Arch Toxicol (2014) 88:1773–1786

DOI 10.1007/s00204-014-1338-z

Review Article

Antioxidative defense mechanisms controlled by Nrf2:

state‑of‑the‑art and clinical perspectives in neurodegenerative
diseases
Jamie L. Lim · Micha M. M. Wilhelmus ·
Helga E. de Vries · Benjamin Drukarch ·
Jeroen J. M. Hoozemans · Jack van Horssen

Received: 24 June 2014 / Accepted: 12 August 2014 / Published online: 28 August 2014
© Springer-Verlag Berlin Heidelberg 2014

Abstract Activation of microglial cells and impaired disorders, only a few Nrf2-activating compounds have
mitochondrial function are common pathological charac- been tested in a clinical setting. We here provide a com-
teristics of many neurological diseases and contribute to prehensive synopsis on the role of ROS in common neu-
increased generation of reactive oxygen species (ROS). rodegenerative disorders and discuss the therapeutic
It is nowadays accepted that oxidative damage and mito- potential of the Nrf2 pathway.
chondrial dysfunction are key hallmarks of classical neu-
roinflammatory and neurodegenerative diseases, such Keywords Reactive oxygen species · Oxidative stress ·
as multiple sclerosis, Alzheimer’s disease, Parkinson’s Neurodegenerative disorders · Nrf2 · Antioxidant enzymes ·
disease and Huntington’s disease. To counteract the det- Free radicals
rimental effects of ROS and restore the delicate redox
balance in the central nervous system (CNS), cells are Abbreviations
equipped with an endogenous antioxidant defense mecha- Aβ  β Amyloid
nism consisting of several antioxidant enzymes. The pro- AD Alzheimer’s disease
duction of many antioxidant enzymes is regulated at the ARE Antioxidant response elements
transcriptional level by the transcription factor nuclear BBB Blood–brain barrier
factor E2-related factor 2 (Nrf2). Although evidence is CNS Central nervous system
accumulating that activation of the Nrf2 pathway rep- CSF Cerebrospinal fluid
resents a promising therapeutic approach to restore the DMF Dimethyl fumarate
CNS redox balance by reducing ROS-mediated neuronal EAE Experimental autoimmune encephalomyelitis
damage in experimental models of neurodegenerative HD Huntington’s disease
HTT Huntingtin
iNOS Inducible nitric oxide synthase
J. L. Lim · H. E. de Vries · J. van Horssen (*)
Keap1 Kelch-like ECH-associated protein 1
Department of Molecular Cell Biology and Immunology,
Neuroscience Campus Amsterdam, VU University Medical MMF Monomethyl fumarate
Center Amsterdam, P.O. Box 7057, 1007 MB Amsterdam, MPTP 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine
The Netherlands MS Multiple sclerosis
e-mail: [email protected]
mtDNA Mitochondrial DNA
J. L. Lim NADPH Nicotinamide adenine dinucleotide phosphate
e-mail: [email protected]
NOX Nicotinamide adenine dinucleotide phosphate
M. M. M. Wilhelmus · B. Drukarch oxidase
Anatomy and Neurosciences, Neuroscience Campus Amsterdam, Nrf2 Nuclear factor E2-related factor 2
VU University Medical Center, Amsterdam, The Netherlands 6-OHDA 6-hydroxydopamine
OxPhos Oxidative phosphorylation
J. J. M. Hoozemans
Pathology, Neuroscience Campus Amsterdam, VU University PERK Protein kinase RNA-like endoplasmic
Medical Center, Amsterdam, The Netherlands reticulum kinase

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PD Parkinson’s disease (Wagener et al. 2003). Heme oxygenases are localized to dif-
ROS Reactive oxygen species ferent cellular compartments, such as the endoplasmic reticu-
SN Substantia nigra lum, nucleus and plasma membrane (Ryter et al. 2006).
tBHQ Tert-butylhydroquinone ROS levels need to be tightly regulated in the central
nervous system (CNS) as it is well known that the brain is
particularly sensitive to oxidative stress. The CNS is char-
Introduction acterized by high oxygen utilization and relatively high
amounts of trace metals, including iron and copper, which
Reactive oxygen species (ROS) are small biological mol- together with hydrogen peroxide give rise to highly reac-
ecules that contain oxygen and one or more unpaired elec- tive hydroxyl radicals, one of the most potent oxidants in
trons. Aerobic organisms continuously produce ROS as a nature. In addition, the CNS is enriched in polyunsaturated
natural by-product of oxygen metabolism. ROS perform fatty acids, making it vulnerable to lipid peroxidation.
diverse physiological functions and play an important role in When ROS levels are dramatically increased in the CNS,
host defense, cell signaling, regulation of gene expression and e.g., under pathological conditions, the cellular antioxidant
cell differentiation (Bedard and Krause 2007). ROS-synthe- capacity is overwhelmed, resulting in oxidative stress and
sizing enzyme systems, including myeloperoxidase, xanthine significant oxidative damage to essential cellular structures.
oxidase and nicotinamide adenine dinucleotide phosphate ROS react rapidly with biological molecules, and various
(NADPH) oxidase (NOX), contribute to ROS production. oxidative markers have been described to study and quantify
In addition, mitochondria, the energy-producing organelles the occurrence of oxidative injury. Protein carbonyl groups and
of the cell, form ROS as a by-product of cellular respiration, 3-nitrotyrosine are biochemical markers used for the detection
particularly at complex I and III of the mitochondrial electron of oxidative modification of amino acid residues in proteins
transport chain. Superoxide, the most common ROS product (Beal 2002). Likewise, 8-hydroxydeoxyguanosine adducts are
of both mitochondrial respiration and NOX, is rapidly con- used as a footprint for oxidative damage to nucleotides (Evans
verted, either spontaneously or enzymatically, by superoxide et al. 2004; Kasai 2002). Mitochondrial DNA (mtDNA) is
dismutases. These metal-containing enzymes, including Cu, highly susceptible to ROS-induced damage since it is located
Zn-superoxide dismutase-1 (McCord and Fridovich 1969), in close vicinity to the initial production site of mitochondria-
Mn-superoxide dismutase-2 (McCord 1976) and extracellu- derived ROS, and mtDNA repair mechanisms are limited. Con-
lar Cu,Zn-superoxide dismutase-3 (Marklund 1982), provide sequently, mutations accrue in mtDNA, ultimately leading to a
the first line of defense against oxidative stress and catalyze decline in mitochondrial function and concomitant enhanced
the dismutation of superoxide anion to molecular oxygen and ROS production (Lin and Beal 2006). Reaction of free radi-
hydrogen peroxide (Johnson and Giulivi 2005). cals with unsaturated lipids may trigger the lipid peroxidation
Hydrogen peroxide itself is not a free radical, but it can eas- chain reaction resulting in the oxidative breakdown of cellular
ily diffuse across biological membranes and may cause severe membranes. Lipid peroxidation is detected using various bio-
oxidative damage to biological macromolecules. However, markers, such as malondialdehyde, 4-hydroxy-2-nonenal or F2
under normal conditions, hydrogen peroxide is effectively isoprostane (Mariani et al. 2005; Morrow et al. 1999). Markers
detoxified by endogenous antioxidant enzymes, like catalase, for oxidative damage can be measured in plasma, cerebrospinal
glutathione peroxidases and peroxiredoxins. Catalase is an fluid (CSF), urine or postmortem tissue by means of high-per-
intracellular antioxidant enzyme that catalyzes the conversion formance liquid chromatography and immunohistochemistry.
of hydrogen peroxide into water and molecular oxygen. It is As oxidative injury is a hallmark of several neurodegen-
located in the peroxisomes and is ubiquitously expressed in a erative diseases, antioxidant therapies have been proposed
wide variety of cells. The family of peroxiredoxins represents to prevent ROS-induced injury. Unfortunately, most studies
antioxidant proteins that are involved in the enzymatic degra- reported disappointing results upon investigating the thera-
dation of hydrogen peroxide, organic hydroperoxides and per- peutic potential of exogenous antioxidants (Moosmann and
oxynitrite (Rhee et al. 2005). Peroxiredoxins are abundantly Behl 2002), indicating the need for alternative strategies to
expressed in the cytosol; however, several isoforms are local- therapeutically counteract the damaging effects of ROS and
ized to mitochondria, peroxisomes, nuclei and membranes restore the cellular redox balance under neurodegenerative
(Hofmann et al. 2002). The glutathione system represents an conditions. To maintain a physiological redox balance, cells
important component of the non-enzymatic branch of ROS are endowed with a selection of endogenous antioxidant
detoxification. Glutathione is able to directly neutralize ROS enzymes. Transcription of these cytoprotective proteins is
or indirectly via glutathione peroxidase. Although heme oxy- under control of the nuclear transcription factor NF-E2-re-
genase-1 and oxygenase-2 are not able to detoxify free radicals lated factor 2 (Nrf2), which plays a central role in the regu-
directly, they protect cells from oxidative stress by converting lation of the cellular redox status (Itoh et al. 2003; Nguyen
toxic heme into the potent antioxidants biliverdin and bilirubin et al. 2003, 2004). Under homeostatic conditions, Nrf2

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transcription is repressed by its negative regulator Kelch- lesions revealed a striking increase in genes and proteins
like ECH-associated protein 1 (Keap1) (Itoh et al. 2003), involved in ROS production. Particularly, NADPH oxidase
but upon exposure to ROS, Nrf2 dissociates from cytosolic subunits were profoundly upregulated in microglia and
Keap1 and translocates to the nucleus where it binds to anti- macrophages in active MS lesions, indicating the impor-
oxidant response elements (ARE) in the promoter region of tance of oxidative burst by activated microglia and infil-
hundreds of genes involved in antioxidant protection and trated macrophages. In addition, enhanced expression of
detoxification, including SODs (McCord and Edeas 2005), inducible nitric oxide synthase (Bo et al. 1994; Liu et al.
glutathione peroxidases (Brigelius-Flohe and Maiorino 2001; De Groot et al. 1997) and myeloperoxidase (Marik
2013), peroxiredoxins (Dringen et al. 2005; Kim et al. 2007), et al. 2007; Gray et al. 2008a, b; Chen et al. 2008) has
heme oxygenases (Ishii et al. 2000; Wagener et al. 2003) and been detected in the brains of patients with MS. Besides
NAD(P)H:quinone oxidoreductase-1 (Li and Jaiswal 1992; enhanced expression of enzymes involved in ROS produc-
Long and Jaiswal 2000; Iskander et al. 2006; Jaiswal 2000). tion, MS brain tissue is characterized by abundant mito-
Together, these free radical scavenging enzymes repre- chondrial defects, which represents another pathogenic
sent a powerful antioxidant defense mechanism. Nowadays, process contributing to oxidative stress. Oxidative damage
various natural and synthetic Nrf2-activating compounds to mtDNA in MS lesions was associated with decreased
have been identified, and the number of reports describ- activity of complex I of the oxidative phosphorylation
ing the beneficial effects of Nrf2 activation in experimental (OxPhos) chain in MS lesions (Lu et al. 2000), whereas
models of neurodegeneration is steadily increasing. Even complex IV activity was significantly increased (Mahad
more excitingly, some of these compounds have entered et al. 2009; Witte et al. 2009). Free radicals produced by
into clinical trials or are already on the market. Here, we activated microglia and macrophages through oxidative
will discuss the current literature on the role of ROS- burst likely contribute to intra-axonal mitochondrial injury
induced injury in neurodegenerative disorders, including by inhibiting OxPhos (Witte et al. 2010; Bolanos et al.
multiple sclerosis, Alzheimer’s disease, Parkinson’s disease 1997; Higgins et al. 2010). In animals with experimental
and Huntington’s disease. Moreover, we will provide an autoimmune encephalomyelitis (EAE), the most common
overview on protective effects of Nrf2-induced antioxidant MS animal model, antioxidant administration, attenuated
protection in experimental models of neurodegeneration. mitochondrial pathology and concomitant axonal degenera-
tion (Nikic et al. 2011). Nitration of mitochondrial proteins
and mitochondrial changes even preceded infiltration of
Reactive oxygen species in multiple sclerosis leukocytes in animals suffering from EAE indicating that
mitochondrial defects occur in the early stages of neuroin-
Multiple sclerosis (MS) is a chronic inflammatory and flammation (Qi et al. 2006). Mitochondrial defects are not
demyelinating disease of the CNS. Patients may suf- restricted to MS white matter lesions, but can be observed
fer from a wide variety of clinical symptoms, including throughout the gray matter. Accumulation of neuronal
visual, motor and cognitive disturbances. The course of mtDNA deletions and decreased neuronal levels of key
the disease is generally episodic, with frequent intervals mitochondrial proteins, including specific OxPhos proteins
of exacerbations followed by periods of remission, known and mitochondrial antioxidant enzymes, have been reported
as relapsing–remitting MS. In time, most patients gradu- (Campbell et al. 2011). Taken together, increased expres-
ally develop secondary progressive MS, a stage character- sion of ROS-generating enzymes by inflammatory cells and
ized by progressive permanent neurological deficits. The mitochondrial dysfunction results in enhanced ROS forma-
immune system is particularly involved in the initial stage tion during neuroinflammation.
of the disease as active demyelinating MS lesions are char- It is now well accepted that ROS play a key role in
acterized by massive microglial cell activation and leuko- pathogenic processes involved in MS lesion development
cyte infiltrates consisting of lymphocytes and macrophages. and progression. ROS induce blood–brain barrier (BBB)
Additional pathological hallmarks of MS plaques include permeability, thereby promoting leukocyte infiltration and
destruction of myelin sheaths, oligodendrocyte cell death, lesion formation. In the early phase of MS lesion forma-
neuro-axonal damage and glial scar formation. During an tion, locally produced ROS induce BBB breakdown,
inflammatory attack, macrophages and activated microglia thereby facilitating transendothelial leukocyte migration
produce a plethora of inflammatory mediators, including (Van der Goes et al. 2001; Schreibelt et al. 2006). Sec-
cytokines, chemokines, nitric oxide and ROS. ondly, ROS cause oxidative damage to CNS cells, resulting
To identify possible sources of ROS production in rela- in oligodendrocyte injury, demyelination and axonal dam-
tion to demyelination and neurodegeneration in MS, a age. Increased levels of indicators of oxidative stress and/or
genome-wide microarray analysis has been performed decreased levels of antioxidant enzymes and antioxidants
(Fischer et al. 2012). Analysis of active demyelinating MS have been observed in blood and CSF during the active

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phases of MS (Karg et al. 1999; Greco et al. 1999; Cala- shown to be markedly increased in active demyelinating
brese et al. 1994; Ferretti et al. 2005; Koch et al. 2006). MS lesions, suggesting activation of the Nrf2 pathway dur-
Additionally, enhanced expression of markers of oxidative ing a neuroinflammatory attack (van Horssen et al. 2008,
damage in MS brain tissue has been reported, indicating the 2010). Immunohistochemical analysis revealed that Nrf2
occurrence of widespread oxidative injury in demyelinating and its downstream targets heme oxygenase-1 and NAD(P)
MS plaques. Immunohistochemical detection of nitrotyros- H:quinone oxidoreductase-1 were upregulated in inflamma-
ine, a footprint for peroxynitrite formation, demonstrated tory MS lesions, particularly in hypertrophic astrocytes and
extensive nitrotyrosine staining in early MS lesions. Addi- myelin-laden macrophages. Intriguingly, oligodendrocytes
tionally, markers for lipid peroxidation, such as malondial- and neurons, the primary cellular victims in MS, expressed
dehyde and 4-hydroxy-2-nonenal, and oxidative damage to relatively low levels of Nrf2 and antioxidant enzymes.
nucleotides are increased in MS lesions (van Horssen et al. Despite the increase in endogenous antioxidant enzymes in
2008; Haider et al. 2011). Oligodendrocytes, in particular active demyelinating MS lesions, oxidative stress and dam-
oligodendrocyte precursor cells, are highly susceptible to age are still prominent in inflammatory lesions. This sug-
oxidative damage as they contain relatively low levels of gests that the observed increase in antioxidant enzymes is
endogenous antioxidant enzymes compared to astrocytes not sufficient to counteract the increased ROS production
(Mitrovic et al. 1994; Thorburne and Juurlink 1996; Husain in MS brain tissue. Hence, additional activation of the Nrf2
and Juurlink 1995; Juurlink et al. 1998). Moreover, oli- pathway may be a potential therapeutic strategy to restore
godendrocytes contain large myelin sheets, which mainly the redox balance in MS.
consist of polyunsaturated fatty acids that can react with Johnson and co-workers elegantly showed the protec-
ROS, thereby triggering lipid peroxidation. It has been tive role of Nrf2 in the EAE animal model. They showed
demonstrated that free radicals are able to block matura- that induction of EAE in Nrf2-deficient mice resulted in
tion of oligodendrocyte precursor cells into myelin-forming more severe disease symptoms and an increase in infil-
cells by downregulation of genes involved in differentia- trated immune cells (Johnson et al. 2010). Sulforaphane
tion and upregulation of genes associated with inhibition of and derivatives of the natural triterpene oleanolic acid, both
maturation (French et al. 2009). well-known Nrf2 activators, suppressed disease in a murine
model of MS by inhibiting the immune system and induc-
ing antioxidant genes (Pareek et al. 2011; Li et al. 2013). In
Nrf2 in multiple sclerosis addition, there is ample evidence that fumaric acid esters
are able to boost the production of endogenous antioxidant
Based on the prominent role of ROS in the pathogenesis enzymes via activation of the Nrf2 pathway (Scannevin
of MS, it is conceivable that stimulating antioxidant pro- et al. 2012). Scannevin and colleagues demonstrated that
duction may be beneficial and can protect CNS cells from administration of dimethyl fumarate (DMF) or monomethyl
ROS-induced damage, thereby limiting disease progres- fumarate (MMF) prior to an oxidative challenge was able
sion. Administration of compounds with antioxidant prop- to prevent ROS-induced cell death of primary astrocytes
erties was shown to ameliorate clinical manifestations and and neurons in an Nrf2-dependent manner. Oral adminis-
inflammation in the EAE animal model (Mao et al. 2013; tration of fumarates attenuated disability progression in a
Hendriks et al. 2004). In contrast, other reports found no chronic EAE mouse model, and more recently, it was dem-
evident protective effect of exogenous antioxidants (Fie- onstrated that preventive DMF treatment reduced the clini-
biger et al. 2013; Spitsin et al. 2002). A possible explana- cal signs of disability in a chronic EAE mouse model and
tion for the lack of therapeutic efficacy is that most exog- that the beneficial effects were Nrf2-dependent, as DMF
enous antioxidants are hydrophilic and therefore not able administration did not affect the disease course in Nrf2-
to efficiently cross the BBB (Gilgun-Sherki et al. 2001; deficient animals. DMF treatment resulted in induction of
Moosmann and Behl 2002; Carlson and Rose 2006). Nrf2 expression in neurons, oligodendrocytes and astro-
Unfortunately, clinical data on successful antioxidant ther- cytes, preservation of myelin and axonal structures and a
apy in MS patients are very limited, emphasizing the need marked decrease in astrogliosis (Linker et al. 2011). Fuma-
for further epidemiological and clinical studies. Another rates have been used in a clinical setting for more than half
therapeutic option would be to activate Nrf2-driven antioxi- a century in the treatment of psoriasis, a chronic skin disor-
dant gene expression in the CNS, thereby limiting oxida- der. Based on the positive results in the treatment of psoria-
tive stress and oxidative cellular injury in MS. sis, Schimrigk et al. performed the first exploratory clinical
Nrf2-regulated proteins are upregulated in brain sam- trial with fumarates in a small cohort of relapsing–remit-
ples of EAE animals, particularly at the peak of disease ting MS patients (Schimrigk et al. 2006). Fumarate treat-
(van Horssen et al. 2011). Likewise, the expression of ment decreased the mean number of gadolinium-enhancing
Nrf2 as well as Nrf2-mediated antioxidant proteins was lesions, an indication of active inflammation, significantly.

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More recently, the potential protective effects of Tecfidera®, 4-hydroxy-2-nonenal levels were shown to be significantly
enteric-coated microtablets containing DMF, have been elevated in the ventricular fluid of AD subjects compared
investigated in two large randomized, double-blind, pla- to control subjects, demonstrating increased lipid peroxida-
cebo-controlled Phase III studies. In these trials, relapsing– tion in AD brain (Lovell et al. 1997).
remitting MS patients were randomly assigned to receive Different potential sources of oxidative stress are pre-
oral Tecfidera® at a dose of 240 mg twice or three times sent in AD brain at already early stages of pathology. AD
daily or placebo (Gold et al. 2012; Fox et al. 2012). Both brains show increased presence of neurotoxic trace ele-
clinical studies clearly demonstrated the clinical efficacy ments, iron, aluminum, mercury and copper, capable of
of Tecfidera®. Taken together, there is now ample evidence enhancing free radical generation (Markesbery 1997;
from experimental animal studies and clinical trials that Shcherbatykh and Carpenter 2007). The abnormal interac-
fumarates represent a promising novel therapeutic in the tions of trace metals with Aβ and NFTs are considered to
treatment of MS. be a potential source of oxidative stress (Bush 2003; Huang
et al. 2004; Doraiswamy and Finefrock 2004). In addition,
neuroinflammation is a prominent feature in AD brain and
ROS in Alzheimer’s disease pathology provides a significant source of oxidative stress (Colton and
Gilbert 1987; Colton et al. 2000; Eckert et al. 2003). Astro-
Alzheimer’s disease (AD) is a progressive neurodegen- cytes and microglia are associated with amyloid plaques
erative disease and the most common type of adult onset and found to be increased in the surrounding tissue (Akiy-
dementia. AD is characterized by loss of neuronal integrity ama et al. 2000). Neuropathological studies show elevated
and consequent memory impairment and cognitive decline expression levels of inducible nitric oxide synthase (iNOS)
as a result of loss of neurons and synapses (Cummings and NOX subunits, particularly in amyloid-plaque-associ-
2004). The major pathological features of AD are amyloid- ated astrocytes and/or microglial cells (Lee et al. 1993; Shi-
containing plaques and neurofibrillary changes, which mohama et al. 2000). Induction of iNOS expression in glial
occur prominently in the neocortical areas. Plaques primar- cells may result in excess release of nitric oxide and nitra-
ily consist of amyloid β (Aβ), which is a cleavage product tive stress (Wallace et al. 1997; Smith et al. 1997), and acti-
of the amyloid precursor protein. As a result of a misbal- vation of the microglial respiratory burst may lead to the
ance between production and removal of Aβ from the brain, NOX catalyzed reduction of molecular oxygen to super-
Aβ builds up in extracellular deposits in the parenchyma oxide and the formation of hydrogen peroxide (Colton and
as well as in the brain blood vessels. Several types of neu- Gilbert 1987; Lambeth 2004). Although the respiratory
rofibrillary changes occur in the AD brain, neurofibrillary burst of microglia is likely to be modulated by numerous
tangles (NFTs), dystrophic neurites and neuropil threads factors, in vitro studies have lucidly shown that Aβ itself
(Braak and Braak 1991). These are composed of intracel- is a potent trigger of microglial respiratory burst activity
lular accumulation of paired helical filaments (PHF), which (Colton et al. 2000; Van Muiswinkel et al. 1996, 1999).
mainly consist of hyperphosphorylated microtubule-associ-
ated protein tau.
AD brains show increased levels of oxidative DNA Nrf2 in Alzheimer’s disease
damage, both nuclear DNA (nDNA) and to a much greater
extent mtDNA, and oxidative damage to RNA (Mecocci In vitro studies show that Nrf2 signaling is essential
et al. 1994; Wang et al. 2005; Ding et al. 2006; Nunomura for counteracting oxidative damage and neuronal death
et al. 2006). In addition, proteins derived from AD brains induced by Aβ (Karkkainen et al. 2014; Kanninen et al.
are more oxidized than those derived from age-matched 2008). Immunohistochemical studies indicate that in nor-
controls and are most pronounced in regions containing mal hippocampus, Nrf2 is predominantly expressed in neu-
severe neurodegeneration (Sultana et al. 2006). Oxidative rons where it is localized in the cytoplasm and the nucleus
damage to proteins often affects the function of proteins (Ramsey et al. 2007). In AD brain, Nrf2 localization in the
and makes them liable for aggregation. Several studies have nucleus is dramatically decreased while the cytoplasmic
shown increased lipid peroxidation in AD brain (Sultana localization of Nrf2 remains unchanged. Nrf2 in AD hip-
et al. 2006; Volkel et al. 2006). Lipid peroxidation produces pocampal neurons does not co-localize with the pathologi-
large amounts of aldehydes, particularly the 4-hydroxyalk- cal hallmarks of AD: Aβ and phosphorylated tau (Ramsey
enals, which are produced by the oxidation of polyunsatu- et al. 2007). Remarkably, neurons in AD brain positive for
rated fatty acids (Markesbery 1997). 4-hydroxy-2-nonenal, 7-hydroxynonenal, a marker of lipid peroxidation, do not
one of the major products of polyunsaturated fatty acid per- contain Nrf2 in the nucleus. So despite the presence of oxi-
oxidation, is highly reactive and responsible for cytotoxic dative stimuli or neurotoxic Aβ, Nrf2 is not translocated
effects found with oxidative stress (Esterbauer et al. 1991). to the nucleus, indicating dysfunctional Nrf2 signaling in

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AD neurons. In APP/PS1 transgenic mice, a mouse model Nrf2-knockout mice show increased levels of phospho-
for AD, the Nrf2-ARE pathway is attenuated in neurons rylated and sarkosyl-insoluble tau in the brain concurrent
when Aβ plaques start to appear in these mice (Kanninen with decreased levels of NDP52, and NDP52 overexpres-
et al. 2008). These findings are in line with the observed sion promotes clearance of phosphorylated tau. These data
decreased neuronal levels of Nrf2 in AD brain (Ramsey suggest that Nrf2 signaling plays a key role in autophagy-
et al. 2007). Interestingly, intrahippocampal gene delivery mediated degradation of phosphorylated tau in vivo (Jo
of Nrf2 in APP/PS1 transgenic mice results in a reduction et al. 2014).
of spatial learning deficits in aged mice (Kanninen et al.
2009). Together with the observation that Nrf2 immuno-
reactivity is prominently present in neurons in human and ROS in Parkinson’s disease pathology
mouse brain, these data suggest that the Nrf2–ARE path-
way plays an important role in protecting neuronal function With a prevalence of approximately 160 per 100,000 in
and preventing cognitive dysfunction. the Western world, Parkinson’s disease is the second most
There have been several studies suggesting that phos- common neurodegenerative disease after AD (Dawson and
phorylation of Nrf2 may contribute to its nuclear exclusion Dawson 2003). PD is characterized by rest tremor, brad-
and degradation. Nrf2 contains many serine, threonine and ykinesia, rigidity and loss of postural reflexes (Jankovic
tyrosine residues, which may provide sites for phospho- 2008). In addition, other clinical features include second-
rylation by different kinases (Bryan et al. 2013). Glycogen ary motor symptoms (e.g., shuffling gait, dysarthria) and
synthase kinase-3β, which shows increased kinase activity non-motor symptoms, such as cognitive and sensory abnor-
in AD and has been proposed as the main kinase involved malities. At the cellular level, PD is characterized by the
in tau phosphorylation, is able to directly phosphorylate preferential loss of dopaminergic neurons in the substan-
Nrf2, thereby inducing its nuclear extraction (Salazar et al. tia nigra (SN) and the presence of α-synuclein-containing
2006). Antisense oligonucleotide against glycogen synthase inclusion bodies (known as Lewy bodies) in the cytoplasm
kinase-3β in an AD mouse model resulted in increased of neurons in various regions of the brain, including the
nuclear localization of Nrf2, a decrease in oxidative stress SN, olfactory bulb, and neocortex (Mosley et al. 2006).
and improved learning and memory (Farr et al. 2014). Although intracellular deposits of highly aggregated forms
Another kinase that is able to directly phosphorylate Nrf2 of α-synuclein are characteristic of PD, in a number of
is protein kinase RNA-like endoplasmic reticulum kinase other neurodegenerative disorders, such as multiple system
(PERK) (Cullinan et al. 2003). PERK is an endoplasmic atrophy and Lewy body dementia, these aggregated forms
reticulum stress sensor and controls the activation of one of of α-synuclein are also found. Therefore, these disorders
the three independent signaling pathways that together act are collectively known as the synucleinopathies (Jellinger
as the unfolded protein response (Walter and Ron 2011). 2008; Beyer and Ariza 2007; Uversky 2007; Springer and
The unfolded protein response is a stress response of the Kahle 2006). In spite of the tremendous efforts over the
endoplasmic reticulum that is activated when misfolded past years, the pathogenesis of idiopathic PD still remains
proteins start to accumulate in the endoplasmic reticulum, largely enigmatic. Nevertheless, in the past two decades,
for instance due to presence of ROS. Increased levels of evidence is mounting that oxidative stress and mitochon-
activated PERK can be observed in neurons already in the drial dysfunction play a major role in the degeneration of
early stages of AD pathology (Hoozemans et al. 2009). nigral dopaminergic neurons.
While Nrf2 is maintained in the cytoplasm in unstressed Increased stress resulting from ROS production is one of
cells via association with Keap1, activation of PERK leads the key mechanisms that results in death of dopaminergic
to phosphorylation and dissociation of Nrf2, enabling neurons in PD, and mitochondrial complex I is considered
nuclear import (Walter and Ron 2011). This mechanism to be the primary source of ROS. Postmortem analysis of
is important to restore protein homeostasis in the endo- PD brain demonstrated an early and profound loss of the
plasmic reticulum after oxidative damage to proteins. The antioxidant glutathione; a reduction in mitochondrial com-
PERK-dependent nuclear translocation of Nrf2 is a fast and plex I activity; increased lipid, protein, and DNA oxidation
transient response (within 2 hours). Prolonged activation and/or nitration; increased superoxide dismutase activ-
of the unfolded protein response results in re-localization ity; and elevated free iron levels in the SN of parkinso-
of Nrf2 back to cytoplasm (Walter and Ron 2011), a situ- nian patients (Van Muiswinkel et al. 2004; Yasuhara et al.
ation that may apply for neurons in AD brain. Recently, it 2007; Alam et al. 1997a, b; Dexter et al. 1989; Yoritaka
was shown that activation of the Nrf2 pathway reduces the et al. 1996; Sofic et al. 1992, 2006; Healy et al. 2004a).
levels of phosphorylated tau by induction of an autophagy In addition, purified mitochondria from frontal cortex of
adaptor protein, NDP52, in neurons. NDP52 has three ARE PD patients showed mitochondrial complex I deficiency
in its promoter region and is strongly induced by Nrf2. (Parker et al. 2008), and in CSF samples of PD patients,

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oxidized coenzyme Q10 and 8-hydroxy-2′-deoxyguanosine Within this context, it is notable that proper DJ-1 function-
were significantly increased, indicating the occurrence of ing is essential for optimal induction of NAD(P)H:quinone
oxidative damage to mitochondria and DNA in PD patients oxidoreductase-1, as loss of DJ-1 was accompanied by
(Isobe et al. 2010). In addition, certain autosomal reces- deficits in NAD(P)H:quinone oxidoreductase-1 expression.
sively inherited forms of PD can be caused by loss of func- Furthermore, DJ-1 stabilizes Nrf2 by preventing associa-
tion mutations in genes coding for mitochondrial proteins tion with its inhibitor Keap1 and Nrf2’s subsequent ubiqui-
(i.e., PINK1 and DJ-1) involved in antioxidant protection, tination (Clements et al. 2006). When DJ-1 is not intact, the
as shown by several genetic studies (Healy et al. 2004a, Nrf2 protein is unstable and transcriptional responses will
b; Valente et al. 2004). These above-described findings be reduced both under basal conditions and after exposure
are supported by a wealth of data obtained from animal to inducing agents like ROS (Clements et al. 2006).
and in vitro models of PD and corroborated by epidemio- Recently, various in vitro and in vivo models provided
logical data that link exposure to mitochondrial toxins, like information on a possible protective role of the Nrf2–ARE
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), pathway in PD. For instance, the highly neurotoxic dopa-
rotenone and paraquat, to PD (Beal 2001; Drechsel and mine analog 6-hydroxydopamine (6-OHDA) activates the
Patel 2008; Bove et al. 2005; Przedborski and Ischiropou- Nrf2–ARE system as part of a cellular defense mecha-
los 2005). In line with these data is the notion that the SN nism to protect against ROS-mediated damage (Jakel
is more vulnerable to complex I dysfunction compared to et al. 2005). On the other hand, the loss of Nrf2 increases
other brain areas due to the generation of ROS by nigral vulnerability to 6-OHDA both in vitro and in vivo, while
dopaminergic neurons during dopamine metabolism upregulation of Nrf2 using tert-butylhydroquinone (tBHQ)
(Chinta and Andersen 2008). However, although an impor- protected against 6-OHDA-induced cell death in an in vitro
tant role for ROS in PD pathophysiology seems firmly setting (Jakel et al. 2005). Transplantation of astroglial
established, it still remains unclear whether oxidative stress cells overexpressing Nrf2 into mouse brain demonstrated
is a primary trigger for PD or merely a by-product of cel- a significant reduction in susceptibility toward 6-OHDA-
lular malfunction. mediated neurotoxicity (Jakel et al. 2007). Likewise, astro-
cytic Nrf2 overexpression attenuated MPTP-mediated tox-
icity in mice indicating that astrocytic modulation of the
Nrf2 in Parkinson’s disease Nrf2-ARE pathway represents an attractive therapeutic
strategy aimed at reducing or preventing neuronal death
Information regarding the functional status of the Nrf2– in PD (Chen et al. 2009). Alternatively, deprenyl, a drug
ARE system in PD is limited, although activation of this applied in the treatment of PD, was shown to stimulate
system in postmortem PD brain tissue is suggested by stud- Nrf2 activity as part of its cytoprotective mechanism of
ies demonstrating strong upregulation of nigral immunore- action (Nakaso et al. 2006). In in vitro studies using cul-
activity for Nrf2-regulated proteins, like NAD(P)H:quinone tured rat neuronal PC12 and glial C6 cells, the flavonoid
oxidoreductase-1 (Van Muiswinkel et al. 2004) and heme luteolin provided protection against the mitochondrial toxin
oxygenase-1 (Schipper 2004; Riedl et al. 1999). However, MPP + (i.e., the active metabolite of MPTP, see above) by
the increased expression of heme oxygenase-1 and NAD(P) activation of the Nrf2 pathway (Wruck et al. 2007). In this
H:quinone oxidoreductase-1 seems largely restricted to latter model, the knockdown of Nrf2 nullified the effect,
(astro)glial cells and is virtually absent in dopaminergic demonstrating that luteolin-induced protection is mediated
neurons. In contrast to NAD(P)H:quinone oxidoreductase-1 solely through Nrf2. Similar effects in PC12 cells were
and heme oxygenase-1, the distribution of Nrf2 in the SN found upon use of the Nrf2 transcriptional activator tBHQ
of PD brain demonstrated both a cytoplasmic and a strong as the cells were protected against the toxicity of another
nuclear immunoreactivity in neurons (Ramsey et al. 2007). PD-associated neurotoxin, deltamethrin (Li et al. 2007).
Interestingly, neurons that survive in the SN of PD patients Together these data suggest that amelioration of the PD
revealed nuclear Nrf2 localization. These data suggest that phenotype in vivo by activation of the Nrf2–ARE pathway
Nrf2 is functional in these neurons, although it remains may be feasible. Finally, genetic variation in the Nrf2 gene
unclear whether the transcriptional machinery is also intact has been linked to both AD progression and PD progres-
(Ramsey et al. 2007). In line with the findings in PD brain sion (von Otter et al. 2010a, b).
tissue, olfactory neurosphere-derived cells from patients
with sporadic PD demonstrated lower glutathione levels,
which could be restored by the Nrf2-activating agent L-sul- ROS in Huntington’s disease pathology
foraphane (Cook et al. 2011). Thus, although the Nrf2–
ARE signaling route appears to be activated in PD, other Huntington’s disease (HD) is a progressive neurodegen-
factors may be hampering effective Nrf2 gene transcription. erative disease of genetic origin clinically characterized

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1780 Arch Toxicol (2014) 88:1773–1786

by cognitive deficits, progressive motor dysfunction and suggesting that early superoxide dismutase upregulation
psychiatric disturbance (Walker 2007). HD is caused by represents a compensatory mechanism to protect cells, but
an expanded CAG repeat (≥35 repeats) in the hunting- that this endogenous defense system becomes less func-
tin (HTT) gene, located in the short arm of chromosome tional in time (Santamaria et al. 2001). In line with these
4. This polyglutamine expansion induces conformational findings, it was shown that cytosolic superoxide dismutase
changes in the HTT protein resulting in the generation of activity was slightly reduced in HD cortex and cerebellum
large nuclear and cytoplasmic aggregates (Scherzinger (Browne et al. 1997). Activities of superoxide dismutase-1
et al. 1997). The predominant pathological hallmark of and glutathione peroxidase are reduced in leukocytes of
HD is severe atrophy of the striatum, but as the disease HD patients when compared to controls (Chen et al. 2007).
progresses, the cerebral cortex and other subcortical struc- GPx activity was unaltered in the striatum of mice trans-
tures are affected as well. The mutation that causes HD was genic for the HD mutation compared with control animals
identified decades ago, yet the precise mechanism leading (Perez-Severiano et al. 2004). Recently, Mason and co-
to the degeneration of neurons in specific brain regions workers, using a combination of genetic and pharmacologi-
remains poorly understood. However, defective mitochon- cal approaches, demonstrated that boosting glutathione per-
drial bioenergetics, oxidative stress and associated impaired oxidase activity is neuroprotective in experimental models
neuronal energy metabolism are likely involved in the etiol- of HD (Mason et al. 2013). Heme oxygenase-1 immuno-
ogy of the disease. reactivity is markedly enhanced in HD brain tissue, pre-
Immunohistochemical analysis revealed increased lev- dominantly in advanced stages of the disease (Browne et al.
els of oxidized nucleotides and lipid peroxidation markers 1999).
in the brain tissue of HD animal models and HD patients Overexpression of superoxide dismutase-1 attenuated
(Browne et al. 1997; Perez-Severiano et al. 2013; Bog- proteasomal dysfunction, mutant HTT aggregation and cell
danov et al. 2001; Browne and Beal 2006). In addition, death in mutant HTT expressing cells, indicating the thera-
increased plasma and urine levels of oxidized nucleotides peutic potential of enhancing antioxidant enzyme levels
have been reported in both this experimental HD model (Goswami et al. 2006). Yet, only a few studies have focused
and HD patients (Hersch et al. 2006; Stoy et al. 2005; Bog- on the effects of the Nrf2-ARE pathway in mouse models
danov et al. 2001), as well as increased concentrations of of HD (Shih et al. 2005a; Calkins et al. 2005). Nrf2-defi-
8-hydroxydeoxyguanosine concentrations with HD dis- cient cells and Nrf2 knockout mice were shown to be sig-
ease progression (Long et al. 2012). Oxidative damage to nificantly more vulnerable to malonic acid and 3-nitropro-
mtDNA is evident in the parietal cortex of late-stage HD pionic acid, two mitochondrial toxins that inhibit complex
individuals and might contribute to subsequent mitochon- II and cause striatal damage reminiscent of HD (Shih et al.
drial dysfunction (Siddiqui et al. 2012). Overall, there is 2005a). Injection of Nrf2-overexpressing astrocytes in the
ample evidence for the occurrence of oxidative damage to striatum before treatment with malonic acid and 3-nitro-
essential biomolecules in experimental models of HD and propionic acid provided further protection against com-
HD patients (yala-Pena 2013). NOX activity was elevated plex II inhibition and had a strong neuroprotective effect
in HD cortex and striatum, particularly in pre-symptomatic (Calkins et al. 2005). Therapeutic strategies aimed at boost-
patients indicating that increased NOX activity is an early ing endogenous antioxidant levels in HD animal models
pathological event occurring before clinical deficits become show promising results. Administration of DMF resulted
apparent (Valencia et al. 2013). Pharmacological inhibition in enhanced Nrf2 immunostaining in a subset of neurons
of NOX by apocynin led to reduction in lipid peroxidation (not astrocytes), improved motor impairment, preserva-
and cellular injury in an experimental HD rat model (Mal- tion of striatal and motor cortex neurons and increased
donado et al. 2010). life span (Ellrichmann et al. 2011). Oral administration of
synthetic triterpenoids, potent inducers of the Nrf2 path-
way, increased levels of Nrf2-driven genes in the CNS,
Nrf2 in Huntington’s disease attenuated oxidative stress, ameliorated motor behavior and
increased longevity in a transgenic mouse model of HD
The involvement of free radicals in the pathology of HD (Stack et al. 2010).
is further highlighted by the observation that antioxi-
dant treatment strategies attenuate disease symptoms in
HD animal models (Klivenyi et al. 2003; Ferrante et al. Conclusion and future perspectives
2002). Relatively few studies focused on the role of endog-
enous antioxidant enzymes in HD animal models and Several research groups have highlighted the protective
patients. Superoxide dismutase activities were increased role of Nrf2 under different pathological conditions indicat-
in young transgenic HD mice, but decreased in older mice, ing that Nrf2 is critically involved in the protection against

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oxidative stress. A large variety of natural and synthetic in Parkinson’s but not incidental Lewy body disease. J Neuro-
compounds that activate the Nrf2 pathway, also referred to chem 69:1326–1329
Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jen-
as ‘Nrf2 activators,’ have been identified, including among ner P, Halliwell B (1997b) Oxidative DNA damage in the par-
others, tert-butyl hydroquinone, sulforaphane, curcumin kinsonian brain: an apparent selective increase in 8-hydroxy-
and dithiolethiones. Still, new small molecule Nrf2 acti- guanine levels in substantia nigra. J Neurochem 69:1196–1203
vators are being designed and synthesized. The Johnson Beal MF (2001) Experimental models of Parkinson’s disease. Nat Rev
Neurosci 2:325–334
lab used an elegant computational approach to discover Beal MF (2002) Oxidatively modified proteins in aging and disease.
novel compounds with the ability to induce Nrf2-mediated Free Radic Biol Med 32:797–803
gene expression (Williamson et al. 2012). The therapeutic Bedard K, Krause KH (2007) The NOX family of ROS-generating
potential of these novel identified compounds needs to be NADPH oxidases: physiology and pathophysiology. Physiol
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in future. Importantly, preclinical data are emerging that inopathies: commonalities and differences. J Neuropathol Exp
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Although there are ample preclinical data demonstrat- Bogdanov MB, Andreassen OA, Dedeoglu A, Ferrante RJ, Beal
ing the therapeutic efficacy of Nrf2 activators, only a few MF (2001) Increased oxidative damage to DNA in a trans-
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Nrf2-activating compounds have been tested in a clinical 79:1246–1249
setting. Biogen Idec developed an oral formulation of DMF Bolanos JP, Almeida A, Stewart V, Peuchen S, Land JM, Clark JB,
known as Tecfidera®, which is now approved for the treat- Heales SJ (1997) Nitric oxide-mediated mitochondrial damage
ment of relapsing–remitting MS. Future studies are needed in the brain: mechanisms and implications for neurodegenera-
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to reveal the efficacy of Tecfidera® in progressive MS Bove J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models
patients. Intriguingly, fumaric acid esters are also effective of Parkinson’s disease. NeuroRx 2:484–494
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are not restricted to the neurodegenerative diseases dis- ease pathogenesis. Antioxid Redox Signal 8:2061–2073
cussed in this review, but represent common pathological Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit
MM, Bird ED, Beal MF (1997) Oxidative damage and meta-
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the therapeutic potential and clinical applicability of Nrf2 tington’s disease. Brain Pathol 9:147–163
Bryan HK, Olayanju A, Goldring CE, Park BK (2013) The Nrf2 cell
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Acknowledgments This work was supported by grants from Neurosci 26:207–214
‘Stichting Vrienden MS Research,’ The Netherlands, project numbers Calabrese V, Raffaele R, Cosentino E, Rizza V (1994) Changes in
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