Nrf2 Dysregulation in Major Depressive and Bipolar Disorders

  • Maryam Ghanbarirad 1. Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran
  • Mehrdad Hashemi 2. Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran 3. Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
  • Seyed Mehdi Saberi 4. Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
  • Ahmad Majd 1. Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran
Keywords: Nrf2, Major Depression Disorder, Bipolar Disorder


Background: Major depressive disorder (MDD) and bipolar disorder (BPD) are two of the most important mental disorders that greatly impact different aspects of life. These conditions imply heavy health and economic burden and are heterogeneous in nature. Inflammation is reported as the etiology of mental disorders. Nrf2 transcription factor plays a key role in the defense mechanisms against inflammation and oxidative stress. So, this study aimed to evaluate the expression level of Nrf2 in MDD and BPD patients and compared it with healthy control subjects. Materials and Methods: In this study, real-time PCR was conducted to evaluate the expression level of Nrf2 in 100 MDD and 100 BPD patients compared to 100 healthy control subjects. Statistical analysis conducted on GraphPad Prism 8 and SPSS21 included ANOVA, Tukey’s test, receiver operating characteristic (ROC), and odds ratio. Results: Results suggest a significant downregulation of Nrf2 in these conditions compared to the control group. ROC curve analysis demonstrates Nrf2 as a biomarker of these psychiatric disorders. Conclusion: The elevated levels of reactive oxygen species and downregulation of detoxifying enzymes were observed in MDD and BPD, which can be associated with the downregulation of Nrf2. Concerning its role in inflammatory response pathways, alternation of Nrf2 expression can be associated with the pathology of these conditions.


Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, et al. Major depressive disorder. Nature reviews Disease primers. 2016;2(1):1-20.


Sheehan DV, Nakagome K, Asami Y, Pappadopulos EA, Boucher M. Restoring function in major depressive disorder: A systematic review. Journal of Affective Disorders. 2017;215:299-313.


Scaini G, Valvassori SS, Diaz AP, Lima CN, Benevenuto D, Fries GR, et al. Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings. Braz J Psychiatry. 2020;42(5):536-51.

PMid:32267339 PMCid:PMC7524405

Vieta E, Berk M, Schulze TG, Carvalho AF, Suppes T, Calabrese JR, et al. Bipolar disorders. Nat Rev Dis Primers. 2018;4:18008.


Fond G. Inflammation in psychiatric disorders. European Psychiatry. 2014;29(8, Supplement):551-2.

Zunszain PA, Hepgul N, Pariante CM. Inflammation and depression. Behavioral neurobiology of depression and its treatment. Springer; 2012. p. 135-51.


Fries GR, Walss-Bass C, Bauer ME, Teixeira AL. Revisiting inflammation in bipolar disorder. Pharmacology Biochemistry and Behavior. 2019;177:12-9.


Goldstein BI, Kemp DE, Soczynska JK, McIntyre RS. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar disorder: a systematic review of the literature. J Clin Psychiatry. 2009;70(8):1078-90.


Bouvier E, Brouillard F, Molet J, Claverie D, Cabungcal J, Cresto N, et al. Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression. Molecular psychiatry. 2017;22(12):1701-13.


Yao W, Zhang J-c, Ishima T, Dong C, Yang C, Ren Q, et al. Role of Keap1-Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice. Scientific Reports. 2016;6(1):30659.

PMid:27470577 PMCid:PMC4965765

Hashimoto K. Essential Role of Keap1-Nrf2 Signaling in Mood Disorders: Overview and Future Perspective. Front Pharmacol. 2018;9:1182-.

PMid:30386243 PMCid:PMC6198170

Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science. 2018;359(6376):693-7.

PMid:29439242 PMCid:PMC5898828

Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015;76(2):155-62.


Ferrari AJ, Stockings E, Khoo JP, Erskine HE, Degenhardt L, Vos T, et al. The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016;18(5):440-50.


. Institute for Health Metrics and Evaluation (IHME). Findings from the Global Burden of Disease Study 2017. Seattle, WA: IHME, 2018.

Gan L, Johnson JA. Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2014;1842(8):1208-18.


Fedoce AdG, Ferreira F, Bota RG, Bonet-Costa V, Sun PY, Davies KJ. The role of oxidative stress in anxiety disorder: cause or consequence? Free radical research. 2018;52(7):737-50.

PMid:29742940 PMCid:PMC6218334

Hamed RA, Elmalt HA, Salama AA, Abozaid SY, Ahmed AS. Biomarkers of Oxidative Stress in Major Depressive Disorder. Open Access Macedonian Journal of Medical Sciences. 2020;8(B):501-6.

Liu T, Zhong S, Liao X, Chen J, He T, Lai S, et al. A Meta-Analysis of Oxidative Stress Markers in Depression. PLoS One. 2015;10(10):e0138904.

PMid:26445247 PMCid:PMC4596519

Erkan Ozcan M, Gulec M, Ozerol E, Polat R, Akyol O. Antioxidant enzyme activities and oxidative stress in affective disorders. International Clinical Psychopharmacology. 2004;19(2):89-95.


Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BWJH. Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology. 2015;51:164-75.


Ren HL, Lv CN, Xing Y, Geng Y, Zhang F, Bu W, et al. Downregulated Nuclear Factor E2-Related Factor 2 (Nrf2) Aggravates Cognitive Impairments via Neuroinflammation and Synaptic Plasticity in the Senescence-Accelerated Mouse Prone 8 (SAMP8) Mouse: A Model of Accelerated Senescence. Med Sci Monit. 2018;24:1132-44.

PMid:29474348 PMCid:PMC5833362

Shmarina GV, Orlova MD, Ershova ES, Jestkova EM, Martynov AV, Veiko NN, et al. NRF2 and HMOX1 Gene Expression against the Background of Systemic Oxidative Stress in Patients with Acute Psychosis. Russian Journal of Genetics. 2020;56(1):96-102.

Martín-Hernández D, Caso JR, Javier Meana J, Callado LF, Madrigal JLM, García-Bueno B, et al. Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants. J Neuroinflammation. 2018;15(1):251.

PMid:30180869 PMCid:PMC6122627

Zhang J-c, Yao W, Dong C, Han M, Shirayama Y, Hashimoto K. Keap1-Nrf2 signaling pathway confers resilience versus susceptibility to inescapable electric stress. European Archives of Psychiatry and Clinical Neuroscience. 2018;268(8):865-70.


Cores Á, Piquero M, Villacampa M, León R, Menéndez JC. NRF2 Regulation Processes as a Source of Potential Drug Targets against Neurodegenerative Diseases. Biomolecules. 2020;10(6).

PMid:32545924 PMCid:PMC7356958

Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, et al. Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol. 2007;66(1):75-85.

PMid:17204939 PMCid:PMC2253896

von Otter M, Landgren S, Nilsson S, Zetterberg M, Celojevic D, Bergström P, et al. Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract. Mechanisms of Ageing and Development. 2010;131(2):105-10.


How to Cite
Ghanbarirad, M., Hashemi, M., Saberi, S. M., & Majd, A. (2021). Nrf2 Dysregulation in Major Depressive and Bipolar Disorders. Galen Medical Journal, 10, e2074.
Original Article