Targeting NRF2 in Type 2 diabetes mellitus and depression: Efficacy of natural and synthetic compounds

https://doi.org/10.1016/j.ejphar.2022.174993Get rights and content

Highlights

  • NRF2 expression and activity are altered in depression and T2DM.

  • Chronic stress and inflammation affect NRF2's cytoprotective action.

  • NRF2 crosstalk with relevant signaling pathways.

  • Antidepressants and antidiabetics modulate NRF2 activity.

  • Natural and synthetic NRF2 activators alter disease progression.

Abstract

Evidence supports a strong bidirectional association between depression and Type 2 diabetes mellitus (T2DM). The harmful impact of oxidative stress and chronic inflammation on the development of both disorders is widely accepted. Nuclear factor erythroid 2-related factor 2 (NRF2) is a pertinent target in disease management owing to its reputation as the master regulator of antioxidant responses. NRF2 influences the expression of various cytoprotective phase 2 antioxidant genes, which is hampered in both depression and T2DM. Through interaction and crosstalk with several signaling pathways, NRF2 endeavors to contain the widespread oxidative damage and persistent inflammation involved in the pathophysiology of depression and T2DM. NRF2 promotes the neuroprotective and insulin-sensitizing properties of its upstream and downstream targets, thereby interrupting and preventing disease advancement. Standard antidepressant and antidiabetic drugs may be powerful against these disorders, but unfortunately, they come bearing distressing side effects. Therefore, exploiting the therapeutic potential of NRF2 activators presents an exciting opportunity to manage such bidirectional and comorbid conditions.

Introduction

A growing body of literature has explored the bidirectional association between depression and Type 2 diabetes mellitus (T2DM) and the underlying pathophysiological mechanisms that fuel this relationship (Berge and Riise, 2015; Pan et al., 2010; Renn et al., 2011). Both conditions are serious, debilitating, and significantly impair the affected individual's life as well as negatively impact the economy and social functioning. The most intensively researched pathophysiological factor linking these two disorders is stress, especially oxidative stress, which seems to be a common denominator of this association. Table 1 compiles relevant clinical studies that report oxidative stress in patients with depression or Type 2 Diabetes. Increased generation of reactive oxygen species (ROS) and the dampening of the antioxidant defense system may result from other factors such as chronic psychological and physiological stress, inflammation, and insulin resistance. These may, in turn, further propel the disease condition (Réus et al., 2019).

Nuclear factor erythroid 2-related factor 2 (NRF2), a basic leucine zipper transcription factor of the Cap-N-Collar family of proteins, is fundamental for maintaining redox homeostasis in the body. It is considered the master regulator of antioxidative responses and has been implicated in various diseases, including depression and T2DM (Stenvinkel et al., 2020). It is closely associated with the Kelch-like ECH-associated protein 1 (KEAP1), its endogenous cytosolic repressor protein (Itoh et al., 1999). During homeostatic conditions, NRF2 is bound to KEAP1 in the cytosol and is subjected to proteasomal degradation. Following various stress conditions, it dissociates from KEAP1 and translocates into the nucleus, where it forms a heterodimer with the small Maf protein, which then binds to the antioxidant response element (ARE) enhancer sequences of target antioxidant and metabolic genes. NRF2 has been found to influence the expression of a large number of genes that encode proteins responsible for detoxification, redox homeostasis, stress response, and metabolism (Itoh et al., 1997). Fig. 1 provides a brief schematic illustration of the NRF2 signaling pathway. In the mitochondria, NRF2 acts as a sensor of redox imbalance and preserves mitochondrial integrity by associating with the outer mitochondrial membrane. Such a response was absent in NRF2-knockout (KO) mice (Strom et al., 2016).

NRF2 signaling is disrupted in both depression and T2DM, as depicted in Fig. 2 and Fig. 3. The expression levels of both NRF2 and KEAP1 were significantly lower in the post-mortem brains of patients who suffered from major depressive disorder (MDD), schizophrenia, and bipolar disorder (J. Zhang et al., 2018). In patients with prediabetes and T2DM, low blood NRF2 levels were associated with redox imbalance (Jiménez-Osorio et al., 2014). Further, NRF2 expression was significantly lowered in the hippocampus of diabetic db/db mice, accompanied by depressive behavior, hyperglycemia, insulin resistance, neuroinflammation, and ROS overproduction (Zhai et al., 2018). Given the supposable protective role of NRF2 in these disease conditions, several studies have explored the preventative and ameliorative role of several NRF2 activators in the disease progression of depression and T2DM. In this review article, we strive to explore the role of NRF2 in depression and T2DM, and expectantly in their bidirectional association. Efforts are mainly focused on elucidating the possibility of a molecular and physiological link between the transcriptional factor and the two interactive disease conditions. Several natural and synthetic inducers of NRF2 in relation to depression and T2DM have also been discussed.

Section snippets

The involvement of NRF2-downstream targets in depression and T2DM

Around 250 ARE-dependent genes have been reported in the literature, and the relevance of several of these to depression and T2DM are discussed in this section. These genes, which are the downstream targets of NRF2, encode proteins that perform antioxidative and cytoprotective functions. For instance, NRF2 induces the expression of several molecules belonging to the major antioxidant defense systems: i) the glutathione (GSH) system consisting of GSH, glutamate-cysteine ligase (GCL), glutathione

NRF2, stress, and inflammation in depression and T2DM

The involvement of stress and inflammation in various diseases has garnered the attention of researchers. Bidirectional depression and T2DM go hand in hand with inflammatory conditions prevailing in the presence of chronic psychological and physiological stress. Acute as well as chronic stress may be adequate to cause the export of NRF2 from the nucleus to the cytosol and increase overall inflammation, as observed in a rodent model of depression (Djordjevic et al., 2015). Chronic restraint

NRF2 crosstalks with some relevant targets in depression and T2DM

Several signaling pathways and their downstream targets have been identified to be associated with NRF2 signaling. NRF2 is found to interact with a broad category of signaling molecules such as the phosphoinositide 3-kinase (PI3K), serine/threonine kinase/protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3β), brain-derived neurotrophic factor (BDNF), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and nuclear factor kappa B (NF-κB).

Antidepressants

Literature on the modulatory effect of classical antidepressants on NRF2 signaling and the involvement of the latter in antidepressant action is sparse, although there are a few studies that explore the presence of such a dialogue.

Natural and synthetic NRF2-TARGETING compounds in depression and T2DM

Both synthetic and natural compounds have been shown to target NRF2 and exhibit efficacy against depression and T2DM. This section compiles available literature on some compounds that elicit NRF2-mediated protection against depression and T2DM and their associated complications. Table 2 explores the role of some natural bioactive compounds that exert therapeutic potential as NRF2 activators in depression and T2DM and the possible mechanisms via which they thwart disease development.

Targeting NRF2 in the clinical setting: a discussion

Pharmacologically activating NRF2 signaling appears to be beneficial in tackling oxidative damage and inflammation in body tissues afflicted with diseases. Expert reviewers have advocated for NRF2 as a promising target for T2DM and psychiatric illnesses (Bhandari et al., 2021; David et al., 2017). Despite mounting evidence on the involvement of NRF2 in these disorders, it is still elusive whether this particular involvement tilts towards cause or consequence. Most studies have painted NRF2 and

Conclusions and future perspectives

NRF2 stands as an attractive pharmacological target in the prevention or management of chronic diseases as it regulates the expression of various cytoprotective genes that maintain redox balance and prevent central and peripheral inflammation. The pathophysiological factors linking mood disorders and metabolic disorders, including depression and T2DM, are currently being uncovered. The downstream targets genes of NRF2 may play intricate roles in the bidirectional association of depression and

Authors’ contributions

Rhea Subba: Conceptualization, Visualization, Literature search, Writing-original draft, and editing; Mir Hilal Ahmad: Figure designing and editing; Balaram Ghosh: Writing-critical reviewing and editing; Amal Chandra Mondal: Conceptualization, Writing-critical reviewing and editing, Supervision.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors do not have any conflict of interest.

Acknowledgments

The authors acknowledge the Department of Biotechnology (BT/ PR32907/MED/122/227/2019), Ministry of Science and Technology (Govt. of India), DBT-BUILDER-Level III (BT/INF/22/SP45382/2022), Council of Scientific & Industrial Research-Senior Research Fellow (09/263(1172)2019-EMR-I), Indian Council of Medical Research, (45/7//2019/MP/BMS) and School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

References (298)

  • C. Blanquicett et al.

    Oxidative stress modulates PPARγ in vascular endothelial cells

    Free Radic. Biol. Med.

    (2010)
  • H.K. Bryan et al.

    The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation

    Biochem. Pharmacol.

    (2013)
  • W. Cai et al.

    Peroxisome proliferator-activated receptor γ (PPARγ): a master gatekeeper in CNS injury and repair

    Prog. Neurobiol.

    (2018)
  • S.H. Choi et al.

    AMPK-mediated GSK3β inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress

    Biochem. Pharmacol.

    (2010)
  • A. Cuadrado et al.

    Transcription factors NRF2 and NF-κB are coordinated effectors of the rho family, GTP-binding protein RAC1 during Inflammation

    J. Biol. Chem.

    (2014)
  • L.A. da Silva et al.

    Effects of aquatic exercise on mental health, functional autonomy and oxidative stress in depressed elderly individuals: a randomized clinical trial

    Clinics

    (2019)
  • L. Das et al.

    Adolescence benzo[a]pyrene treatment induces learning and memory impairment and anxiolytic like behavioral response altering neuronal morphology of hippocampus in adult male Wistar rats

    Toxicol Rep

    (2019)
  • L. Ding et al.

    Nrf2 exerts mixed inflammation and glucose metabolism regulatory effects on murine RAW264.7 macrophages

    Int. Immunopharm.

    (2019)
  • A.T. Dinkova-Kostova et al.

    An exceptionally potent inducer of cytoprotective enzymes

    J. Biol. Chem.

    (2010)
  • J. Djordjevic et al.

    Alterations in the Nrf2-Keap1 signaling pathway and its downstream target genes in rat brain under stress

    Brain Res.

    (2015)
  • M.M. dos Santos et al.

    Modulation of redox and insulin signaling underlie the anti-hyperglycemic and antioxidant effects of diphenyl diselenide in zebrafish

    Free Radic. Biol. Med.

    (2020)
  • R. Dringen

    Metabolism and functions of glutathione in brain

    Prog. Neurobiol.

    (2000)
  • A.J. Eisch et al.

    Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression

    Biol. Psychiatr.

    (2003)
  • T. Farkhondeh et al.

    The therapeutic effect of resveratrol: focusing on the Nrf2 signaling pathway

    Biomed. Pharmacother.

    (2020)
  • A. Fujinami et al.

    Serum brain-derived neurotrophic factor in patients with type 2 diabetes mellitus: relationship to glucose metabolism and biomarkers of insulin resistance

    Clin. Biochem.

    (2008)
  • P. Galecki et al.

    Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment

    Pharmacol. Rep.

    (2009)
  • V. Ganesh Yerra et al.

    Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy

    Redox Biol.

    (2013)
  • S. Ghosh et al.

    Inflammation-induced behavioral changes is driven by alterations in Nrf2-dependent apoptosis and autophagy in mouse hippocampus: role of fluoxetine

    Cell. Signal.

    (2020)
  • P. Golpour et al.

    Improvement of NRF2 gene expression and antioxidant status in patients with type 2 diabetes mellitus after supplementation with omega-3 polyunsaturated fatty acids: a double-blind randomised placebo-controlled clinical trial

    Diabetes Res. Clin. Pract.

    (2020)
  • Y. Guan et al.

    Quercetin reverses chronic unpredictable mild stress-induced depression-like behavior in vivo by involving nuclear factor-E2-related factor 2

    Brain Res.

    (2021)
  • S.A. Abuelezz et al.

    Insights into the potential antidepressant mechanisms of cilostazol in chronically restraint rats: impact on the Nrf2 pathway

    Behav. Pharmacol.

    (2018)
  • H. Ai et al.

    Antidiabetic drug metformin ameliorates depressive-like behavior in mice with chronic restraint stress via activation of AMP-activated protein kinase

    Aging. Dis.

    (2020)
  • T. Ali et al.

    Melatonin act as an antidepressant via attenuation of neuroinflammation by targeting Sirt1/Nrf2/HO-1 signaling

    Front. Mol. Neurosci.

    (2020)
  • B.I. Arioz et al.

    Melatonin attenuates LPS-induced acute depressive-like behaviors and microglial NLRP3 inflammasome activation through the SIRT1/Nrf2 pathway

    Front. Immunol.

    (2019)
  • A.S. Axelsson et al.

    Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes

    Sci. Transl. Med.

    (2017)
  • I. Azarova et al.

    Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes

    Mol. Biol. Rep.

    (2020)
  • S. Azizi et al.

    Oxidative stress and nitrate/nitrite (NOx) status following citrulline supplementation in type 2 diabetes: a randomised, double-blind, placebo-controlled trial

    J. Hum. Nutr. Diet.

    (2021)
  • Z. Bahadoran et al.

    Potential efficacy of broccoli sprouts as a unique supplement for management of type 2 diabetes and its complications

    J. Med. Food

    (2013)
  • W. Bao et al.

    Plasma heme oxygenase-1 concentration is elevated in individuals with type 2 diabetes mellitus

    PLoS One

    (2010)
  • L.I. Berge et al.

    Comorbidity between type 2 diabetes and depression in the adult population: directions of the association and its possible pathophysiological mechanisms

    Internet J. Endocrinol.

    (2015)
  • R. Bhandari et al.

    The Nrf2 pathway in psychiatric disorders: pathophysiological role and potential targeting

    Expert Opin. Ther. Targets

    (2021)
  • M.S. Bitar et al.

    A defect in nrf2 signaling constitutes a mechanism for cellular stress hypersensitivity in a genetic rat model of type 2 diabetes

    Am. J. Physiol. Endocrinol. Metab.

    (2011)
  • E. Bouvier et al.

    Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

    Mol. Psychiatr.

    (2017)
  • B. Boyuk et al.

    Relationship between levels of brain-derived neurotrophic factor and metabolic parameters in patients with type 2 diabetes mellitus

    J. Diabetes Res.

    (2014)
  • I. Branchi et al.

    Early social enrichment augments adult hippocampal BDNF levels and survival of BRDU-positive cells while increasing anxiety- and “depression”-like behavior

    J. Neurosci. Res.

    (2006)
  • D. Carling et al.

    The regulation of AMP-activated protein kinase by upstream kinases

    Int. J. Obes.

    (2008)
  • R.L. Castillo et al.

    Quercetin prevents diastolic dysfunction induced by a high-cholesterol diet: role of oxidative stress and bioenergetics in hyperglycemic rats

    Oxid. Med. Cell. Longev.

    (2018)
  • K. Chandra et al.

    Effect of Cichorium intybus seeds supplementation on the markers of glycemic control, oxidative stress, inflammation, and lipid profile in type 2 diabetes mellitus: a randomized, double-blind placebo study

    Phytother Res.

    (2020)
  • N. Chatterjee et al.

    Keap1-Independent regulation of Nrf2 activity by protein acetylation and a BET bromodomain protein

    PLoS Genet.

    (2016)
  • J.-J. Chen et al.

    The antidepressant effects of resveratrol are accompanied by the attenuation of dendrite/dendritic spine loss and the upregulation of BDNF/p-cofilin1 levels in chronic restraint mice

    Neurochem. Res.

    (2021)
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