Open access peer-reviewed chapter

Nrf2 as a Potential Therapeutic Target for Treatment of Huntington’s Disease

Written By

Saravanan Jayaram, Praveen Thaggikuppe Krishnamurthy, Meghana Joshi and Vishnu Kumar

Submitted: 06 December 2021 Reviewed: 10 February 2022 Published: 21 March 2022

DOI: 10.5772/intechopen.103177

From the Edited Volume

From Pathophysiology to Treatment of Huntington's Disease

Edited by Natalia Szejko

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Oxidative stress-induced neuronal damage plays a significant role in pathogenesis of several neuro-degenerative disorders including Huntington’s disease. In Huntington’s disease, oxidative stress-induced neuronal damage is reported to be mediated by PGC-1α and microglial cells. This development led to various clinical trials that tested the efficacy of several exogenous antioxidants such as vitamin E, vitamin C, etc. to prevent the oxidative stress-induced cell damage in several neuro-degenerative disorders. But these randomized clinical trials did not find any significant beneficial effects of exogenous antioxidants in neuro-degenerative disorders. This forced scientists to search endogenous targets that would enhance the production of antioxidants. Nrf2 is one such ideal target that increases the transcription of genes involved in production of antioxidants. Nrf2 is a transcription factor that controls the expression of antioxidant genes that defend cells against oxidative stress. This chapter focuses on the role of oxidative stress in Huntington’s disease and explores the therapeutic benefits of Nrf2 activators.


  • Nrf2
  • oxidative stress
  • Keap 1
  • Huntington’s disease

1. Introduction

Huntington’s disease is an inherited autosomal dominant neurodegenerative disorder characterized by a triad of psychiatric, cognitive and motor symptoms. Every human has two copies of the huntingtin gene (HTT) that codes for huntingtin protein (htt) [1]. The exact functions of huntingtin protein still remain unclear, but it is believed to be involved in the development and formation of cortical and striatal excitatory synapses, surveillance and biogenesis of mitochondrial function, activation of glial cells, upregulation of the expression of brain derived neurotrophic factor, balance of histone acetylation and deacetylation, axonal transport, regulation of signaling pathways and autophagy [2, 3, 4, 5]. The HTT gene, also called as IT15 (‘interesting transcript 15’) gene, is located on the short arm (p) of chromosome number 4 at 4p16.3 [6]. The 5′ end of the HTT gene comprises a three-nucleotide base sequence, cytosine-adenine-guanine (CAG), which is repeated multiple times and codes for the amino acid glutamine. The number of CAG repetitions in a healthy individual varies between 7 and 35. This region of CAG repeats called the trinucleotide repeats varies in length from person to person and may vary in length from generation to generation. The length of the CAG region in the HTT gene is increased due to a hereditary mutation in the HTT gene. The length of the CAG repeats ranges between 36 and 120 in people with HD. Individuals with CAG repeats between 36 and 39 may or may not develop signs of Huntington’s disease, whereas individuals with 40 or more repeats always display the characteristic signs and symptoms of Huntington’s disease. This expansion of CAG repeats due to the inherited mutation in the HTT gene leads to the production of an unusually long version of huntingtin protein (mHtt) [7]. The mutant huntingtin protein is highly susceptible to cleavage, and this results in the creation of shorter fragments containing polyglutamine expansion. These protein fragments are susceptible to misfolding and aggregation, producing fibrillar aggregates in which non-native polyglutamine strands from different proteins are bonded together by hydrogen bonds. These aggregates share the same basic β-amyloid structure seen in other protein deposition diseases [8]. One of the pathways through which mHtt causes cell death is mitochondrial dysfunction [9]. The impairment of mitochondrial electron transport chain by mHtt increases the level of free radicals and oxidative stress [10]. Following the irrefutable role of oxidative stress and associated neuroinflammation in the pathogenesis of neurodegenerative disorders including Huntington’s disease, several exogenous antioxidants were expected to have protective and therapeutic benefits in these degenerative diseases of the brain. But large-scale randomized clinical trials failed to establish any conclusive data to support the hypothesis that exogenous antioxidants could possess neuroprotective or therapeutic benefit in neurodegenerative diseases. Nevertheless, these clinical trials do not refute the fact that oxidative stress and associated neuroinflammation play a key role in the pathogenesis of neurodegenerative diseases. So, it appears logical to stimulate endogenous targets that would reduce oxidative stress and associated neuroinflammation in diseases associated with oxidative stress. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is one such target. Nrf2 is a transcription factor present in the cytoplasm of cells [11]. By upregulating the expression of almost 200 cytoprotective genes, Nrf2 assists cells adapt to inflammation and oxidative stress. Keap1, a repressor protein, controls the level of Nrf2 in the cytoplasm. Keap1 is a cysteine-rich protein that binds to Nrf2 and activates the ubiquitin-proteasome pathway to degrade Nrf2 in the cytoplasm. During oxidative stress, the degradation of Nrf2 by Keap1 is blocked. This results in an increased level of Nrf2 in the cytoplasm of cells. The free Nrf2 moves into the nucleus of cell and increases the transcription of many genes that code for detoxification enzymes and cytoprotective proteins [12]. The potential of Nrf2 to negate oxidative stress and associated neuroinflammation makes it an effective target in the prevention and treatment of Huntington’s disease. The focus of this chapter is to review the role of oxidative stress and associated neuroinflammation in Huntington’s disease and the potential beneficial effects of Nrf2 activators in Huntington’s disease.


2. Oxidative stress in Huntington’s disease

Reactive oxygen species (ROS) are highly reactive molecules or molecular fragments formed from oxygen through biochemical reactions that occur during cellular respiration. Reactive oxygen species and reactive nitrogen species exert both beneficial and harmful effects on the living systems [13]. At low to moderate cellular levels, free radicals play a physiological role in destroying the invading pathogenic microorganisms, regulation of signaling pathways and induction of mitogenic response. At high cellular concentrations, free radicals exert a deleterious effect on lipids, proteins, nucleic acids and other cellular structures [14]. In many pathological conditions including Huntington’s disease, an increase in the level of free radicals and cellular damage due to free radicals is observed. But it still remains unclear whether free radical induced damage in pathological conditions is a cause or downstream consequence of the underlying pathological process.


3. Antioxidants in Huntington’s disease

Antioxidants are substances that are capable of scavenging the free radicals and thereby counteracting the free radical induced oxidative damage and inflammation. There are two classes of antioxidants—enzymatic and non-enzymatic antioxidants. Enzymatic antioxidants include superoxide dismutase (SOD), glutathione peroxidase (Gpx) and catalase (CAT). Ascorbic acid (Vitamin C), carotenoids, α-tocopherol, glutathione (GSH), retinoic acid and flavonoids are examples of non-enzymatic antioxidants. Many of these antioxidants have proven their efficacy in several in vitro and animal models but not in randomized clinical trials. The following table summarizes the findings of the studies that evaluated the efficacy of antioxidants in Huntington’s disease (Table 1).

α-Tocopherolα-Tocopherol treatment (50 and 100 mg/kg, p.o.) significantly reversed the various behavioral, biochemical and mitochondrial alterations in malonic acid treated animals.[15]
MetalloporphyrinsMetalloporphyrins are a class of metallic antioxidants with a potential to scavenge free radicals. In an in vitro model of HD, a manganese porphyrin (manganese (III)tetrakis(4-benzoic acid) porphyrin) reduced significant cell death.[16]
Grape seed Polyphenolic Extract (GSPE)GSPE is a natural compound and a strong antioxidant that has been reported to inhibit polyQ aggregation in phaeochromocytoma (PC)-12 cell line.[17]
MelatoninIn the kainic acid animal model of neurodegeneration, melatonin has shown to be neuroprotective. Melatonin increased neuronal survival while reducing DNA damage. Melatonin therapy effectively reduced the increase in lipid peroxidation, protein carbonyls, and SOD activity inside the striatum in another investigation employing the 3-NP model of HD.[18, 19]
SeleniumIn rats treated with quinolinic acid, selenium reduced lipid peroxidation and enhanced neuronal morphology in the striatum in a dose-dependent manner.[20]
PyruvateTreatment with pyruvate protected against striatal neurodegeneration in a quinolinic acid striatal lesion model of HD. Although smaller dosages had no effect, higher doses had a substantial neuroprotective effect, lowering the striatal lesion area when compared with controls.[21]
TUDCATUDCA (tauroursodeoxycholic acid) is an antioxidant-rich hydrophilic bile acid. In a 3-NP rat model of HD, TUDCA reduced striatal degeneration and improved locomotor and cognitive impairments.[22]
NACTreatment of rats with N-acetylcysteine (NAC), a known glutathione precursor, before exposure to 3-NP protected them from oxidative damage caused by 3-NP, as determined by electron paramagnetic resonance (EPR) and protein carbonyl analyzes on a Western blot. Furthermore, NAC therapy prior to 3-NP delivery reduced striatal lesion volumes considerably.[23]
LycopeneIn a 3-NP induced mouse model of HD, lycopene, a carotenoid pigment and phytochemical naturally found in fruits and vegetables, decreased oxidative stress markers and improved behavior.[24]
α-TocopherolIn patients with mild to moderate HD symptoms, a year-long placebo-controlled, double-blind research was conducted. Although α-tocopherol had no effect on neurologic or neuropsychiatric symptoms in the overall therapy group, post hoc analysis revealed that it had a substantial effect on neurologic symptoms in HD patients early in the disease’s course.[25]
IdebenoneA double-blind, placebo-controlled trial of idebenone in 92 HD patients was performed and no effect on primary outcome measures when compared with placebo controls were detected.[26]

Table 1.

List of antioxidants studied in Huntington’s disease.


4. PGC1α-mediated oxidative stress in Huntington’s disease

The peroxisome proliferator-activated receptor co-activator-1α (PGC1α) is a transcriptional regulator present in tissues that have a high energy demand such as the brain, liver, cardiomyocytes, adipocytes, skeletal muscles and the kidneys [2728]. PGC1α plays a key role in mitochondrial biogenesis, metabolism, peroxisomal remodeling and detoxification of reactive oxygen species [29]. An important and effective mechanism through which PGC1α confers neuroprotection is by its antioxidant activity. Oxidative stress is suppressed by PGC1α by inducing the formation of antioxidant enzymes such as SOD1, SOD2, Gpx-1 and mitochondrial uncoupling proteins [30]. PGC1α also regulates the expression of SIRT3 in mitochondria and SIRT3 in turn activates SOD2 via deacetylation and reduces the level of reactive oxygen species [3132]. In short, PGC1α plays a key role in improving mitochondrial function, biogenesis, expression of antioxidant enzymes and amelioration of oxidative stress induced neuronal damage. A deficiency of PGC1α in the brain affects the integrity of mitochondrial structure and increases the level of reactive oxygen species leading to cellular senescence and disorders related to aging [33]. PGC1α expression has been found to be disturbed in neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease and multiple sclerosis, resulting in mitochondrial abnormalities and elevated ROS levels [34, 35, 36]. Therapeutic agents that can activate endogenous antioxidant systems such as Nrf2/ARE pathway leading to increased expression of antioxidant enzymes hold great promise as neuroprotective agents in Huntington’s disease. Transcriptional modification of Nrf2 pathway, therefore, is considered an excellent approach to counteract the oxidative stress-mediated neuronal damage in Huntington’s disease.

In Huntington’s disease, mHtt causes an increase in oxidative stress mediated by PGC1α. mHtt binds to the promoter sequence of PGC1α and reduces the transcriptional level of PGC1α [37]. mHtt also supresses the expression of mitochondrial uncoupling proteins and antioxidant enzymes by direct binding and inactivation of PGC1α [30]. mHtt disrupts the balance between mitochondrial fission-fusion process by interfering with the function of Drp1 [38]. mHtt induces leakage of calcium ions through the calcium channel ryanodine receptors, further resulting in opening of the mitochondrial permeability transition pore (mPTP), which contributes to mitochondrial oxidative stress [39]. PGC-1α transcription and activity impact the enzyme system that combats reactive oxygen species (ROS). As a result, ROS defense genes such as SOD1, SOD2 and glutathione peroxidase (GPx1) are downregulated, resulting in increased oxidative damage and neuronal death in Huntington’s disease (Figure 1).

Figure 1.

PGC1α-mediated oxidative stress in Huntington’s disease.


5. Microgliosis, oxidative stress and associated neuroinflammation in Huntington’s disease

Microglial cells are the resident immune cells of the central nervous system (CNS) and make up between 10 and 15% of all glial cells in the brain. Microglial cells develop from pro-erythromyeloid progenitor cells in the yolk sac during embryogenesis and go through three stages of development: early, pre and adult microglia. They then migrate into the CNS, using white matter tracts as guiding structures, until the blood-brain barrier is formed. Microglial cells, once inside the CNS, multiply and disseminate evenly to various regions of the brain and maintain a constant population through self-renewal [40]. Microglial cells have numerous slender and elongated processes branching from the small oval-shaped body, which makes them appear ramified. However, when the brain is exposed to potential dangers such as infection, trauma or other factors, these cells lose their branches and take on an amoeboid shape. Microglial cells in the CNS are involved in the establishment and remodeling of neural circuits, protection and repair of the brain, phagocytosis of apoptotic cells in the developing brain, organization of synapses, neurogenesis, control of myelin turnover, control of neuronal excitability and programmed cell death [41, 42]. Homeostatic microglial cells interact with practically every component of the CNS to maintain homeostasis, development and repair by continuously monitoring ongoing actions in the brain. When microglial cells detect a threat to the CNS’s homeostasis, they become activated and produce a variety of cytokines and pro-inflammatory mediators to neutralize the threat. Although this acute response of microglial cells is protective and necessary for maintaining CNS homeostasis, over-activation of microglial cells has been linked to a variety of neurodegenerative diseases [43]. Microglial cells, after activation, release pro-inflammatory mediators and several cytokines that lead to severe oxidative stress and neuroinflammation. According to recent research, activated microglial cells release cytokines and pro-inflammatory mediators, which are the main contributors to neuroinflammation in neurodegenerative diseases [44, 45, 46].

A significant increase in microgliosis has been observed in the autopsied brains of the patients with Huntington’s disease compared with the controls. Accumulation of glial cells has been observed in all grades of Huntington’s disease, and the density of microglial cells finely correlates with the degree of neuronal loss [47, 48]. A significant activation of microglial cells in the regions of the brain affected by Huntington’s disease has been reported in an in vivo positron emission tomography [49, 50]. In Huntington’s disease, microglial cells are activated by mHtt protein, and activated glial cells cause degeneration of neurons in the striatal region of the brain by releasing a variety of proinflammatory cytokines and free radicals [51, 52].


6. Structure of Nrf2

The Nrf2 protein contains 6 highly conserved regions called Nrf2-ECH (Neh) homology domains. The first domain (Neh1) carries the CNC-bZIP domain that mediates heterodimerization with Maf (musculoaponeurotic fibrosarcoma oncogene homolog) proteins. Two degrons called DLG and ETGF, present in the second domain (Neh2) specifically bind to Keap1 protein that leads to degradation of Nrf2 [53]. The third domain (Neh3) is considered to improve the stability of Nrf2 and also acts as the transactivation domain. The fourth (Neh4) and fifth (Neh5) domains of Nrf2 also act as transactivation domains by binding to cAMP response Element Binding Protein (CREB). The sixth domain (Neh6) plays a role in the degradation of Nrf2 by E3 ubiquitin ligase [54].


7. Structure of Keap1

‘Kelch-like ECH-associated protein 1(Keap 1) is a protein that interacts with Nrf2 leading to degradation of Nrf2. Keap1 is a protein of BTB-Kelch family, composed of four domains. The N-terminal domain—Broad complex, Tramtrack and Bric a Bric (BTB) control homodimerization of Keap 1 and its interaction with cul3. This domain also contains Cys-151 residue that plays an important role in sensing oxidative stress. The second domain called the intervening region (IVR) domain contains Cys-273 and Cys-288. These two cysteine residues play a secondary role in sensing oxidative stress. The third domain, double glycine repeat (DGR) and the fourth domain, C-terminal region (CTR) binds to ETGE and DLG motifs of Nrf2 and causing its degradation (Figure 2) [54].

Figure 2.

Structure of Nrf2 and Keap1.


8. Mechanism of action of Nrf2 activators

Nrf2 is a transcription factor that regulates the expression of many antioxidant enzymes, phase I and phase II enzymes and several anti-inflammatory mediators. Nrf2 acts as an important defense mechanism in the neurons and glial cells against oxidative stress, neuroinflammation and other pathological insults. Nrf2 dysregulation has been reported in many oxidative-stress-related diseases such as Huntington’s disease [54]. This makes Nrf2 activators excellent agents to increase antioxidant capacity, decrease neuroinflammation and alleviate pathology in Huntington’s disease (Figure 3).

Figure 3.

Mechanism of action of Nrf2 activators.

Nuclear factor E2-related factor (Nrf2) is a transcription factor composed of 605 amino acids that controls the expression of as many as 200 genes [55, 56, 57]. The proteins encoded by Nrf2 genes are control several functions such as anti-inflammation, antioxidant defense, apoptosis, detoxification, removal of oxidized protein by proteasome and DNA repair [58, 59, 60]. In physiological conditions, the half-life of Nrf2 is very short (<20 minutes) as it is continuously degraded by Kelch-like ECH-associated protein 1 (Keap 1) [61]. Keap 1 is a regulatory protein that regulates the levels of Nrf2 in the cytoplasm of cell. In basal conditions, the Neh2 domain of Nrf2 binds to the β-barrel structure of Keap-1. This is followed by binding of Cullin-3 to Keap-1-Nrf2 complex, and this results in the formation of ubiquitin 3-ligase complex. The ubiquitin 3-ligase complex bins to many ubiquitin molecules resulting in polyubiquitination of Nrf2, which serves as a signal for proteasomal degradation [62]. Keap-1 contain a lot of cysteines in their structure and the free sulfhydryl (∙SH) of cysteine help keap-1 to act as sensors of oxidative stress. During oxidative stress, electrophiles alkylate keap-1 and prevent keap-1 from degrading Nrf2. This leads to accumulation of recently synthesized Nrf2 that increases the antioxidant potential by promoting the transcription of antioxidant and detoxifying genes. In an alternative pathway, Nrf2 is degraded by phosphorylation by glycogen synthase kinase 3β (GSK3β). This degradation of Nrf2 by GSK3β is also blocked by elevated levels of oxidants that leads to accumulation of freshly synthesized Nrf2 [63]. In another pathway, Keap-1 itself is degraded by p62. In this pathway, p62 is phosphorylated by TANK-binding kinase 1 (TBK1) and mechanistic target of rapamycin complex 1 (mTORC1). The phosphorylated p62 makes a complex with keap-1, and this complex is degraded by autophagy in cells [63]. Activation of all these pathways by oxidants leads to accumulation of newly synthesized Nrf2. Nrf2 escapes breakdown into the nucleus and forms heterodimers with sMaf (Nrf2/sMaf). In the nucleus, the activity of Nrf2 is negatively regulated by BACH-1, which competes with Nrf2 to form heterodimers with sMaf [63]. The binding of Nrf2/sMaf to antioxidant response elements promotes the expression of as many as 200 cytoprotective genes.


9. Nrf2 activators in Huntington’s disease

Minhee Jang et al. have reported that gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, alleviated the severity of neurological impairment and lethality following 3-nitropropionic acid treatment in laboratory animals through activation of Nrf2. The authors of this study conclude that gintonin might be an innovative therapeutic candidate to treat HD-like syndromes because of its potential to activate Nrf2 and decrease oxidative stress and neuroinflammation [64]. A similar study evaluated the effect of Sulforaphane in animal model of 3-NP acid-induced Huntington’s disease. The study revealed that pre-treatment with sulforaphane activated Nrf2 in animals and decreased the formation of a lesion area, neuronal death, succinate dehydrogenase activity, apoptosis, microglial activation and expression of inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, inducible nitric oxide synthase and cyclooxygenase-2 in the striatum after 3-NP treatment [65]. Similarly, curcumin is also reported to have beneficial effects in HD via activation of Nrf2 [66]. D. Moretti et al. have reported that compound 2, a covalent KEAP1 binder, demonstrated an ability to stimulate the expression of genes known to be regulated by Nrf2 in neurons and astrocytes separated from wild-type rat, wild-type mouse and zQ175 (an HD mouse model) embryo [67].


10. Challenges facing Nrf2 activators

One of the main challenges associated with Nrf2 activators is achieving effective therapeutic concentrations as these agents are metabolized faster leading to a low bioavailability in distal organs [68, 69, 70]. The second concern with Nrf2 activators is lack of selectivity as these agents have been reported to act on other signaling pathways and affect associated physiological processes. For instance, sulforophane, a widely reported Nrf2 activator, suppresses the activation of inflammosome [71, 72] and causes cell arrest [73]. Nrf2 activators have been reported to promote the development of cancer [74, 75, 76] and development of resistance to anti-cancer drugs [77, 78, 79, 80].

11. Current status of Nrf2 activators

Oxidative stress plays a significant role in pathophysiology of numerous diseases. Initially, exogenous antioxidants were expected to have a protective and therapeutic role in the management of diseases associated with oxidative stress. But randomized clinical trials failed to find any significant therapeutic benefits of exogenous antioxidants. This unexpected outcome led to a search for endogenous targets that would enhance the antioxidant potential of the cells and tissues to prevent oxidative stress-induced damage. This quest for an endogenous antioxidant target led to the discovery of Nrf2 in the year 1994 [81]. Five years later, in 1999, it was discovered that the levels of Nrf2 in the cytoplasm are controlled by a negative regulator, Keap-1 [61]. In recent years, many potential Nrf2 activators are in pre-clinical and different stages of clinical trials for various diseases associated with oxidative stress. Table 2 provides a list of potential Nrf2 activators in clinical trials and possible indications.

CompoundIndicationsClinical trialReference
Bordoxolone methylPulmonary arterial hypertension
Alport syndrome
Type I diabetes,
Polycystic kidney disease
OmaveloxoloneFriedreich’s ataxiaII[82]
Bordoxolone methylType II diabetes
Chronic kidney disease
ALK8700Multiple SclerosisIII[82]
OT551Dry eye macular degeneration.II[82]
CXA10Primary focal segmental glomerulosclerosis
Pulmonary arterial hypertension
SFX-01Subarachnoid hemorrhage
ER+ metastatic breast cancer (in combination with tamoxifen and fulvestrant)
Compound AChronic obstructive pulmonary diseasePreclinical[83]
KEAP1 inhibitorsParkinson’s disease
Amyotrophic lateral sclerosis
M102Amyotrophic lateral sclerosis
Neurodegenerative diseases.
RS9Retinovascular diseasePreclinical[84]
TFM735Progression of experimental
autoimmune encephalitis
CAT4001Friedreich ataxia
Amyotrophic lateral sclerosis
ML334Type II diabetes
Chronic obstructive pulmonary disease.
HPP971Blood, lung, eye, kidney and bone diseases.Preclinical[87]
VCB101Multiple SclerosisPreclinical[82]
Atopic asthmatics
Chronic obstructive pulmonary disease
Prostate cancer
Breast cancer
Lung cancer
Diabetes Mellitus
Helicobacter pylori infection
Different stages of clinical trials[88]
CurcuminAcute kidney injury
Type 2 diabetes
Chronic kidney disease
Alzheimer’s disease
Crohn’s disease
Prostate cancer
Major depression abdominal aortic aneurysm
ITH12674Brain ischemiaPreclinical[88]
ResveratrolType 2 diabetes
Colon cancer
Chronic Obstructive Pulmonary Disease Endometriosis
Alzheimer’s disease
Huntington’s disease
Chronic renal insufficiency
Non-ischemic cardiomyopathy
Non-alcoholic fatty liver Friedreich ataxia
CXA-10Acute kidney injury
Pulmonary arterial hypertension
Primary focal segmental glomerulosclerosis.
RTA 408Topical application[89]
FimasartanUnilateral ureteral obstructionPreclinical[90]
ArtesunateSepsis induced lung injuryPreclinical[91]
IsovitexinLPS-induced acute lung injury[92]
Sappanone ALPS-induced mortalityPreclinical[93]
BixinVentilation injured lung injuryPreclinical[94, 95]
EriodictyolCisplatin-induced kidney injuryPreclinical[96]

Table 2.

List of current Nrf2 activators.

12. Conclusion

As free radicals-induced oxidative stress has been proven to play a major role in the pathogenesis of several diseases, it is quintessential to develop antioxidant therapies to negate oxidative stress-induced damage. The initial expectation that exogenous antioxidants such as vitamin E, vitamin C might have a therapeutic benefit in diseases associated with oxidative stress has failed to find any significant beneficial proof in randomized clinical trials. So, it is time to find agents that activate endogenous antioxidant mechanisms such as Nrf2. Nrf2 activators might offer a beneficial action in diseases associated with oxidative stress such as Huntington’s disease.


The authors would like to thank the Department of Science and Technology—Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST-FIST), New Delhi, for their infrastructure support to our department. We acknowledge the generous research infrastructure and support from JSS College of Pharmacy, JSS Academy of Higher Education & Research, Rocklands, Ooty, The Nilgiris, Tamil Nadu, India.


  1. 1. McGarry A, Biglan K, Marshall F. Huntington’s disease: Clinical features, disease mechanisms, and management. In: Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease. London, UK: Elsevier; 2020. pp. 135-145. DOI: 10.1016/b978-0-12-813866-3.00009-6
  2. 2. Cisbani G, Cicchetti F. An in vitro perspective on the molecular mechanisms underlying mutant huntingtin protein toxicity. Cell Death and Disease. 2012;3. DOI: 10.1038/cddis.2012.121
  3. 3. Saavedra A, García-Díaz Barriga G, Pérez-Navarro E, Alberch J. Huntington’s disease: Novel therapeutic perspectives hanging in the balance. Expert Opinion on Therapeutic Targets. 2018;22:385-399. DOI: 10.1080/14728222.2018.1465930
  4. 4. Munoz-Sanjuan I, Bates GP. The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease. Journal of Clinical Investigation. 2011;121:476-483. DOI: 10.1172/JCI45364
  5. 5. Franco-Iborra S, Plaza-Zabala A, Montpeyo M, Sebastian D, Vila M, Martinez-Vicente M. Mutant HTT (huntingtin) impairs mitophagy in a cellular model of Huntington disease. Autophagy. 2021;17:672-689. DOI: 10.1080/15548627.2020.1728096
  6. 6. MacDonald ME, Ambrose CM, Duyao MP, Myers RH, Lin C, Srinidhi L, et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993;72:971-983. DOI: 10.1016/0092-8674(93)90585-E
  7. 7. McColgan P, Tabrizi SJ. Huntington’s disease: A clinical review. European Journal of Neurology. 2018;25:24-34. DOI: 10.1111/ene.13413
  8. 8. Rubinsztein DC, Carmichael J. Huntington’s disease: Molecular basis of neurodegeneration. Expert Reviews in Molecular Medicine. 2003;5:1-21. DOI: 10.1017/S1462399403006549
  9. 9. Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L. Oxidative stress in neurodegenerative diseases: From molecular mechanisms to clinical applications. Oxidative Medicine and Cellular Longevity. 2017;2017. DOI: 10.1155/2017/2525967
  10. 10. Kumar A, Ratan RR. Oxidative stress and Huntington’s disease: The good, the bad, and the ugly. Journal of Huntington’s Disease. 2016;5:217-237. DOI: 10.3233/JHD-160205
  11. 11. Gazaryan IG, Thomas B. The status of Nrf2-based therapeutics: Current perspectives and future prospects. Neural Regeneration Research. 2016;11:1708-1711. DOI: 10.4103/1673-5374.194706
  12. 12. Tkachev VO, Menshchikova EB, Zenkov NK. Mechanism of the Nrf2/Keap1/ARE signaling system. Biochemistry (Moscow). 2011;76:407-422. DOI: 10.1134/S0006297911040031
  13. 13. di Meo S, Venditti P. Evolution of the knowledge of free radicals and other oxidants. Oxidative Medicine and Cellular Longevity. 2020;2020. DOI: 10.1155/2020/9829176
  14. 14. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry and Cell Biology. 2007;39:44-84. DOI: 10.1016/j.biocel.2006.07.001
  15. 15. Kalonia H, Kumar P, Kumar A. Targeting oxidative stress attenuates malonic acid induced Huntington like behavioral and mitochondrial alterations in rats. European Journal of Pharmacology. 2010;634:46-52. DOI: 10.1016/J.EJPHAR.2010.02.031
  16. 16. Petersén Å, Castilho RF, Hansson O, Wieloch T, Brundin P. Oxidative stress, mitochondrial permeability transition and activation of caspases in calcium ionophore A23187-induced death of cultured striatal neurons. Brain Research. 2000;857:20-29. DOI: 10.1016/S0006-8993(99)02320-3
  17. 17. Wang J, Pfleger CM, Friedman L, Vittorino R, Zhao W, Qian X, et al. Potential application of grape derived polyphenols in Huntington’s disease. Translational Neuroscience. 2010;1:95-100. DOI: 10.2478/V10134-010-0022-Y
  18. 18. Túnez I, Montilla P, Muñoz MDC, Feijóo M, Salcedo M. Protective effect of melatonin on 3-nitropropionic acid-induced oxidative stress in synaptosomes in an animal model of Huntington’s disease. Journal of Pineal Research. 2004;37:252-256. DOI: 10.1111/J.1600-079X.2004.00163.X
  19. 19. Uz T, Giusti P, Franceschini D, Kharlamov A, Manev H. Protective effect of melatonin against hippocampal DNA damage induced by intraperitoneal administration of kainate to rats. Neuroscience. 1996;73:631-636. DOI: 10.1016/0306-4522(96)00155-8
  20. 20. Santamaría A, Salvatierra-Sánchez R, Vázquez-Román B, Santiago-López D, Villeda-Hernández J, Galván-Arzate S, et al. Protective effects of the antioxidant selenium on quinolinic acid-induced neurotoxicity in rats: In vitro and in vivo studies. Journal of Neurochemistry. 2003;86:479-488. DOI: 10.1046/J.1471-4159.2003.01857.X
  21. 21. Ryu JK, Kim SU, McLarnon JG. Neuroprotective effects of pyruvate in the quinolinic acid rat model of Huntington’s disease. Experimental Neurology. 2003;183:700-704. DOI: 10.1016/S0014-4886(03)00214-0
  22. 22. Keene CD, Rodrigues CMP, Eich T, Linehan-Stieers C, Abt A, Kren BT, et al. A bile acid protects against motor and cognitive deficits and reduces striatal degeneration in the 3-nitropropionic acid model of Huntington’s disease. Experimental Neurology. 2001;171:351-360. DOI: 10.1006/EXNR.2001.7755
  23. 23. la Fontaine MA, Geddes JW, Banks A, Allan BD. Effect of exogenous and endogenous antioxidants on 3-nitropionic acid-induced in vivo oxidative stress and striatal lesions: Insights into Huntington’s disease. Journal of Neurochemistry. 2000;75:1709-1715. DOI: 10.1046/J.1471-4159.2000.0751709.X
  24. 24. Kumar P, Kumar A. Effect of lycopene and epigallocatechin-3-gallate against 3-nitropropionic acid induced cognitive dysfunction and glutathione depletion in rat: A novel nitric oxide mechanism. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association. 2009;47:2522-2530. DOI: 10.1016/J.FCT.2009.07.011
  25. 25. Peyser CE, Folstein M, Chase GA, Starkstein S, Brandt J, Cockrell JR, et al. Trial of d-alpha-tocopherol in Huntington’s disease. The American Journal of Psychiatry. 1995;152:1771-1775. DOI: 10.1176/AJP.152.12.1771
  26. 26. Ranen NG, Peyser CE, Coyle JT, Bylsma FW, Sherr M, Day L, et al. A controlled trial of idebenone in Huntington’s disease. Movement Disorders : Official Journal of the Movement Disorder Society. 1996;11:549-554. DOI: 10.1002/MDS.870110510
  27. 27. Tritos NA, Mastaitis JW, Kokkotou EG, Puigserver P, Spiegelman BM, Maratos-Flier E. Characterization of the peroxisome proliferator activated receptor coactivator 1 alpha (PGC 1alpha) expression in the murine brain. Brain Research. 2003;961:255-260. DOI: 10.1016/S0006-8993(02)03961-6
  28. 28. Esterbauer H, Oberkofler H, Krempler F, Patsch W. Human peroxisome proliferator activated receptor gamma coactivator 1 (PPARGC1) gene: CDNA sequence, genomic organization, chromosomal localization, and tissue expression. Genomics. 1999;62:98-102. DOI: 10.1006/GENO.1999.5977
  29. 29. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): Transcriptional coactivator and metabolic regulator. Endocrine Reviews. 2003;24:78-90. DOI: 10.1210/ER.2002-0012
  30. 30. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127:397-408. DOI: 10.1016/J.CELL.2006.09.024
  31. 31. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metabolism. 2010;12:662-667. DOI: 10.1016/J.CMET.2010.11.015
  32. 32. Ozden O, Park SH, Kim HS, Jiang H, Coleman MC, Spitz DR, et al. Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. Aging. 2011;3:102-107. DOI: 10.18632/AGING.100291
  33. 33. Kim SB, Heo JI, Kim H, Kim KS. Acetylation of PGC1α by histone deacetylase 1 downregulation is implicated in radiation-induced senescence of brain endothelial cells. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences. 2019;74:787-793. DOI: 10.1093/GERONA/GLY167
  34. 34. Witte ME, Nijland PG, Drexhage JAR, Gerritsen W, Geerts D, van het Hof B, et al. Reduced expression of PGC-1α partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex. Acta Neuropathologica. 2013;125:231-243. DOI: 10.1007/S00401-012-1052-Y
  35. 35. Che HVB, Metzger S, Portal E, Deyle C, Riess O, Nguyen HP. Localization of sequence variations in PGC-1 influence their modifying effect in Huntington disease. Molecular Neurodegeneration. 2011;6:1-7. DOI: 10.1186/1750-1326-6-1/TABLES/6
  36. 36. Pacelli C, de Rasmo D, Signorile A, Grattagliano I, di Tullio G, D’Orazio A, et al. Mitochondrial defect and PGC-1α dysfunction in parkin-associated familial Parkinson’s disease. Biochimica et Biophysica Acta. 1812;2011:1041-1053. DOI: 10.1016/J.BBADIS.2010.12.022
  37. 37. Chaturvedi RK, Hennessey T, Johri A, Tiwari SK, Mishra D, Agarwal S, et al. Transducer of regulated creb-binding proteins (TORCs) transcription and function is impaired in Huntington’s disease. Human Molecular Genetics. 2012;21:3474-3488. DOI: 10.1093/hmg/dds178
  38. 38. Shirendeb U, Reddy AP, Manczak M, Calkins MJ, Mao P, Tagle DA, et al. Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: Implications for selective neuronal damage. Human Molecular Genetics. 2011;20:1438-1455. DOI: 10.1093/HMG/DDR024
  39. 39. Suzuki M, Nagai Y, Wada K, Koike T. Calcium leak through ryanodine receptor is involved in neuronal death induced by mutant huntingtin. Biochemical and Biophysical Research Communications. 2012;429:18-23. DOI: 10.1016/J.BBRC.2012.10.107
  40. 40. Matcovitch-Natan O, Winter DR, Giladi A, Aguilar SV, Spinrad A, Sarrazin S, et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science. 2016;353. DOI: 10.1126/science.aad8670
  41. 41. Bachiller S, Jiménez-ferrer I, Paulus A, Yang Y, Swanberg M, Hayley S, et al. Microglia in neurological diseases: A road map to brain-disease dependent-inflammatory response. Frontiers in Cellular Neuroscience. 2018;12:1-17. DOI: 10.3389/fncel.2018.00488
  42. 42. Li Q , Barres BA. Microglia and macrophages in brain homeostasis and disease. Nature Publishing Group. 2017;18:225-242. DOI: 10.1038/nri.2017.125
  43. 43. Ginhoux F, Lim S, Hoeffel G, Low D, Huber T, Cuadros MA. Origin and differentiation of microglia. Frontiers in Cellular Neuroscience. 2013;7:1-14. DOI: 10.3389/fncel.2013.00045
  44. 44. Liu C, Wang X, Liu C, Zhang H, Di L, Mannelli C. Pharmacological targeting of microglial activation: New therapeutic approach. Frontiers in Cellular Neuroscience 2019;13:1-19. DOI: 10.3389/fncel.2019.00514
  45. 45. Galloway DA, Phillips AEM, Owen DRJ, Moore CS, Moore CS. Phagocytosis in the brain : Homeostasis and disease. Frontiers in Immunology. 2019;10:1-15. DOI: 10.3389/fimmu.2019.00790
  46. 46. Bachiller S, Jiménez-Ferrer I, Paulus A, Yang Y, Swanberg M, Deierborg T, et al. Microglia in neurological diseases: A road map to brain-disease dependent-inflammatory response. Frontiers in Cellular Neuroscience. 2018;12:488. DOI: 10.3389/FNCEL.2018.00488/BIBTEX
  47. 47. Sapp E, Kegel KB, Aronin N, Hashikawa T, Uchiyama Y, Tohyama K, et al. Early and progressive accumulation of reactive microglia in the Huntington disease brain. Journal of Neuropathology & Experimental Neurology. 2001;60:161-172. DOI: 10.1093/JNEN/60.2.161
  48. 48. Myers RH, Vonsattel JP, Paskevich PA, Kiely DK, Stevens TJ, Cupples LA, et al. Decreased neuronal and increased oligodendroglial densities in Huntington’s disease caudate nucleus. Journal of Neuropathology & Experimental Neurology. 1991;50:729-742. DOI: 10.1097/00005072-199111000-00005
  49. 49. Politis M, Pavese N, Tai YF, Kiferle L, Mason SL, Brooks DJ, et al. Microglial activation in regions related to cognitive function predicts disease onset in Huntington’s disease: A multimodal imaging study. Human Brain Mapping. 2011;32:258-270. DOI: 10.1002/HBM.21008
  50. 50. Pavese N, Gerhard A, Tai YF, Ho AK, Turkheimer F, Barker RA, et al. Microglial activation correlates with severity in Huntington disease. Neurology. 2006;66:1638-1643. DOI: 10.1212/01.WNL.0000222734.56412.17
  51. 51. Zhao T, Hong Y, Li S, Li XJ. Compartment-dependent degradation of mutant huntingtin accounts for its preferential accumulation in neuronal processes. The Journal of neuroscience: The official journal of the Society for Neuroscience. 2016;36:8317-8328. DOI: 10.1523/JNEUROSCI.0806-16.2016
  52. 52. Li H, Li SH, Johnston H, Shelbourne PF, Li XJ. Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nature Genetics. 2000;25:385-389. DOI: 10.1038/78054
  53. 53. Canning P, Sorrell FJ, Bullock AN. Structural basis of Keap1 interactions with Nrf2. Free Radical Biology and Medicine. 2015;88:101-107. DOI: 10.1016/j.freeradbiomed.2015.05.034
  54. 54. Deshmukh P, Unni S, Krishnappa G, Padmanabhan B. The Keap1–Nrf2 pathway: Promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophysical Reviews. 2017;9:41-56. DOI: 10.1007/s12551-016-0244-4
  55. 55. Nioi P, Mahon MMC, Itoh K, Yamamoto M, Hayes JD. Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H: Quinone oxidoreductase 1 gene : Reassessment of the ARE consensus sequence. Biochemical Journal. 2003;348:337-348
  56. 56. Friling RS, Bensimon A, Tichauer Y, Daniel V. Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proceedings of the National Academy of Sciences of the United States. 1990;87:6258-6262
  57. 57. Banning A, Deubel S, Kluth D, Zhou Z, Brigelius-flohe R. The GI-GPx gene is a target for Nrf2. Molecular & Cellular Biology. 2005;25:4914-4923. DOI: 10.1128/MCB.25.12.4914
  58. 58. Kobayashi EH, Suzuki T, Funayama R, Nagashima T, Hayashi M, Sekine H, et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nature Communications. 2016;7:1-14. DOI: 10.1038/ncomms11624
  59. 59. Ushida Y, Talalay P. Sulforaphane accelerates acetaldehyde metabolism by inducing aldehyde dehydrogenases: Relevance to ethanol intolerance. Alcohol and Alcoholism (Oxford, Oxfordshire). 2013;48:526-534. DOI: 10.1093/ALCALC/AGT063
  60. 60. Pickering AM, Linder RA, Zhang H, Forman HJ, Davies KJA. Nrf2-dependent induction of proteasome and Pa28αβ regulator are required for adaptation to oxidative stress. The Journal of Biological Chemistry. 2012;287:10021. DOI: 10.1074/JBC.M111.277145
  61. 61. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes and Development. 1999;13:76-86. DOI: 10.1101/gad.13.1.76
  62. 62. Li Y, Paonessa JD, Zhang Y. Mechanism of chemical activation of Nrf2. PLoS One. 2012;7. DOI: 10.1371/journal.pone.0035122
  63. 63. Forman HJ, Zhang H. Targeting oxidative stress in disease: Promise and limitations of antioxidant therapy. Nature Reviews Drug Discovery. 2021;20:689-709. DOI: 10.1038/s41573-021-00233-1
  64. 64. Jang M, Choi JH, Chang Y, Lee SJ, Nah SY, Cho IH. Gintonin, a ginseng-derived ingredient, as a novel therapeutic strategy for Huntington’s disease: Activation of the Nrf2 pathway through lysophosphatidic acid receptors. Brain, Behavior, and Immunity. 2019;80:146-162. DOI: 10.1016/J.BBI.2019.03.001
  65. 65. 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-κB pathways. Molecular Neurobiology. 2016;53:2619-2635. DOI: 10.1007/S12035-015-9230-2
  66. 66. Labanca F, Ullah H, Khan H, Milella L, Xiao J, Dajic-Stevanovic Z, et al. Therapeutic and mechanistic effects of curcumin in Huntington’s disease. Current Neuropharmacology. 2021;19:1007-1018. DOI: 10.2174/1570159X18666200522201123
  67. 67. Moretti D, Tambone S, Cerretani M, Fezzardi P, Missineo A, Sherman LT, et al. NRF2 activation by reversible KEAP1 binding induces the antioxidant response in primary neurons and astrocytes of a Huntington’s disease mouse model. Free Radical Biology and Medicine. 2021;162:243-254. DOI: 10.1016/J.FREERADBIOMED.2020.10.022
  68. 68. Lipton S, Satoh T. Recent advances in understanding NRF2 as a druggable target: Development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate. F1000Research. 2017;6. DOI: 10.12688/f1000research.12111.1
  69. 69. Couch RD, Browning RG, Honda T, Gribble GW, Wright DL, Sporn MB, et al. Studies on the reactivity of CDDO, a promising new chemopreventive and chemotherapeutic agent: Implications for a molecular mechanism of action. Bioorganic & Medicinal Chemistry Letters. 2005;15:2215-2219. DOI: 10.1016/J.BMCL.2005.03.031
  70. 70. Jiang ZY, Lu MC, You QD. Discovery and development of Kelch-like ECH-associated protein 1. Nuclear factor erythroid 2-related factor 2 (KEAP1:NRF2) protein-protein interaction inhibitors: Achievements, challenges, and future directions. Journal of Medicinal Chemistry. 2016;59:10837-10858. DOI: 10.1021/acs.jmedchem.6b00586
  71. 71. Greaney AJ, Maier NK, Leppla SH, Moayeri M. Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism. Journal of Leukocyte Biology. 2016;99:189-199. DOI: 10.1189/JLB.3A0415-155RR
  72. 72. Kwon JS, Joung H, Kim YS, Shim YS, Ahn Y, Jeong MH, et al. Sulforaphane inhibits restenosis by suppressing inflammation and the proliferation of vascular smooth muscle cells. Atherosclerosis. 2012;225:41-49. DOI: 10.1016/J.ATHEROSCLEROSIS.2012.07.040
  73. 73. Roy SK, Srivastava RK, Shankar S. Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. Journal of Molecular Signaling. 2010;5. DOI: 10.1186/1750-2187-5-10
  74. 74. Satoh H, Moriguchi T, Takai J, Ebina M, Yamamoto M. Nrf2 prevents initiation but accelerates progression through the kras signaling pathway during lung carcinogenesis. Cancer Research. 2013;73:4158-4168. DOI: 10.1158/0008-5472.CAN-12-4499
  75. 75. Wiel C, le Gal K, Ibrahim MX, Jahangir CA, Kashif M, Yao H, et al. BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell. 2019;178:330-345.e22. DOI: 10.1016/J.CELL.2019.06.005
  76. 76. Tao S, Rojo de la Vega M, Chapman E, Ooi A, Zhang DD. The effects of NRF2 modulation on the initiation and progression of chemically and genetically induced lung cancer. Molecular Carcinogenesis. 2018;57:182. DOI: 10.1002/MC.22745
  77. 77. Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, et al. Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2009;15:3423-3432. DOI: 10.1158/1078-0432.CCR-08-2822
  78. 78. Roh JL, Kim EH, Jang H, Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biology. 2017;11:254-262. DOI: 10.1016/J.REDOX.2016.12.010
  79. 79. Jiang T, Chen N, Zhao F, Wang XJ, Kong B, Zheng W, et al. High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Research. 2010;70:5486-5496. DOI: 10.1158/0008-5472.CAN-10-0713
  80. 80. Shibata T, Kokubu A, Gotoh M, Ojima H, Ohta T, Yamamoto M, et al. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology. 2008;135. DOI: 10.1053/J.GASTRO.2008.06.082
  81. 81. Moi P, Chant K, Asunis I, Cao A, Kant YWAI. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the f-globin locus control region. 1994;91:9926-9930
  82. 82. Cuadrado A, Rojo AI, Wells G, Hayes JD, Cousin SP, Rumsey WL, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature Reviews Drug Discovery. 2019;18:295-317. DOI: 10.1038/s41573-018-0008-x
  83. 83. Davies TG, Wixted WE, Coyle JE, Griffiths-Jones C, Hearn K, McMenamin R, et al. Monoacidic Inhibitors of the Kelch-like ECH-associated protein 1: Nuclear factor erythroid 2-related factor 2 (KEAP1:NRF2) protein-protein interaction with high cell potency identified by fragment-based discovery. Journal of Medicinal Chemistry. 2016;59:3991-4006. DOI: 10.1021/acs.jmedchem.6b00228
  84. 84. Nakagami Y, Masuda K, Hatano E, Inoue T, Matsuyama T, Iizuka M, et al. Novel Nrf2 activators from microbial transformation products inhibit blood-retinal barrier permeability in rabbits. British Journal of Pharmacology. 2015;172:1237-1249. DOI: 10.1111/bph.12999
  85. 85. Higashi C, Kawaji A, Tsuda N, Hayashi M, Saito R, Furusako S, et al. The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. European Journal of Pharmacology. 2017;802:1-9. DOI: 10.1016/j.ejphar.2017.02.044
  86. 86. Hu L, Magesh S, Chen L, Wang L, Lewis TA, Chen Y, et al. Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorganic & Medicinal Chemistry Letters. 2013;23:3039-3043. DOI: 10.1016/j.bmcl.2013.03.013
  87. 87. Attucks OC, Jasmer KJ, Hannink M, Kassis J, Zhong Z, Gupta S, et al. Induction of heme oxygenase I (HMOX1) by HPP-4382: A novel modulator of Bach1 activity. PLoS One. 2014;9:e101044. DOI: 10.1371/JOURNAL.PONE.0101044
  88. 88. Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Activators and inhibitors of NRF2: A review of their potential for clinical development. Oxidative Medicine and Cellular Longevity. 2019;2019. DOI: 10.1155/2019/9372182
  89. 89. Reisman SA, Goldsberry AR, Lee CI, Grady MLO, Proksch JW, Ward KW, et al. Topical application of RTA 408 lotion activates Nrf2 in human skin and is well- tolerated by healthy human volunteers. BMC Dermatology. 2015;15:1-11. DOI: 10.1186/s12895-015-0029-7
  90. 90. Kim S, Kim SJ, Yoon HE, Chung S, Choi BS, Park CW, et al. Fimasartan, a novel angiotensin-receptor blocker, protects against renal inflammation and fibrosis in mice with unilateral ureteral obstruction: The possible role of Nrf2. International Journal of Medical Sciences. 2015;12:891. DOI: 10.7150/IJMS.13187
  91. 91. Hui CT, Gen JS, Sheng FD, Kang K, Jiang L, Yuan LZ, et al. Artesunate protects against sepsis-induced lung injury via heme oxygenase-1 modulation. Inflammation. 2016;39:651-662. DOI: 10.1007/S10753-015-0290-2
  92. 92. Lv H, Yu Z, Zheng Y, Wang L, Qin X, Cheng G, et al. Isovitexin exerts anti-inflammatory and anti-oxidant activities on lipopolysaccharide-induced acute lung injury by inhibiting MAPK and NF-κB and activating HO-1/Nrf2 pathways. International Journal of Biological Sciences. 2016;12:72. DOI: 10.7150/IJBS.13188
  93. 93. Lee S, Choi SY, Choo YY, Kim O, Tran PT, Dao CT, et al. Sappanone A exhibits anti-inflammatory effects via modulation of Nrf2 and NF-κB. International Immunopharmacology. 2015;28:328-336. DOI: 10.1016/J.INTIMP.2015.06.015
  94. 94. Tao S, Rojo De La Vega M, Quijada H, Wondrak GT, Wang T, Garcia JGN, et al. Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner. Scientific Reports. 2016;6:1-13. DOI: 10.1038/srep18760
  95. 95. Aboonabi A, Singh I. Chemopreventive role of anthocyanins in atherosclerosis via activation of Nrf2-ARE as an indicator and modulator of redox. Biomedicine & Pharmacotherapy (Biomedecine & Pharmacotherapie). 2015;72:30-36. DOI: 10.1016/J.BIOPHA.2015.03.008
  96. 96. Zhu GFA, Guo HJ, Huang YAN, Wu CT, Zhang XF. Eriodictyol , a plant flavonoid , attenuates LPS-induced acute lung injury through its antioxidative and anti-inflammatory activity. Experimental and Therapeutic Medicine. 2015;10(6):2259-2266. DOI: 10.3892/etm.2015.2827

Written By

Saravanan Jayaram, Praveen Thaggikuppe Krishnamurthy, Meghana Joshi and Vishnu Kumar

Submitted: 06 December 2021 Reviewed: 10 February 2022 Published: 21 March 2022