Spahis S, Vanasse M, Bélanger SA, Ghadirian P, Grenier E, Levy E. Lipid profile, fatty acid composition and pro-and anti-oxidant status in pediatric patients with attention-deficit/hyperactivity disorder. Prostaglandins Leukot Essent Fatty Acids 2008; 79(1-2):47-53.

Bulut M, Selek S, Gergerlioglu HS, Savas HA, Yilmaz HR, Yuce M, et al. Malondialdehyde levels in adult attention-deficit hyperactivity disorder. J Psychiatry Neurosci 2007; 32(6):435.

Iuga C, Alvarez-Idaboy JR, Vivier-Bunge A. ROS initiated oxidation of dopamine under oxidative stress conditions in aqueous and lipidic environments. J Phys Chem B 2011; 115(42):12234-12246.

El Adham EK, Hassan AI, El Aziz El-Mahdy A. Nutritional and metabolic disturbances in attention deficit hyperactivity disease. Res J Med Med Sci 2011; 6(1):10-16.

Sheng XJ, Tu HJ, Chien WL, Kang KH, Lu DH, Liou HH, et al. Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation. PloS One 2017; 12(8): e0183076.

He Q, Song N, Jia F, Xu H, Yu X, Xie J, Jiang H. Role of alpha-synuclein aggregation and the nuclear factor E2-related factor 2/heme oxygenase1 pathway in iron-induced neurotoxicity. Int J Biochem Cell Biol Jun 2013; 45(6):1019-1030.

Kwon SH, Lee SR, Park YJ, Ra M, Lee Y, Pang C, Kim KH. Suppression of 6 Hydroxydopamineınduced oxidative stress by hyperoside via activation of NRF2/HO-1 signaling in dopaminergic neurons. Int J Mol Sci 2019; 20(23).

Calkins MJ, Jakel RJ, Johnson DA, Chan K, Kan YW, Johnson JA. Protection from mitochondrial complex II inhibition in vitro and in vivo by NRF2- mediated transcription. PNAS USA 2005; 102(1): 244-249.

Innamorato NG, Jazwa A, Rojo AI. Different susceptibility to the Parkinson's toxin MPTP in mice lacking the redox master regulator NRF2 or its target gene heme oxygenase-1. PloS One 2010; 5(7):e11838.

Hung SY, Liou HC, Kang KH, Wu RM, Wen CC, Fu WM. Overexpression of heme oxygenase-1 protects dopaminergic neurons against 1-methyl4 phenylpyridinium-induced neurotoxicity. Mol Pharmacol 2008; 74(6):1564-1575.

Zakaria A, Rady M, Mahran L, Abou-Aisha K. Pioglitazone attenuates lipopolysaccharide-induced oxidative stress, dopaminergic neuronal loss and neurobehavioral impairment by activating NRF2/ARE/HO-1. Neurochem Res 2019.