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Antioxidant Effects of Curcumin in Models of Neurodegeneration, Ageing,

Oxidative and NITROSATIVE Stress: A Review

Article  in  Neuroscience · February 2019

DOI: 10.1016/j.neuroscience.2019.02.020

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NEUROSCIENCE
REVIEW
Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21

Antioxidant effects of curcumin in models of neurodegeneration, aging,

oxidative and nitrosative stress: A review
Shameemah Abrahams,a,* William L. Haylett, a,b Glynis Johnson,c Jonathan A. Carr,d and Soraya Bardien a
a
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University,
South Africa
b
Division of Endocrinology, Department of Medicine, Stellenbosch University, Cape Town, South Africa
c
DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division
of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
d
Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

Abstract—The global burden of neurodegenerative disorders has increased substantially over the past 2 decades due to
rising rates of population aging. Although neurodegenerative disorders differ in their clinical presentation, the underlying
pathobiological processes are largely shared. Oxidative stress, among other mechanisms, is strongly implicated in
neurodegenerative disorders and aging, and can potentially be targeted by antioxidative agents. Curcumin, a component
of turmeric, is a compound that has received considerable attention for its therapeutic properties, and it is considered
to be a powerful antioxidant. In this review, we analyzed the evidence for curcumin as an antioxidant in models of neuro-
degenerative disorders as well as oxido-nitrosative stress. A total of 1451 articles were found from 3 scientific literature
databases (PubMed, Scopus, and Web of Science). After all exclusions, a final total of 64 articles were included in
this review. The majority of the studies showed that curcumin, or derivatives thereof, were protective against oxidative
and/or nitrosative stress in various cellular and animal models. Overall, curcumin protected against lipid and protein
oxidation with a reduction in levels of malondialdehyde, and protein carbonyls, thiols and nitrotyrosines. Furthermore,
it stimulated the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. In

*Corresponding author.
E-mail address: shameemah@sun.ac.za (Shameemah Abrahams).
Abbreviations: 3-NP, 3-nitropropionic acid; 6-OHDA, 6-hydroxydopamine; Aβ40 or Aβ42, 40- or 42-amino acid amyloid-β peptide; A172, human glioma cells;
A53T, point-mutation resulting in alanine to threonine change at amino acid 53 of α-synuclein; AD, Alzheimer's disease; Akt, serine/threonine protein kinase
B; AKR1B4, aldo-keto reductase family 1, member B4; AKR1B8, aldo-keto reductase family 1, member B8; ALAS1, 5′-aminolevulinate synthase 1; AlCl3,
aluminum chloride; AP-1, activated protein 1; APE1, apurinic/apyrimidinic endonuclease; AOX1, aldehyde oxidase 1; APP, amyloid precursor protein;
ARE, antioxidant responsive element; b.w., body weight; C6, rat glioma cells; Ca2+, calcium; CAT, catalase; curcumin D1, di-piperoyl; CoCl2, cobalt chloride;
Cu(II), copper(II); curcumin D2, di-valinoyl; curcumin D3, di-glutamoyl; DAF-FM DA, 4-Amino-5-methylamino-2′,7′-difluorofluorescein diacetate; DCHF-DA,
dichlorodihydrofluorescein diacetate; DHR123, dihydrorhodamine 123; DMC, demethoxycurcumin; DMSO, dimethyl sulfoxide; DNPH, 2,4-dinitrophenylhydrazine;
DPPH, 2,2-diphenyl-1-picryl-hydrazyl-hydrate; DTNB, 5,5-dithio-bis-(2-nitrobenzoic acid) or Ellman's reagent; ELISA, enzyme-linked immunosorbent assay; FRAP,
ferric reducing antioxidant power; G6PD, glucose-6-phosphate dehydrogenase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GFAP, glial fibrillary acidic
protein; GFP, green fluorescent protein; GGT1, gamma-glutamyltransferase 1; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; GST,
glutathione S-transferase; GSTA5, glutathione S-transferase alpha 5; GSTD1, glutathione S-transferase D1; GSTP1, glutathione S-transferase pi 1; h, hours;
H2O2, hydrogen peroxide; HA-sp, human spinal cord-derived astrocytes; HD, Huntington's disease; HEK293, human kidney cells; HFP, hydroxyl radical
and peroxynitrite sensor; HMOX1, heme oxygenase 1; HNE, 4-hydroxy-2-nonenal; HT22, mouse hippocampal cells; ICV-STZ, intracerebroventricular–
streptozotocin; IκBα, inhibitors-of-kappaB; IL-6, interleukin-6; IMR-32, human brain neuroblastoma cells; iNOS, inducible nitrogen oxide synthase; i.p.,
intraperitoneally; LC, liquid chromatography; LPO, malondialdehyde-thiobarbituric assay; LPS, lipopolysaccharide; LRRK2, leucine-rich repeat kinase 2;
MAPK, mitogen-activated protein kinases; MDA, malondialdehyde; MGST1, microsomal glutathione S-transferase 1; min, minutes; MnCl2, manganese
chloride; MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; MS/MS, tandem mass spectrometry;
mth, methuselah; N27, rat dopaminergic neurons; N9, mouse microglia; NDD, neurodegenerative disorder; Neuro-2a, mouse neuroblastoma cells; NF-κB, nuclear-
factor κB; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; NQO1, NAD(P)H quinone dehydrogenase 1; NO, nitric oxide; NO2, nitrogen dioxide; N2O3,
dinitrogen trioxide; NR8383, gerbil macrophages; Nrf1/2, nuclear factor-E2-related factor 1/2; O2−, superoxide anion; O2−2, peroxide; OH, hydroxyl radical;
OLN-93, rat oligodendrocytes; PC12, rat pheochromocytoma cells; PD, Parkinson's disease; Plp1, proteolipid protein 1; PN, peroxynitrate; p.o., per os/orally
ingested; ppm, parts per million; Rh-123, rhodamine 123; RNS, reactive nitrogen species; ROS, reactive oxygen species; RT-PCR, real time polymerase
chain reaction; SAMP8, senescence accelerated mouse-prone 8; SAMR1, senescence-resistant 1 mice; s.c., subcutaneous injection; SH-SY5Y and SK-N-SH,
human bone marrow neuroblastoma cells; SMA, spinal muscular atrophy; SMN, survival of motor neuron; SOD, superoxide dismutase; SOD1/2, superoxide
dismutase 1/2; TAC, total antioxidant capacity; TBA, thiobarbituric acid; TBARS, thiobarbituric acid-reactive substances; t-BHP, tert-Butyl hydroperoxide;
TEAC, trolox equivalent antioxidant capacity assay; TNF-α, tumor necrosis factor α; TRPM2, transient receptor potential cation subfamily M, member 2, channel;
TTCA, trichloroacetic acid assay; WST, cell proliferation assay; w/v, percent weight/volume; w/w, percent mass.

https://doi.org/10.1016/j.neuroscience.2019.02.020
0306-4522/© 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

1
2 Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
conclusion, curcumin appears to be a promising compound for phytomedicine. However, due to some concerns about its
efficacy, further targeted experiments are needed to identify its exact molecular targets and pathways responsible for its
antioxidant effects. © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.
Key words: curcumin, neurodegenerative disorders, antioxidant, oxidative stress, nitrosative stress, curcumin derivatives.
INTRODUCTION
Neurodegenerative disorders (NDDs) are becoming significant
global health burdens which are exacerbated by escalating
numbers of the elderly in both developed and developing
countries (Kassebaum et al., 2016). Most NDDs, including
Alzheimer's disease (AD), Parkinson's disease (PD) and
Huntington's disease (HD) remain essentially incurable. The
paucity of therapeutic options to prevent or treat NDDs is of
concern, as the prevalence and disability resulting from these
disorders are predicted to increase significantly (WHO, 2006).
NDDs are characterized by degenerative processes and are
thought to share several pathobiological pathways. Inflamma-
tion, impaired protein processing, mitochondrial dysfunction,
oxidative stress, and disruptions in the autophagy-lysosomal
system (Vidoni et al., 2016; Wolfe, 2018) are proposed as
pathobiological pathways where initial perturbations in 1
pathway may cascade into a vicious cycle of cellular impair-
ment and neurodegeneration. Of particular interest is the
oxidative stress response, which is strongly implicated in
NDDs and aging, and which can potentially be targeted by
antioxidative agents (Jiang et al., 2016; Liguori et al., 2018).
One antioxidative compound that has received considerable
attention is the natural polyphenol curcumin, one of the
major components of turmeric. A growing body of evidence
reports the various antioxidative, anticarcinogenic and anti-
inflammatory effects of curcumin across many cellular and
animal models of different disorders (Pulido-Moran et al.,
2016), while chemical modification of this promising com-
pound can increase its bioavailability, structural stability and
efficacy (Oliveira et al., 2015). While curcumin potentially
has many protective properties, the poor intestinal absorp-
tion, structural instability, limited blood–brain barrier penetra-
tion and rapid degradation of curcumin in the body limit the
potential as a therapeutic agent in clinical trials (Ullah et al.,
2017). Studies reported lower plasma curcumin compared
to the ingested amount of curcumin, for example one study
showed that of the 8 g/day of curcumin ingested orally, only
22–41 ng/ml of curcumin was detected in the plasma (Dhillon
et al., 2008; Ullah et al., 2017). The hydrophobic nature of
curcumin reduces its ability to solubilize in aqueous solutions
which poses a challenge for improving its bioavailability.
Therefore, studies are investigating the effect of modifying
the curcumin structure to improve bioavailability without
compromising on its protective properties. Studies have
attempted to improve bioavailability by altering curcumin's
chemical structure, conjugating curcumin with lipids, encap-
sulating curcumin in a nanoparticle, constructing complexes
with manganese or co-treating curcumin with piperine
(Chen et al., 2011, 2018; Sandhir et al., 2014; Squillaro
et al., 2018). In some instances, the modified curcumin
has higher antioxidant ability, solubility or absorption rates
compared to free curcumin (Jangra et al., 2016; Shelat and
Acharya, 2016). However, other studies showed that curcu-
min had a greater protective effect compared to the deriva-
tives; while altering curcumin's structure reduced the
efficacy as an antioxidant (Begum et al., 2008; Agrawal
et al., 2012). Hence, curcumin may be a beneficial anti-
oxidative and neuroprotective agent with valuable clinical
implications for NDDs if the technical challenges can be
met. Here, we review the evidence of the antioxidant proper-
ties of curcumin in various models of NDDs, aging as well
as oxidative and nitrosative stress.
OXIDO-NITROSATIVE STRESS PATHWAYS
A salient feature of NDDs is the presence of oxido-nitrosative
stress, or the imbalance of reactive oxygen and nitrogen
species (ROS and RNS), in affected neurons. In order to
contextualize the experimental findings of the reviewed litera-
ture, we provide a brief introduction to the ROS and RNS
pathways and how these are experimentally measured. In
cells, free radicals are unstable compounds which readily bind
to oxygen to become reactive species such as ROS and
RNS, with many cytotoxic consequences (Gebicki, 2016).
Free radicals can form in response to external factors includ-
ing exposure to radiation, environmental pollution or pesti-
cides, as well as, due to internal bodily processes such as
energy metabolism, phagocytosis and inflammation (Lobo
et al., 2010). Physiological levels of ROS and RNS also play
important roles in cell signaling and the innate immune
system; hence, an imbalance in ROS and RNS levels can
shift the scale towards being either damaging or beneficial.
Common cellular free radicals include superoxide anion
(O2−), hydrogen peroxide (H2O2), hydroxyl radical (OH) and
nitric oxide (NO) (Finkel and Holbrook, 2000; Bharath et al.,
2002; Hayyan et al., 2016). Cellular O2− is highly reactive
and is reduced by superoxide dismutase (SOD) to the less
reactive H2O2, which is further reduced by catalase to water
and oxygen. In addition, ROS are neutralized by glutathione
peroxidase (GPx) in a reaction that converts the cellular
antioxidant glutathione from its reduced state (GSH) to its
oxidized form (GSSG). In turn, glutathione reductase (GR)
regenerates GSH from GSSG thereby replenishing the
GSH pool. Therefore, the measurement of the levels and/or
enzymatic activity of SOD, catalase, GPx, GSH, GSSG and
GR is a useful indicator of cellular oxidative stress.
Cellular RNS originate from NO produced by various nitric
oxide synthase (NOS) enzymes, such as inducible NOS
(iNOS), endothelial NOS and neuronal NOS. NO readily
reacts with O2− to form peroxynitrate, a slow-acting RNS
which can damage cellular biomolecules. Moreover, peroxy-
nitrate can react with other molecules to form additional
 Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
RNS, including nitrogen dioxide (NO2) and dinitrogen trioxide
(N2O3) (Weidinger and Kozlov, 2015).
ROS and RNS cause DNA damage, lipid peroxidation and
protein oxidation, which damage cellular components and
thereby impair cellular function. The oxidation of proteins
results in the formation of protein carbonyls, thiols and nitro-
tyrosines, which negatively affect protein function. These
compounds form readily when ROS or RNS interact with pro-
teins and are relatively stable, which make them suitable as
markers of oxidative or nitrosative stress (Suzuki et al.,
2010). Similarly, peroxidation of cellular lipids by ROS and
RNS produces malondialdehyde (MDA), isoprostanes and
4-hydroxy-2-nonenal (HNE), and therefore high levels of
these are good indicators of oxidative or nitrosative stress.
LITERATURE SEARCH STRATEGY
For this review, 1451 articles were found after literature
searches in 3 databases (PubMed, Scopus, and Web of
Science) using the following search terms: [(“curcumin”) AND
(“anti-oxidant” OR “antioxidant”) AND (“neurodegenerative
disease” OR “neurodegeneration”)]. Literature searches and
article selection were completed during August–September
2017 by 2 of the authors, independently. All non-English
articles, non-original research articles, reviews and conference
abstracts were excluded.
From our search, we selected 64 original articles that
investigated curcumin's role as an antioxidant in models of
neurodegeneration, aging and oxido-nitrosative stress. These
included the ‘classical’ NDDs (AD, PD and HD) as well as
related disorders, multiple sclerosis (MS) and spinal muscular
atrophy (SMA). We also included articles on dementia as it
is considered to be relevant to the topic. These articles
are reviewed in detail in the sections that follow and are
summarized in Tables 1–4. The data from cellular models will
be presented first followed by animal models, with articles
sub-categorized into models of (1) neurodegenerative dis-
orders and (2) oxido-nitrosative stress. Following on this,
the remaining articles on dementia and aging are reported
on. We conclude with a section on the possible mechanistic
actions of curcumin as collated from the reviewed studies.
STUDIES PERFORMED IN CELLULAR MODELS
Antioxidant effects of curcumin in neurodegenerative
disorders
To date, 17 studies have investigated the antioxidant properties
of curcumin in various cellular models of NDDs (Table 1). The
majority of these studies were performed on the ‘classical’
NDDs (11 were on PD and 4 were on AD) and there was 1
each on the related disorders (SMA and MS). All of the
studies, except 2 (Van Meeteren et al., 2004; Ortiz-Ortiz
et al., 2009), showed curcumin to be protective against oxida-
tive and/or nitrosative stress. Notably, this effect was
observed irrespective of whether the curcumin treatment
was before, during or after the toxin/transfection exposure,
suggesting that curcumin's antioxidant effect is independent
of the timing of when oxidative stress occurs. Also, curcumin
3
was shown to be protective across a wide range of different
concentrations and exposure times as well as for various tox-
ins applied. Further detail on each study is provided in the
sections that follow.
Alzheimer's disease
AD is the most common NDD, with an incidence of 5.3 million
in the United States (Alzheimer Association, 2015). It is
characterized by widespread, progressive degeneration
in the brain, particularly affecting cholinergic neurons, with
the pathological hallmark being amyloid-β and tau fibrillary
tangles (Braak et al., 1999).
Four studies investigated the antioxidant properties of
curcumin in cellular models of AD (Table 1). To induce fea-
tures of AD, 2 of these involved exposure to amyloid-β, 1
used nerve growth factor starvation and the fourth used
H2O2 exposure. The 1 study on toxic amyloid-β exposure
pre-treated primary rat hippocampal neurons with the curcu-
min metabolite, tetrahydrocurcumin (Mishra et al., 2011).
Tetrahydrocurcumin reduced ROS levels when compared
to the untreated and amyloid-β only treatment groups. The
authors suggested that the antioxidant effects of tetrahydro-
curcumin protected against apoptosis. Since exposure to
pesticides and environmental toxins has been implicated in
AD progression, Sarkar et al. (2017) investigated the anti-
oxidant effects of curcumin against toxic exposure to the pes-
ticide, monocrotophos, in human SH-SY5Y neuroblastoma
cells and amyloid-β exposure in human IMR-32 neuroblas-
toma cells. Curcumin pre-treatment reduced amyloid-β- and
monocrotophos-induced ROS production by 10% and 18%,
respectively. From immunofluorescence imaging, the authors
proposed that the antioxidant effect of curcumin was mediated
via the nuclear factor erythroid 2–related factor 2 (Nrf2) and
apurinic/apyrimidinic endonuclease 1 (APE1) pathways.
In another study, nerve growth factor (NGF) receptor was
overexpressed in rat PC12 pheochromocytoma cells and
pre-treated with a cocktail of polyphenols, including curcumin
(Amara et al., 2015). Subsequently, cells were exposed to
NGF-free media to elicit an AD phenotype. NGF is beneficial
for growth and maintenance of cholinergic neurons which
makes it an important therapeutic target for AD (Ruberti
et al., 2000). ROS levels were decreased in NGF-deprived
cells pre-treated with curcumin alone or with a cocktail of poly-
phenols, including curcumin (Amara et al., 2015). In another
study in which both mouse Neuro-2a neuroblastoma and
human HEK293 kidney cells were used, curcumin was given
as a pre-treatment followed by H2O2 exposure (Morales et al.,
2017). Curcumin protected against cell damage mediated by
oxidative stress in these cells.
Parkinson's disease
PD is caused by the loss of dopaminergic neurons in the sub-
stantia nigra which results in a variety of motor and non-motor
symptoms (Lees et al., 2009). The majority of PD cases have
an unknown cause, while approximately 5–10% of cases are
caused by genetic mutations within genes involved in various
processes including mitochondrial health (PRKN, PINK1,
LRRK2 and DJ1; Dodson and Guo, 2007).
 4
Table 1. Summary of the studies investigating the effect of curcumin in cellular models of neurodegenerative disorders.

Disease Cell model Toxin applied Curcumin treatment Assay/technique Main findings References
AD Primary rat hippocampal cells Amyloid-β Curcumin derivative, tetrahydro- DCHF-DA fluorescence assay Tetrahydrocurcumin, a curcumin (Mishra et al., 2011)
(n = 9) (concentration: 2 μM; curcumin (pre-treatment concen- metabolite, reduced ROS levels
duration: 20 h) tration: 5 μM; duration: 1.5 h) induced by amyloid-β toxicity.
AD PC12 cells Nerve growth factor starvation Free CurcuminA Flow cytometry with DCHF-DA Curcumin decreased ROS levels and (Amara et al., 2015)
(rat pheochromocytoma, n = 3) (nerve growth factor-free media; (pre-treatment: 1 and 10 μM; fluorescence assay also protected against reduced mito-

Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21

6 or 24 h) overnight) chondrial membrane potential and cell
death.
AD Neuro-2a H2O2 Free Curcumin Immunocytochemistry, confocal Curcumin protected against cell (Morales et al., 2017)
(mouse neuroblastoma, n = 2) (50 μM; 24 h) (pre-treatment: 5 and 15 μM; 24 h) microscopy morphological damage mediated by
and HEK293 cells (human H2O2-induced oxidative stress.
kidney, n = 2)
AD IMR-32 and SH-SY5Y cells Amyloid-β and organophosphate Free Curcumin Nitroblue tetrazolium (NBT) Curcumin reduced ROS production (Sarkar et al., 2017)
(human neuroblastoma, n = 3) pesticides, monocrotophos and (pre-treatment: 10 μM; 4 h) assay, western blotting, immuno- via regulating the colocalization of
hlorpyrifos fluorescence and confocal Nrf2 and APE1.
(10 μM; 24 or 48 h) microscopy
PD SK-N-SH cells Rotenone Curcumin derivative, CNB-001 DCHF-DA fluorescence assay The neuroprotective effects of the (Jayaraj and Tamilselvam,
(human neuroblastoma, n = 4) (100 nM; 24 h) (pre-treatment: 2 μM; 2 h) curcumin derivative, CNB-001, acted 2013)
via antioxidant pathways which
assisted in mitochondrial membrane
protection and antiapoptotic effects.
PD SH-SY5Y cells Rotenone Curcumin derivative, demethoxy- DCHF-DA fluorescence assay Demethoxycurcumin, a curcumin deri- (Ramkumar et al., 2017)
(n = 4) (100 nM; 24 h) curcumin (pre-treatment: 50 nM; vative, protected against rotenone
2 h) toxicity by decreasing ROS levels.
PD SH-SY5Y cells Paraquat Free Curcumin DCHF-DA fluorescence assay, Curcumin reduced ROS levels and (Jaroonwitchawan et al.,
(n = 3) (0.5 mM; 24 h) (pre-treatment: 5 μM; 24 h) RT-PCR increased expression of the anti- 2017)
oxidant genes, SOD and GPX.
PD Transfected SH-SY5Y cells Transfected wild type Free Curcumin DCHF-DA fluorescence assay Curcumin suppressed ROS produc- (Wang et al., 2010)
(n = 3) α-synuclein (using (48 h post-transfection: tion induced by both oligomeric and
α-synuclein/GFP fusion 4 μM; 24 h) intracellular α-synuclein
protein plasmid DNA) aggregates.
PD PC12 cells Induced mutant A53T Free Curcumin DCHF-DA fluorescence assay Curcumin reduced ROS levels and (Liu et al., 2011)
(n = 3) α-synuclein expression (co-treatment: 500 nM; protected cells against oxidative
(withdrawal of doxycycline 1–6 days) stress and cell death induced by
using tetracycline-off gene α-synuclein.
regulatory system)
PD N27 cells Buthionine sulfoximine toxin Free Curcumin and bioconjugates, LPO assay, DCHF-DA Curcumin and the bioconjugates (Harish et al., 2010)
(rat dopaminergic neurons, induced glutathione depletion curcumin D1, D2 and D3 fluorescence assay and protected against oxidative stress
n = not specified) (1.5 μM; 24 h) (pre- and post-treatments: 0.5 μM; in silicoB analyses (predictive by reducing lipid peroxidation, H2O2
24 h) GSH-depletion model) levels and ROS levels, and by also
increasing levels of GSH and GST.
 Disease Cell model Toxin applied Curcumin treatment Assay/technique Main findings
PD Primary rat mesencephalic MPP +
Free Curcumin DCHF-DA fluorescence and Curcumin reduced ROS production, (Yu et al., 2016)
astrocytes (800 μM; 48 h) (pre-treatment: 8 μM; 30 min) GSH assays TNF-α and IL-6 but increased GSH
(n = not specified) levels, thereby effectively reversing
the oxidative effects of MPP+.
PD PC12 cells MPP+ Free Curcumin Flow cytometry with DHR123 Curcumin attenuated nitric oxide (Chen et al., 2006)
(n = 5) (0.5 mmol/L; 12 or 24 h) (co-treatment: 20 μmol/L; fluorescence assay synthase and ROS levels, and may
12 or 24 h) act via the glutathione- and mito-
chondria-dependent nitric oxide-
ROS pathways.
PD PC12 cells MPP+ Free Curcumin and derivatives, DPPH and TEAC assays Curcumin and curcumin derivatives (Marchiani et al., 2013)
(n = not specified) (0.5 mM; 24 h), H2O2 (75 μM; dehydrozingerone, O-methyl protected against H2O2-induced toxi-
24 h) and MnCl2 (0.75 mM; derivative, zingerone, and city. Also, curcumin had a high activity
24 h) biphenyl analogues for scavenging free radicals, which
(pre-treatment: 40 μM; 20 min) was shown by the reduced DPPH
levels and increased TEAC activity

Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21

(cell-free).
PD N27 cells Peroxynitrate Free Curcumin Western blotting of nitrosative The peroxynitrate levels in the mito- (Mythri et al., 2011)
(n = 3) (750 μM; 24 h), MPP+ (pre-treatment: 0.5 μM; 24 h) stress related proteins and chondria were significantly reduced
(100 μM; 24 h) biochemicalC analysis by curcumin and curcumin D3 bio-
conjugate, thereby reducing nitrosa-
tive stress.
PD N27 cells Paraquat Free Curcumin Flow cytometry, western Curcumin increased ROS production; (Ortiz-Ortiz et al., 2009)
(n = 3) (250 μM; 24 h) (co-treatment: 0.001, 0.01, blotting, TaqMan gene and however, nitrosative stress (iNOS,
0.1 μM, 10 nM; 24 h) RNA expression assay nitrotyrosine) markers were reduced.
SMA Patient-derived dermal Loss of function mutation Free Curcumin DCHF-DA fluorescence assay, Curcumin inhibited oxidative stress, (Köstel et al., 2012)
fibroblast cells in SMN gene (only treatment: 20 μM; 24 h) RT-PCR of 84 antioxidant via reducing ROS production.
(n = not specified) response genes
MS OLN-93 LPS Free Curcumin WST assay, Griess assay, Curcumin did not protect OLN-93 (Van Meeteren et al., 2004)
(rat oligodendrocytes, (1 mg/mL; single dose), (co-treatment: 2.5–25 μg/ml; western blotting of iNOS protein cells against H2O2-induced oxidative
n = 4) and NR8383 cells H2O2 (10−5–10−2 M; 3 h) 48 h) damage and LPS-induced nitrosa-
(gerbil macrophages, n = 4) tive stress.
A53T: point-mutation resulting in alanine to threonine change at amino acid 53 of α-synuclein; AD: Alzheimer's disease; APE1: apurinic/apyrimidinic endonuclease; CAT: catalase; curcumin D1: di-piperoyl; curcumin D2: di-valinoyl; curcumin D3: di-glutamoyl;
DCHF-DA: dichlorodihydrofluorescein diacetate; DPPH: 2,2-diphenyl-1-picryl-hydrazyl-hydrate; GFP: green fluorescent protein; GPX: glutathione peroxidase; GSH: glutathione; GST: glutathione S-transferase; GSTD1: glutathione S-transferase D1; h: hours;
IL-6: interleukin-6; IMR-32: human brain neuroblastoma cells; iNOS: inducible nitrogen oxide synthase; i.p.: intraperitoneally; H2O2: hydrogen peroxide; HEK293: human kidney cells; LPO: malondialdehyde-thiobarbituric assay; LPS: lipopolysaccharide,
MDA: malondialdehyde; min: minutes; MnCl2: manganese chloride; MPP+: 1-methyl-4-phenylpyridinium; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MS: multiple sclerosis; MTH: methuselah; N27: rat dopaminergic neurons; Neuro-2a:
mouse neuroblastoma cells; NGF: nerve growth factor; NR8383: gerbil macrophages; Nrf2: nuclear factor erythroid 2–related factor 2; OLN-93: rat oligodendrocytes; PC12: rat pheochromocytoma cells; PD: Parkinson's disease; p.o.: per os/orally
ingested; ROS: reactive oxygen species; RT-PCR: real time polymerase chain reaction; s.c.: subcutaneous injection; SH-SY5Y and SK-N-SH: human bone marrow neuroblastoma cells; SMA: spinal muscular atrophy; SMN: survival of motor neuron;
SOD1/2: superoxide dismutase 1/2; TBARS: thiobarbituric acid-reactive substances; TEAC: trolox equivalent antioxidant capacity assay; TNF-α: tumor necrosis factor α; WST: cell proliferation assay.
A
The antioxidant cocktail mixture contained curcumin, resveratrol, quercetin, N-acetylcysteine, hydroxytyrosol and lycopene.
B
in silico: theoretically analyzing the antioxidant effects of structural changes in curcumin using biologically-derived mathematical and computational modelling (systems biology).
C
Biochemical: analyzing the antioxidant effects of curcumin using biochemical, cell-free experiments.

5

Table 2. Summary of the studies investigating the effect of curcumin in cellular models of oxidative stress.
Cell model
A172
(human glioma) and HA-sp cells
(human spinal cord-derived astro-
cytes, n = not specified)
PC12 cells
(rat pheochromocytoma, n = 3)
Primary astrocytes derived from
knock-out mouse model
(n = 3)
Neuro-2a cells
(mouse neuroblastoma, n = 3)
Transfected SH-SY5Y cells
(human neuroblastoma, n = 3)
N9 cells
(mouse microglia, n = not
specified)
Primary rat cortical neurons
(n = not specified)
Neuro-2a
(n = 2) and HEK293 cells (human
kidney, n = 2)
6
Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
Toxin applied Curcumin treatment Assay/technique Main findings References
H2O2 (concentration: Free Curcumin Western blotting and Curcumin protected cells against cytotoxic (Daverey and Agrawal,
50 μM; duration: 24 h) (pre- and post-treatment concentra- immunofluorescence effects of oxidative stress, including disrup- 2016)
tions:1 μM; duration: 24 h) tion of cytonemes and F-actin aggregates,
decreased GFAP, vimentin, and caspase 1.
H2O2 Free Curcumin DCHF-DA fluorescence assay Curcumin prevented DNA damage and (Fu et al., 2016)
(0.5 mM; 2 h) (pre-treatment: 50 and 100 μM; 12 h) oxidative stress via ROS inhibition and the
protective action of curcumin seemed to be
via the cell growth-death MAPK and Akt
pathways.
H2O2 Free Curcumin DCHF-DA fluorescence assay Curcumin inhibited oxidative stress via the (Jiang et al., 2011)
(200 μM; 30 min) (pre-treatment: 10 μM; 24 h) Nrf2/ARE pathway.
H2O2 Free Curcumin Flow cytometry with DCHF-DA Curcumin reduced intracellular ROS and pro- (Zhao et al., 2011)
(30 μM; 24 h) (pre-treatment: 20 μg/ml; 1 h) fluorescence assay tected cells against H2O2-induced damage.
Also, curcumin inhibited oxidative stress-
inducing IκBα degradation and NF-κB
nuclear translocation.
H2O2-induced TRPM2 Free Curcumin Rh-123 fluorescence assay Curcumin decreased ROS levels and thereby (Öz and Çelik, 2016)
activation (transfected (co-treatment: 5 μM; 24 h) inhibited oxidation via TRPM2 channels.
with TRPM2)
LPS Free Curcumin and curcumin deriva- Nitrite assay (absorbance), Curcumin and a curcumin derivative de- (Zhang et al., 2010)
(1 μg/ml; 48 h) tive, DMC DCHF-DA fluorescence assay creased levels of ROS, nitrite and iNOS via
(pre-treatment: 0.1–10 μM; 48 h) regulating the NF-κβ and MAPK pathways.
Cu(II) Free Curcumin DCHF-DA fluorescence and Curcumin reduced oxidative ROS and H2O2 (Huang et al., 2011)
(20 μM; 1 h) (pre-treatment: 1–20 μM; 23 or 24 h) hydrogen peroxide assays levels, and protected cell viability against Cu
(II)-induced oxidative damage.
Iron, Fe2+ Free Curcumin Immunocytochemistry, confocal Curcumin protected against cell morphologi- (Morales et al., 2017)
(80 μM; 24 h) (pre-treatment: 5 and 15 μM; 24 h) microscopy cal damage mediated by redox iron-induced
oxidative stress.
 Cell model Toxin applied Curcumin treatment Assay/technique Main findings
Primary rat cerebellar granule Iodoacetate Free Curcumin DCHF-DA fluorescence assay Curcumin reduced iodoacetate-induced ROS (Reyes-Fermin et al., 2012)
neurons (18 μM; 30 min) (pre-treatment: 10 μM; 24 h) levels and increased heme oxygenase
(n = 4) expression, thereby inhibiting oxidative stress.
HT22 cells Hypoxia Free Curcumin DCHF-DA fluorescence assay Curcumin reduced ROS levels and thereby (Chhunchha et al., 2013)
(mouse hippocampal, n = 3) (1% O2 and CoCl2: 100 (pre-treatment: 2 μM; 12 h) regulated cellular signaling through attenua-
and 200 μM; 24–72 h) tion of hypoxia-induced oxidative and endo-
plasmic reticulum stressors.
PC12 cells Glutamate Free Curcumin DCHF-DA fluorescence assay Curcumin reduced release of Ca 2+ influx, (Chang et al., 2014)
(n = 6) (0–20 mM; 24–48 h) (pre-treatment: 5 μM; 48 h) and GSH and ROS levels which led to
reduced cell death.
Primary rat cerebellar granule Glutamate Curcumin derivative, J147 DCHF-DA, HFP, DAF-FM DA, The curcumin derivative, J147, protected (Chen et al., 2015)
and cortical neurons (75 μM; 2–24 h) (pre-treatment: 1–10 μM; 24 h) and DHR123 fluorescence against elevated levels of ROS and RNS
(n = not specified), and PC12 assays (H2O2, hydroxyl radical, nitric oxide, and
cells (n = not specified) peroxynitrite). J147 inhibited oxidative
stress induced by glutamate and t-BHP.

Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21

Primary rat cortical neurons and NMDA Free Curcumin RT-PCR of the iNOS gene Curcumin suppressed iNOS expression in (Lin et al., 2011)
astrocytes (n = 3) (50 μM; 30 min) (pre-treatment: 1 μM; 1 h) astrocytes under non-stressed conditions.
C6 cells none Free Curcumin Affymetrix Rat GeneChip Curcumin upregulated expression of genes (Panchal et al., 2008)
(rat glioma, n = 2) (only treatment: 5 μM; 0–48 h) expression array involved in the antioxidant response, including
the ALAS1, AKR1B8, AKR1B4, AOX1,
G6PD, GGT1, GSTA5, GSTP1, HMOX1,
MGST1, NQO1 genes.
A172: human glioma cells; Akt: serine/threonine protein kinase B; AKR1B4: aldo-keto reductase family 1, member B4; AKR1B8: aldo-keto reductase family 1, member B8; ALAS1: 5′-aminolevulinate synthase 1; AOX1: aldehyde oxidase 1;
ARE: antioxidant responsive element; C6: rat glioma cells; Ca2+: calcium; CoCl2: cobalt chloride; Cu(II): copper(II); DCHF-DA: dichlorodihydrofluorescein diacetate; DAF-FM DA: 4-Amino-5-methylamino-2′,7′-difluorofluorescein diacetate; DHR123:
dihydrorhodamine 123; DMC: demethoxycurcumin; G6PD: glucose-6-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GGT1: gamma-glutamyltransferase 1; GSH: glutathione; GSTA5: glutathione S-transferase alpha 5; GSTP1:
glutathione S-transferase pi 1; h: hours; IκBα: inhibitors-of-kappaB; iNOS: inducible nitrogen oxide synthase; H2O2: hydrogen peroxide; HA-sp: human spinal cord-derived astrocytes; HEK293: human kidney cells; HFP: hydroxyl radical and peroxynitrite
sensor; HMOX1: heme oxygenase 1; HT22: mouse hippocampal cells; LPS: lipopolysaccharide; MAPK: mitogen-activated protein kinases; MGST1: microsomal glutathione S-transferase 1; min: minutes; N9: mouse microglia; Neuro-2a: mouse
neuroblastoma cells; NF-κB: nuclear-factor κB; NMDA: N-methyl-D-aspartate; NQO1: NAD(P)H quinone dehydrogenase 1; Nrf2: nuclear-factor -E2-related factor 2; PC12: rat pheochromocytoma cells; Rh-123: rhodamine 123; ROS: reactive oxygen
species; RNS: reactive nitrogen species; RT-PCR: real time polymerase chain reaction; SH-SY5Y: human bone marrow neuroblastoma cells; t-BHP: tert-Butyl hydroperoxide; TRPM2: transient receptor potential cation subfamily M, member 2,
channel.

7

Table 3. Summary of the studies investigating the effect of curcumin in animal models for neurodegenerative disorders.
Disease Animal model
AD Transgenic male and female mice
(n = 28; age: 10 months; low and high
dose curcumin, untreated transgenic,
and untreated non-transgenic groups)
AD Sprague–Dawley female rats
(n = 20; age: 9-month-old ‘middle-aged’
and 19-month-old ‘aged’ rats; middle-
aged: low-dose curcumin, and control
groups; aged: high-dose curcumin, con-
trol, and ibuprofen groups)
AD Transgenic C57BL6/J male and female
mice
(n = 5–11; age: 3–4 months; 5 groups:
acute and chronic treatment of curcumin
and tetrahydrocurcumin in both trans-
genic, and non-transgenic groups)
AD Transgenic C57BL6 × SJL F1 male and
female mice
(n = 4; age: 10 months; non-transgenic
untreated, transgenic untreated, and
transgenic and curcumin-treated groups)
AD Transgenic Sprague–Dawley male rats
(n = 24; age: 3 months; transgenic
untreated, non-transgenic untreated,
transgenic and curcumin-treated, and
non-transgenic and curcumin-treated
groups)
AD Wistar male and female rats
(n = 64; age: 1 month; untreated,
vehicle control, AlCl3-treated, curcumin
control, and various curcuminoid-treat-
ment groups)
PD Wistar albino male rats
(n = 40; age: not specified; sham control, (10 μg/2 μL, single injection
lesion control, lesion and curcumin- in striatum)
treated, lesion and demethoxycurcumin-
treated, and lesion and bisdemethoxycur-
cumin-treated groups)
PD C57BL/6 male mice MPTP
(n = 24; age: adult; vehicle control, (30 mg/kg; 4 days)
MPTP only, CNB-001 only, and CNB-
001- and MPTP-treated groups)
Toxin applied
Tg2576 APPSw transgenic
(overexpressing a mutant form
of human APP: K670 M/N671 L)
Aβ40 and Aβ42
(intraventricular injection, Aβ42:
0.2 μg, 1 μg, Aβ40: 0.7 μg;
1–3 months)
Tg2576 APPsw transgenic
(overexpressing a mutant form
of human APP: K670M/N671L)
and LPS-injection (100 nM; 24 h)
Tg2576 APP transgenic
(overexpressing a mutant form
of human APP: K670M/N671L)
Tg2576 APP transgenic
(overexpressing a mutant form
of human APP: K670M/N671L)
AlCl3
(17 mg/kg; 15 days)
6-OHDA
Curcumin treatment
Free Curcumin
(post-transfection concentration: 160
and 5000 ppm; duration: 6 months)
Free Curcumin
(pre-treatment: 500 and 2000 ppm; kit (ELISA)
2 months)
Free Curcumin and derivative,
tetrahydrocurcumin
(post-transfection: 0.2–0.4 μmol or
1.25 mg/day; 2 days or 4 months,
for LPS-injection; pre-treatment:
2.5 μM; 1 h)
Free Curcumin
(post-transfection: 500 ppm;
6 months)
Curcumin derivative, J147
(post-transfection: 200 ppm;
5 months)
Curcumin derivative,
CUR-CA-THIONE
(post-treatment: 500 mg/kg;
15 days)
Free Curcumin and curcumin
derivatives, demethoxycurcumin
and bisdemethoxycurcumin
(pre-treatment: 60 mg/kg orally;
3 weeks)
Curcumin derivative, CNB-001
(pre-treatment: 4 mg/kg; 1 h)
8
Assay/technique Main findings References
Oxyblot kit (DNPH) Low and high-dose curcumin reduced (Lim et al.,
levels of oxidized protein carbonyls. 2001)
8EPI-F2 immunoassay Curcumin protected against fatty acid (Frautschy
oxidation by reducing isoprostane et al., 2001)
levels (marker of lipid peroxidation).
LC/tandem mass Curcumin decreased protein nitrotyro- (Begum et al.,
spectrometry (MS/MS) sines and carbonyls, and isoprostanes. 2008)
Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
Immunohistochemistry Curcumin suppressed lipid peroxida- (Seo et al.,
(HNE staining) tion in the spinal cord of APP trans- 2010)
genic mice and rescued motor
function deficits.
Immunohistochemistry Curcumin derivative, J147, prevented (Chen et al.,
(HNE staining), the increase in HO-1 levels in the 2011)
spectrophotometry hippocampus.
(MDA levels)
DTNB absorbance and Curcumin derivative, CUR-CA- (Shelat and
TBA assays THIONE suppressed the increase Acharya, 2016)
in MDA levels, inhibiting lipid
peroxidation, and increased GSH
and CAT levels. CUR-CA-THIONE
also improved exploratory behavior
and locomotor function.
TBARS assay (lipid peroxi- Curcumin, demethoxycurcumin and (Agrawal et al.,
dation), spectrophotometer bisdemethoxycurcumin suppressed 2012)
(enzymatic activity) the 6-OHDA-induced decrease in
GSH, GPx, GR, SOD and CAT
levels; as well as decreasing lipid
peroxidation. Curcuminoids also
improved motor function.
TBARS assay, absorbance CNB-001, the curcumin derivative, (Jayaraj et al.,
(GSH and GPx), nitro blue inhibited oxidative stress by decreas- 2014)
tetrazolium absorbance ing MDA, SOD and CAT levels while
(SOD activity), H2O2 increasing GSH and GPx levels.
decomposition levels CNB-001 also improved locomotive
(CAT activity) and exploratory behavior
 Disease Animal model Toxin applied Curcumin treatment Assay/technique Main findings
PD Lewis male rats Rotenone Free Curcumin DCHF-DA fluorescence
Curcumin suppressed the rotenone- (Cui et al.,
(n = 24; age: 7–8 weeks; vehicle con- (1 ml/kg/day, 2 injections (pre- and co-treatment: 100 mg/kg, mediated oxidative stress possible
assay, TBARS assay (lipid 2016)
trol, rotenone only, rotenone and curcu- subcutaneously; 50 days) 2 injections intragastrically; via the Akt/Nrf2 signaling pathway.
peroxidation), spectrophot-
min-treated, and curcumin only groups) 50 days) Curcumin treatment regulated rota-
ometer (enzymatic activity)
tional behavior, and speed, time
and distance of movement were
improved.
PD Swiss albino male mice Rotenone Free Curcumin Greiss assay, Pyrogallol Curcumin increased GSH, SOD and (Khatri and
(n = 30; age: not specified; vehicle con- (1 mg/kg, 1 injection intraperitoneally; (pre- and co-treatment: 50, 100 and auto-oxidation assay, GSH CAT levels but decreased nitrite and Juvekar, 2016)
trol, rotenone only, rotenone and curcu- 21 days) 200 mg/kg orally; 1 h and 21 days) assay, spectrophotometry MDA levels; thereby inhibiting oxida-
min treated (50 mg/kg), rotenone and (MDA levels) tive stress. Curcumin also attenu-
curcumin treated (100 mg/kg), and rote- ated loss of locomotor function.
none and curcumin treated (200 mg/kg)
groups
PD Drosophila melanogaster male flies Paraquat Free Curcumin RT-PCR of oxidative Curcumin did not change the mRNA (Park et al.,

Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21

(n = 18; age: 2–3 days; control, para- (20 mM, soaked filter paper; 48 h) (pre-treatment: 0.02% solution on stress-related genes levels of SOD1, SOD2, CAT, 2012)
quat only, curcumin- and paraquat-trea- filter paper; 48 h pre-fed after GSTD1 and mth. Curcumin also alle-
ted, quercetin- and paraquat-treated 4 h starvation) viated locomotor dysfunction.
group, S. officinalis extracts and para-
quat-treated, and Z. rhizoma extracts
and paraquat-treated groups)
PD LRRK2-transgenic Drosophila melano- H2O2 Free Curcumin OxyBlot protein oxidation kit Curcumin reduced the levels of oxi- (Yang et al.,
gaster flies (0.1%; 2 weeks in feed), transgenic (co-treatment: 1 mM in feed; dized proteins and also improved 2012)
(gender: not specified; n = 30; age: not LRRK2 (UAS-LRRK2–1, 2 weeks) locomotor defects.
specified; DMSO control, H2O2 only, UAS-G2019S-2)
H2O2- and curcumin-treated, H2O2-
and LRRK2 inhibitor treated, curcumin
only, and LRRK2 inhibitor groups)
HD Wistar female rats 3-NP Encapsulated Curcumin, C-SLN TBA, DCHF-DA, dinitro- Curcumin nanoparticle, C-SLN, pro- (Sandhir et al.,
(n = 20; age: not specified; vehicle con- (20 mg/kg; 3 days) (post-treatment: 40 mg/kg daily; phenylhydrazone, fluoro- tected against oxidative stress due 2014)
trol, C-SLN-only, 3-NP only, and 3-NP 7 days) metric and hydroxylamine to the activation of the regulatory
and C-SLN-treated groups) autoxidation assays Nrf2 pathway. C-SLN also amelio-
rated neuromotor deficits.
SMA Transgenic AR97Q male mice Tg2576 APP transgenic Curcumin derivative, ASC-JM17 RT-PCR of Nrf1, Nrf2 and The curcumin derivative, ASC-JM17, (Bott et al.,
(n = not specified; age: 16 weeks; (overexpressing a mutant form (post-transfection:120 mg/kg; proteasome-encoding activated expression of both Nrf1 2016)
vehicle control, and transgenic and of human APP: K670 M/N671 L) 6 weeks) genes and Nrf2 which led to increased
ASC-JM17-treated groups) expression of downstream genes
coding for proteasome subunits.
ASC-JM17 also increased motor
function.
3-NP: 3-nitropropionic acid; 6-OHDA: 6-hydroxydopamine; Aβ40 or Aβ42: 40- or 42-amino acid amyloid-β peptide; Akt: serine/threonine protein kinase B; AlCl3: aluminum chloride; AD: Alzheimer's disease; APP: amyloid precursor protein; CAT:
catalase; DCHF-DA: dichlorodihydrofluorescein diacetate; DMSO: dimethyl sulfoxide; DNPH: 2,4-dinitrophenylhydrazine; DTNB: 5,5-dithio-bis-(2-nitrobenzoic acid) or Ellman's reagent; ELISA: enzyme-linked immunosorbent assay; GPx: glutathione
peroxidase; GR: glutathione reductase; GSH: glutathione; GSTD1: glutathione S-transferase D1; h: hours; H2O2: hydrogen peroxide; HD: Huntington's disease; HNE: 4-hydroxy-2-nonenal; HO-1: heme oxygenase 1; LC: liquid chromatography; LPS:
lipopolysaccharide; LRRK2: leucine-rich repeat kinase 2; MDA: malondialdehyde; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MS/MS: tandem mass spectrometry; mth: methuselah; Nrf1/2: nuclear factor-E2-related factor 1/2; PD: Parkinson's
disease; Plp1: proteolipid protein 1; ppm: parts per million; RT-PCR: real time polymerase chain reaction; SMA: spinal muscular atrophy; SOD: superoxide dismutase; SOD1/2: superoxide dismutase 1/2; TBA: thiobarbituric acid; TBARS: thiobarbituric
acid-reactive substances.

9

Table 4. Summary of the studies investigating the effect of curcumin in animal models of oxidative stress, dementia and aging.
Phenotype Animal model
Oxidative Swiss Albino male mice
stress (n = not specified; age: 6 weeks; 9
groups: vehicle control, and various
concentrations of curcumin and
Theracumin®)
Oxidative Swiss Albino male mice
stress (n = 48; age: not specified; 8 groups:
untreated, and various concentra-
tions of LPS and curcumin)
Oxidative Sprague–Dawley rats
stress (gender: not specified; n = 40; age:
not specified; control, aluminum
only, aluminum and curcumin, and
curcumin only groups)
Oxidative Wistar male rats
stress (n = 40; age: 8 weeks; control, lead
acetate only, lead acetate and curcu-
min, lead acetate and training, and
lead acetate, training and curcumin
groups)
Oxidative Wistar male rats
stress (n = not specified; age: 6 months; 6
groups: untreated and dopamine-
treated groups at 3 different
concentrations)
Oxidative Swiss Albino male mice
stress (n = 28; age: 4 weeks; control, kainic
acid, curcumin and kainic acid, and
curcumin only groups)
Oxidative Wistar male rats
stress (n = 56; age: 9–10 weeks; vehicle
control, curcumin and kainic acid
treated, and curcuminoids and kainic
acid treated groups)
Oxidative Wistar female rats
stress (n = 40; age: not specified; control,
parathion only, curcumin and para-
thion, and curcumin only groups)
10
Toxin applied Curcumin treatment Assay/technique Main findings References
Sodium nitroprusside Free Curcumin and encapsulated No oxidative assay used (only Theracumin protected against (Nazari et al.,
(concentration: 10 nmol; dura- curcumin, Theracumin® indirect measure) motor dysfunction and neuronal 2014)
tion: 24 h) (pre-treatment concentration: loss.
Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
100–200 mg/kg; duration: 24 h)
LPS Free Curcumin TBARS and Griess assays Curcumin dose-dependently pre- (Jangra et al.,
(0.83 mg/kg; 3 h) (pre-treatment: 100, 200, 400 mg/kg, vented the increase in MDA and 2016)
orally ingested; 7 days) nitrates, and protected against
the reduction in GSH.
Aluminum Free Curcumin DTNB spectrophotometry Curcumin prevented depletion of (Sood et al.,
(100 mg/kg; 8 weeks) (co-treatment: 50 mg/kg, GSH levels in the cerebral cortex, 2011)
intraperitoneal injection; 8 weeks) midbrain and cerebellum.
Lead acetate Free Curcumin Thiobarbituric acid, serum TAC Curcumin inhibited lipid peroxida- (Hosseinzadeh
(20 mg/kg; 8 weeks) (co-treatment: 30 mg/kg; 8 weeks) (hydroxyl radical) assays tion as indicated by reduced MDA et al., 2013)
levels, while also increasing the
total antioxidant capacity in plasma.
Dopamine Free Curcumin Western blotting of AP-1 Curcumin protected against pro- (Luo et al.,
(2 μmol; 24 h) (pre-treatment: 1–10 μmol; 24 h) longed activation of AP-1 and 1999)
thereby inhibited oxidative stress
in the striatum.
Kainic acid Free Curcumin Immunohistochemistry Curcumin reduced the number (Shin et al.,
(30 mg/kg; 48 h) (pre-treatment: 200 mg/kg; 24 h) of HO-1 positive cells in the 2007)
hippocampus.
Kainic acid Free Curcumin and curcuminoids, Western blotting of nitrosative Curcuminoids prevented the (Sumanont
(10 mg/kg) diacetylcurcumin and manganese stress-related protein, increase of nitric oxide levels and et al., 2007)
(pre-treatment: 50 mg/kg; 24 h) immunohistochemistry mRNA expression of the iNOS
gene.
Parathion Free Curcumin Colorimetric assay Curcumin suppressed MDA (Canales-Aguirre
(inhalation; 2 months) (pre-treatment: 200 mg/kg; levels in hippocampus. et al., 2012)
2 months)
 Phenotype
Oxidative Swiss Albino male mice
stress (n = 28; age: 1.5 months; control
and 3 experimental groups)
Oxidative Male rats
stress (type: not specified; n = 60; age:
8 weeks; untreated, nicotine treated,
and nicotine and curcumin treated
groups)
Oxidative White New Zealand male rabbits
stress (n = 16; age: not specified; control,
high fat diet, simvastatin treated
and high fat diet, and curcumin trea-
ted and high fat diet groups)
Dementia Wistar male rats
(n = 40; age: 1 year; sham-oper-
ated, vehicle-treated control, sham-
operated and curcumin-treated,
ICV-STZ-infused and vehicle-treated
lesioned, and ICV-STZ-infused and
curcumin- treated groups)
Dementia Wistar male rats
(n = 32; age: adult; untreated, ery-
thropoietin treated, curcumin treated,
and both erythropoietin and curcu-
min-treated groups)
Dementia Sprague Dawley male rats
(n = 40; age: adult; 8 groups:
untreated and various combinations
of curcumin and STZ groups)
aging Laca male mice
(n = 72; age: 2–3 months; vehicle,
D-galactose, low dose curcumin and
D-galactose, high dose curcumin and
D-galactose, and curcumin groups)
aging Wistar rats
(gender: not specified; n = 42; age:
16 weeks and 20 months; 7 groups:
vehicle controls, various concentra-
tions and combinations of curcumin
and piperine)
Animal model Toxin applied Curcumin treatment Assay/technique Main findings
Fluoride Free Curcumin Trichloroacetic acid (TCA) assay:
Curcumin protected against the (Sharma et al.,
(120 ppm; 30 days) (co-treatment: 30 mg/kg b.w.; 15% w/v thiobarbituric acid increase in MDA in the 2014)
30 days) (TBA), 0.375% hydrochloric acid hippocampus.
Nicotine Free Curcumin Thiobarbituric acid assay, absor-
Curcumin dose-dependently (Motaghinejad
(6 mg/kg/day, subcutaneous (co-treatment: 10, 20, 40 and 60 mg/ bance, NADPH assay decreased MDA, increased et al., 2017)
injection; 21 days) kg, intraperitoneal injection; 21 days) GSH, decreased GSSG, and
increased SOD, GPx and GR
enzyme activities. Curcumin
also prevented behavioral
defects.
High fat dietA Free Curcumin Griess assay, LDH kit, spectro- Curcumin increased SOD activity (Manogaran
(co-treatment: 80 mg/kg; 16 weeks) photometry (NBT) and prevented lipid peroxidation et al., 2015)
Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
Streptozotocin Free Curcumin Colorimetric assay, spectrophoto- Curcumin inhibited lipid peroxida- (Ishrat et al.,
(1.5 mg/kg b.w.; incubation: (post-treatment: 80 mg/kg; 3 weeks) metry (trichloroacetic acid) tion and stimulated GSH-linked 2009)
single dose) antioxidant activity, and led to
the inhibition of STZ-induced cog-
nitive decline in the hippocampus
and cerebral cortex.
Streptozotocin Free Curcumin Colorimetric assay Curcumin suppressed the increase (Samy et al.,
(3 mg/kg; single dose) (post-treatment: 80 mg/kg/day; in MDA and depletion of GSH, 2016)
3 months) thereby inhibiting lipid peroxidation
and promoting antioxidant activity.
Streptozotocin Free Curcumin ELISA assay (tetra-ethoxy pro- Curcumin prevented the increase (Agrawal et al.,
(3 mg/kg; 14 days) (pre- and post-treatment: pane for MDA; 2-nitro-benzoic in MDA and the decrease in GSH 2010)
200 mg/kg; 1 h) acid for GSH) in the hippocampus and cortex.
D-galactose Free Curcumin Thiobarbituric acid, Griess assays, Curcumin prevented the increase (Kumar et al.,
(100 mg/kg; 6 weeks) (co-treatment: 15 and 30 mg/kg, DTNB spectrophotometry in MDA and nitrites. Curcumin also 2011)
orally ingested; 6 weeks) protected against the reduction of
GSH levels, as well as SOD, GST
and CAT enzyme activities.
D-galactose Free Curcumin DNPH spectrophotometry, FRAP Curcumin increased the total anti- (Banji et al.,
(150 mg/kg; 56 days) (pre- and co-treatment: 20 and assay oxidant capacity and inhibited 2013)
40 mg/kg; 60 days) and piperine protein oxidation. Curcumin also
(pre- and co-treatment: 7.5 and protected against motor
15 mg/kg; 60 days) dysfunction.
(continued on next page)
11
 12
Table 4 (continued)
Phenotype Animal model Toxin applied Curcumin treatment Assay/technique Main findings References
aging Wistar rats D-galactose Free Curcumin DTNB spectrophotometry, Curcumin inhibited MDA, carbo- (Banji et al.,
(gender: not specified; n = 42; age: (150 mg/kg; 56 days) (pre- and co-treatment: 50 and thiobarbituric acid assay nyls and advanced oxidation pro- 2014)
16 weeks; 6 groups: vehicle con- 100 mg/kg; 63 days) and hesperidin tein products in the hippocampus.

Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21

trols, various concentrations and (pre- and co-treatment: 10 and
combinations of curcumin and 25 mg/kg; 63 days)
hesperidin)
aging Kunming mice D-galactose Free Curcumin TBA assay Curcumin prevented the decrease (Fu et al., 2017)
(gender: not specified; n = 4; age: (conditions not specified) (pre-treatment: 10 and 150 mg/kg; in GPx, SOD and CAT enzyme
not specified; vehicle control group, 7 weeks) activities, and increase in MDA
D-galactose only group, curcumin levels when compared to the
only, and D-galactose and curcumin D-galactose group.
groups)
aging SAMP8 and SAMR1 male mice SAMP8 and SAMR1 strains Free Curcumin TBARS assay, SOD commercial Curcumin reduced MDA levels (Sun et al.,
(n = 88; age: 6 months; SAMR1 (senescence-accelerated-resis- (post-transfection: 20 and kits and increased SOD activity in 2013)
untreated, SAMP8 untreated, and tant strain mice) 50 mg/kg b.w.; 25 days) the hippocampus.
SAMP8 mice and curcumin treated
groups)
aging Wistar Albino female rats None Free Curcumin Western blotting of nitrosative Curcuminoids down-regulated (Rastogi et al.,
(n = 24; age: 2–3 months and (only treatment: 100 mg/kg; stress-related proteins neuronal NOS in mitochondria. 2014)
24–25 months; young control, aging 3 months)
control, curcuminoid-treated young,
and curcuminoid-treated aging
groups)
AP-1: activated protein 1; b.w.: body weight; CAT: catalase; DTNB: 5,5-dithio-bis-(2-nitrobenzoic acid) or Ellman's reagent; ELISA: enzyme-linked immunosorbent assay; FRAP: ferric reducing antioxidant power; GSH: glutathione; GST:
glutathione S-transferase; h: hours; ICV-STZ: intracerebroventricular–streptozotocin; iNOS: inducible nitrogen oxide synthase; HO-1: heme oxygenase 1; LPS: lipopolysaccharide; MDA: malondialdehyde; ppm: parts per million; SAMP8:
senescence accelerated mouse-prone 8; SAMR1: senescence-resistant 1 mice; SOD: superoxide dismutase; TAC: total antioxidant capacity; TBA: thiobarbituric acid; TBARS: thiobarbituric acid-reactive substances; TCA: trichloroacetic
acid assay; w/v: percent weight/volume; w/w: percent mass.
A
bengal gram (30% w/w), sucrose (25% w/w), whole milk powder (16% w/w), yeast (1% w/w), hydrogenated groundnut oil (10% w/w), cholesterol (5% w/w), sodium chloride (5% w/w), shark liver oil (2% w/v) and egg yolk powder (7% w/w).
 Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
Eleven studies used toxin-treated or transfected cellular mod-
els of PD to investigate the therapeutic effect of curcumin
against oxidative stress (Table 1). In 2 studies, SH-SY5Y
and SK-N-SH neuroblastoma cells were pre-treated with curcu-
min derivatives and thereafter exposed to rotenone, an estab-
lished model for PD (Jayaraj and Tamilselvam, 2013;
Ramkumar et al., 2017). In both studies, the authors con-
cluded that rotenone-induced oxidative stress was sup-
pressed by the curcumin derivatives, and thereby apoptosis
was reduced. Another study pre-treated SH-SY5Y cells with
curcumin followed by paraquat exposure to mimic neuronal
damage observed in NDDs (Jaroonwitchawan et al., 2017).
Curcumin reduced ROS levels in paraquat-exposed cells
and increased expression of the antioxidant genes, SOD
and GPx. In two additional studies, SH-SY5Y and PC12 cells
were transfected with mutant α-synuclein and cells were incu-
bated post-transfection with curcumin (Wang et al., 2010; Liu
et al., 2011). Both studies found that curcumin attenuated
α-synuclein-mediated ROS production. However, it should
be noted that curcumin had no effect on ROS when the cells
were not induced with mutant α-synuclein, which might indi-
cate that the protective properties of curcumin may only occur
in response to an oxidative stressor.
One study exposed N27 neuronal cells to buthionine
sulfoximine to inhibit GSH, proposed as an early trigger of
oxidative stress in PD (Harish et al., 2010). Cells were treated
with curcumin and 3 bioconjugates before and after exposure
to buthionine sulfoximine. Curcumin and its bioconjugates were
shown to reduce levels of ROS, MDA and H2O2 while only
curcumin, additionally, increased GSH and glutathione
S-transferase (GST) protein levels. It should also be noted
from the study's findings that the structural alterations of the cur-
cumin bioconjugates affected its protective ability.
Four studies used MPP + (1-methyl-4-phenylpyridinium)
treatment as a cellular model of PD. In one, primary rat astro-
cytes were pre-treated with curcumin and subsequently ex-
posed to the toxin (Yu et al., 2016). Curcumin reduced the
protein levels of ROS, TNF-α and IL-6 while restoring GSH
levels and thereby inhibited oxidative stress. Curcumin also
reduced TLR4, MyD88 and TRIF protein levels, therefore impli-
cating the TLR4 immune response pathway in the curcumin-
mediated antioxidant response. In a further study, in which
PC12 cells were co-treated with both curcumin and MPP +, it
was found that curcumin reduced MPP +-mediated ROS
levels, resulting in the prevention of apoptosis and mitochon-
drial membrane instability (Chen et al., 2006). Curcumin was
also shown to reduce iNOS levels and thereby prevent the
toxic overexpression of RNS. Pre-treatment of curcumin
improved cell viability in the MPP +- and H2O2-mediated
PC12 cell models of PD (Marchiani et al., 2013). Although
free radical levels were not assessed in PC12 cells, the
cell-free experiments in this study showed that curcumin
and its derivatives had a high affinity for scavenging free radi-
cals. In another study, N27 cells underwent a curcumin pre-
treatment followed by MPP + exposure (Mythri et al., 2011).
Although curcumin improved cell viability, no nitrosative
stress markers were investigated. Additionally, cell-free
experiments of isolated mitochondria showed that curcumin
and a curcumin derivative reduced peroxynitrate levels
13
(Mythri et al., 2011), therefore providing indirect support for
the anti-nitrosative stress effect of curcumin.
Notably, in contrast to the other studies on cellular models
of PD, Ortiz-Ortiz et al. (2009) showed that curcumin
increased ROS production in paraquat-exposed N27 cells.
Although curcumin did not reduce cell viability, curcumin
pre-treatment increased levels of markers of apoptosis.
However, the vehicle control for curcumin was not tested in
this study, possibly explaining these conflicting results.
Ortiz-Ortiz et al. (2009) also showed that curcumin protected
against the degradation of Iĸβ, prevented the translocation
of NFĸ-β, and thereby suppressed nitrosative stress in
paraquat-treated N27 cells. The authors implied that curcumin
may act via the NFĸ-β signaling pathway to protect against
nitrosative stress.
Spinal muscular atrophy
SMA is an autosomal recessive disorder, related to NDDs,
with mutations or deletions in the survival of motor neuron
(SMN) gene. Lack of the SMN protein causes degeneration
and results in clinical evidence of anterior horn cell dysfunc-
tion (Lunn and Wang, 2008). Although SMA pathogenesis
has been linked to dysfunctional SMN protein processing,
oxidative damage has also been proposed as a possible
mechanism underlying SMA pathology.
Currently, there is only 1 study in which the antioxidant
properties of curcumin were studied in a cellular model of
SMA (Table 1). Köstel et al. (2012) showed that curcumin
protected SMA patient-derived fibroblasts against oxidative
stress by reducing ROS levels. Interestingly, curcumin
increased ROS in fibroblasts from both healthy controls and
SMA carriers. The authors proposed that the basal oxidative
stress levels are lower in the controls and SMA carriers, com-
pared to SMA patients, and therefore curcumin was believed
to act as a pro-oxidant in the controls and carriers. However,
the antioxidants vitamin E and N-acetylcysteine, which were
also investigated in this study, decreased ROS in both
controls and carriers regardless of the basal ROS levels.
Multiple sclerosis
MS is a disorder in which there are features of progressive
neurological dysfunction, in which the immune system
damages the myelin sheath in the brain and spinal cord
(Benn et al., 2001). MS affects several cells with myelin-
producing oligodendrocytes being the major affected cell
type. Oligodendrocytes are vulnerable to oxidative stress
and produce RNS, which in turn affects demyelination of
neurons.
Only 1 study has investigated the antioxidant effects of curcu-
min in MS (Table 1). The authors investigated the effects of
several dietary compounds, including curcumin, on H2O2-
exposed oligodendrocytes (OLN-93) and lipopolysaccharide
(LPS)-exposed macrophages (Van Meeteren et al., 2004).
Notably, curcumin did not protect against H2O2-induced
oxidative damage and LPS-induced nitrosative stress in
these cells. The authors speculated that the poor efficacy of
curcumin observed in their study, compared to other studies,
could be due to the differences in cell lines, macrophage
stimulation and the source of curcumin used.
14 Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
Antioxidant effects of curcumin in models of
oxidative/nitrosative stress
We identified 14 studies which investigated the effect of
curcumin in cellular models of oxidative stress, which
were linked to neurodegeneration in general and not a
specific type of NDD (Table 2). No studies, to date, have
been performed on models of nitrosative stress. More details
on each study are provided below but in summary, all of the
studies showed significant antioxidant effects of curcumin.
Curcumin treatment was mainly administered prior to the
toxin exposure (pre-treatment), with a wide range of toxins
and various human and animal cell lines (both primary and
immortalized) were used. Again, this indicates that curcu-
min's therapeutic properties are observed at various concen-
trations of different toxins and acting on a wide range of
cell types.
Hydrogen peroxide-induced model
To date, 5 studies have used H2O2 exposure as a model. In
1 study, glioblastoma A172 and primary spinal cord HA-sp
astrocytic cells were both pre- and post-treated with curcumin
(Daverey and Agrawal, 2016), with the finding that curcumin
treatment protected cells against oxidative stress, including
the disruption of cytonemes and F-actin aggregates.
The neurodegenerative astrocyte activation was inhibited
in curcumin-treated cells. Moreover, curcumin prevented
alterations in mitochondrial morphology following oxidative
stress. Another study pre-treated PC12 cells with curcumin,
which was then followed by H2O2 exposure (Fu et al.,
2016), with results demonstrating that curcumin improved cell
viability and prevented DNA damage and apoptosis. Further-
more, the authors showed that the protective action of curcu-
min acted via the cell growth-death MAPK (mitogen-activated
protein kinases) and Akt (serine/threonine protein kinase)
pathways. Jiang et al. (2011) pre-treated astrocytes with cur-
cumin before H2O2 exposure. The astrocytes were obtained
from mice with (Nrf2 +/+) and without the antioxidant-inducer
Nrf2 (Nrf2 −/−). Curcumin reduced ROS production in Nrf2 +/+
astrocytes but not in Nrf2 −/−. Additionally, curcumin increased
expression of the antioxidant genes and proteins, heme
oxygenase 1 (HO-1), glutamate cysteine ligase (GCL) and
quinine oxidoreductase 1 (NQO1), but only in Nrf2 +/+ cells.
However, it should be noted that only the findings between
curcumin-treated and untreated groups were statistically sig-
nificant which constrain the interpretation of the results. In a
Neuro-2A cell model, cells were pre-treated with curcumin
followed by H2O2 exposure (Zhao et al., 2011). Curcumin
reduced ROS and calcium, and inhibited the IκBα degrada-
tion and NF-κB nuclear translocation from the cytosol. Finally,
1 study (Öz and Çelik, 2016) transfected SH-SY5Y cells with
transient receptor potential melastatin-like 2 (TRPM2) chan-
nel protein, and subsequently treated with curcumin and
H2O2. Curcumin inhibited the H2O2-induced activation of
TRPM2, and reduced TRPM2 protein levels. Curcumin also
decreased ROS levels in transfected cells (vs. untreated
transfected) and non-transfected cells (vs. untreated non-
transfected). The authors concluded that curcumin reduced
apoptosis and inhibited oxidation via the TRPM2 channels.
Lipopolysaccharide-induced model
In LPS-induced oxidative stress, mouse N9 microglial cells
were pre-treated with curcumin or a curcumin derivative and
subsequently exposed to LPS (Zhang et al., 2010). The
derivative dose-dependently decreased levels of ROS, nitrite
(NO −) and iNOS in cells. Moreover, curcumin and its deriva-
tive inhibited the LPS-induced phosphorylation of IκBα (NF-κβ
pathway), ERK1/2, p38 MAPK, and JNK (MAPK pathway).
Metal ion-induced model
Rat cortical neurons were pre-treated with curcumin followed
by exposure to copper, Cu(II), to induce oxidative damage
(Huang et al., 2011). Curcumin dose-dependently reduced
ROS and H2O2 levels, thereby inhibiting oxidative stress.
The authors proposed that the antioxidant effects of curcumin
prevented Cu(II)-induced apoptosis. In curcumin pre-treated
Neuro-2A and HEK293 cells exposed to iron, Fe 2+ (Morales
et al., 2017), curcumin protected against oxidative damage
induced by iron exposure.
Iodoacetate-induced model
Iodoacetate inhibits the glycolytic enzyme glyceraldehyde 3-
phosphate dehydrogenase (GAPDH) that leads to oxidative
stress (Schmidt and Dringen, 2009). Rat cerebellar granule
neurons were pre-treated with curcumin followed by expo-
sure to iodoacetate (Reyes-Fermin et al., 2012). Curcumin
reduced iodoacetate-induced ROS levels in cells. Indepen-
dently of iodoacetate toxicity, curcumin dose-dependently
increased heme oxygenase 1 activity in healthy cells.
Hypoxia-induced model
Chhunchha et al. (2013) pre-treated HT22 mouse hippocam-
pal cells with curcumin followed by hypoxia-induced oxidative
stress. Curcumin pre-treatment reduced ROS expression
when compared to hypoxia exposure only. Curcumin pre-
vented downregulation of the cytoprotective peroxiredoxin
(Prdx6) protein which led to reduced ROS levels, and thereby
attenuated hypoxia-induced damage.
Excitotoxicity model
Glutamate upregulation has been linked to excitotoxicity and
oxidative stress (Albrecht et al., 2010). Exposure to gluta-
mate was used in 2 studies using a PC12 cell model. In 1
study, the neuroprotective effects of curcumin were tested
in a glutamate hyperstimulated PC12 cell model (Chang
et al., 2014). Curcumin reduced GSH, SOD and nitric oxide
protein levels, which led to reduced cell death. It is unclear
whether curcumin-mediated reduction in SOD levels pro-
moted antioxidant activity. However, the reduction in nitric
oxide indicates that curcumin reduced nitrosative stress in
PC12 cells. Overall, the authors claimed that curcumin's pro-
tective effects acted via GSH and mitochondria-dependent
nitric oxide–ROS pathways. In the second study, cells were
pre-treated with the curcumin derivative, J147, and thereafter
exposed to either glutamate or tert-butyl hydroperoxide
(t-BHP) (Chen et al., 2015). J147 reduced the levels of ROS
and RNS specifically H2O2, OH, nitric oxide and peroxynitrite.
One study used N-methyl- -aspartic acid (NMDA) as a model
of oxidative-inducing excitotoxicity, in which rat neuronal and
astrocytic cells were treated with curcumin and thereafter
 Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
with NMDA (Lin et al., 2011). Although curcumin inhibited
iNOS expression under non-stressed conditions, iNOS
expression was not measured under NMDA-toxic conditions
and therefore the anti-nitrosative effects of curcumin were
not analyzed.
‘Non-toxin’ model
As opposed to studies using induction of oxidative stress,
Panchal et al. (2008) analyzed gene expression in rat glioma
C6 cells following curcumin treatment under non-externally
stressed conditions. Eight main clusters were identified from
the Hierarchical Ordered Partitioning and Collapsing Hybrid
clustering (HOPACH) analysis of 1223 genes differentially
expressed between curcumin-treated and control cells. The
oxidative stress pathway was one of the pathways with a high
number of differentially expressed genes. Curcumin treat-
ment was shown to increase the mRNA expression of the
glutathione S-transferase A5 (GSTA5) and heme-oxygenase
1 (HMOX1) genes, which are both involved in oxidative
stress. The quinine oxidoreductase 1 (NQO1), catalase
(CAT), microsomal glutathione S-transferase 1 (MGST1),
and superoxide dismutase 2 (SOD2) genes involved in the
antioxidant response were also increased in curcumin-
treated cells.
STUDIES PERFORMED IN ANIMAL MODELS
Antioxidant effects of curcumin in
neurodegenerative disorders
In addition to cellular models, 14 studies investigated the anti-
oxidant properties of curcumin in toxin-treated or transgenic
animal models of NDDs (Table 3). There were 6 studies
performed on AD, 6 on PD and 1 each on HD and SMA. On
review of these studies, there appears to be an overall consen-
sus that curcumin, or derivatives thereof, suppressed toxin-
induced oxidative stress in animal models. In addition to anti-
oxidant effects, curcumin treatment improved balance, speed
of movement and coordination. The animal models included
transgenic and various toxin-induced models, as well as a
range of animals including rats, mice and Drosophila. How-
ever, some of these studies were constrained by the lack of
cytotoxicity analysis of curcumin, absence of properly con-
trolled groups and small sample sizes which may account
for some of the contradictory findings between the studies.
Alzheimer's disease
Six studies reported curcumin's effect in animal models of AD
(Table 3). Four of these used transgenic animals over-
expressing amyloid precursor protein. In 1 study, amyloid pre-
cursor protein Tg2576 transgenic mice were fed with low- and
high-dose curcumin-containing chow for 6 months (Lim et al.,
2001). Both curcumin dosages suppressed levels of oxidized
protein carbonyls up to 60%. The authors suggested that
curcumin is effective at low dosages and that the inhibition
of protein oxidation may be responsible for the suppression
of amyloid-β accumulation in mice. In another mouse model,
Tg2576 amyloid transgenic mice were fed curcumin and its
derivative in chow for 4 months (Begum et al., 2008). A sepa-
rate group of mice received oral gavage of curcumin 2 days
15
prior to LPS injection, which elicited inflammation and oxida-
tive damage. Both models of curcumin administration had
similar effects. Curcumin and its derivative prevented the
increase of isoprostanes and iNOS mRNA. However, only
curcumin treatment suppressed the protein carbonyl and
nitrotyrosine levels. Seo et al. (2010) fed transgenic Tg2576
amyloid mice with curcumin for 6 months and demonstrated
suppression of lipid peroxidation in the spinal cord. It was
suggested that the curcumin-mediated reduction of lipid per-
oxidation in the spinal cord led to the rescue against demye-
lination and neuronal loss in mice. J147 curcumin derivative
was administered, for 5 months, to amyloid transgenic mice
(Chen et al., 2011), and it was shown to prevent an increase
in heme oxygenase 1 levels. The authors stated that J147
uniquely acted on several disease mechanisms involved in
AD, namely oxidative damage, inflammatory response,
amyloid-β deposition and neuronal loss.
In a rat model of AD, rats were pre-treated with curcumin
for 2 months prior to intraventricular injection of amyloid-β
(Frautschy et al., 2001). Curcumin protected against the
increase in isoprostane levels in the cortex, and therefore
suppressed fatty acid oxidation. In another study, rats were
injected with aluminum chloride (AlCl3) to induce AD symp-
toms and were orally post-treated with a novel curcumin
derivative, CUR-CA-THIONE (Shelat and Acharya, 2016).
This compound inhibited AlCl3-induced increase in lipid
peroxidation. Furthermore, although it increased GSH and
catalase protein levels it also reduced SOD levels. The
authors provide no explanation for the conflicting finding in
which CUR-CA-THIONE increased protein levels of some
antioxidant enzymes (GSH and catalase) but reduced levels
of other antioxidants (SOD). The duration of exposure and
the intensity of the oxidative stressors are factors which
influence whether a decrease or increase in the antioxidant
enzyme levels is observed, and this might explain the discre-
pancies observed.
Parkinson's disease
Six studies investigated the antioxidant effect of curcumin in
animal models of PD (Table 3). Of these, 2 used rotenone
and the rest used 6-OHDA, MPTP, paraquat or H2O2 (1 study
for each) to elicit a PD phenotype. Curcumin and its deriva-
tives were pre-treated orally prior to the neurotoxic 6-OHDA
striatal injection in rats (Agrawal et al., 2012). Curcumin
and its derivatives prevented the 6-OHDA-induced reduction
in the GSH, GPx, GR, and SOD and catalase enzyme
levels. In addition, curcumin and its derivatives reduced lipid
peroxidation as measured by reduced MDA levels. There-
fore, curcumin reduced oxidative stress, a finding associated
with improved motor function and inhibition of neuronal loss
in the 6-OHDA treated rats. Notably, curcumin or its deriva-
tives did not restore the antioxidant activity to the untreated
level. It would, therefore, be interesting to determine the
duration of protection afforded by curcumin.
In a study by Jayaraj et al. (2014), C57BL/6 mice were pre-
treated with the curcumin derivative (CNB-001) prior to MPTP
exposure followed by co-treatment for 4 to 7 days thereafter.
This study showed that the MPTP only group developed
locomotive and exploratory behavior deficits and impaired
16 Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
GSH levels. The CNB-001- and MPTP-treated group was
noted to have inhibition of oxidative stress as evidenced by
the reduced lipid peroxidation and increased levels of GSH
and GPx. Contrary to other studies; the combination of
CNB-001- and MPTP-treatments suppressed the levels of
protective SOD and catalase enzymes. It was proposed that
the increased SOD and catalase levels were due to an adap-
tive response to the oxidation-inducing MPTP.
In a rotenone-mediated PD model, rats were initially treated
with curcumin for 4 days and thereafter co-treated with curcu-
min and rotenone for 50 days (Cui et al., 2016). Similarly to
the 6-OHDA model, curcumin treatment suppressed the
rotenone-mediated oxidative stress by elevating GSH levels,
while reducing ROS and MDA levels. The study also showed
that curcumin's antioxidant effects seemed to act via the
Akt/Nrf2 signaling pathway, due to the phosphorylation of
Akt and Nrf2, and the upregulation of heme oxygenase 1 and
quinine oxidoreductase 1 protein expression. Another study
investigated curcumin's effect in the rotenone-mediated PD
model with a shorter treatment duration of 21 days in Swiss
albino mice (Khatri and Juvekar, 2016). Curcumin dose-
dependently prevented the rotenone-induced increase in
MDA and nitrite levels, while preventing the decrease in
GSH, SOD and catalase levels. However, it should be noted
that there was no curcumin only treatment group, a limitation
which constrains interpretation of the results.
Two studies used Drosophila melanogaster as a model. In
1 study, the flies were pre-fed curcumin followed by paraquat
exposure (Park et al., 2012). Paraquat caused locomotor
dysfunction, increased mortality and reduced expression of
antioxidant genes. Although curcumin improved survival
and locomotor deficits, it did not upregulate the expression
of antioxidant genes. This may indicate that in flies curcumin
may act via another pathway, and not the antioxidant
pathway. In a transgenic Drosophila LRRK2 model of PD,
flies were co-fed curcumin and H2O2 (Yang et al., 2012).
Curcumin reduced the total oxidized protein levels in both
LRRK2 wild type and LRRK2 mutant flies fed H2O2. It was
found that curcumin improved survival rates of the flies and
inhibited mutant LRRK2 activity. This study showed that
curcumin protected against oxidative stress but also may be
an LRRK2 kinase inhibitor.
Huntington's disease
HD is a monogenic, autosomal dominant disorder in which
pathogenic CAG repeat expansions in the HTT gene result in
the production of mutant huntingtin protein (The
Huntington's Disease Collaborative Research, 1993). The
symptoms of HD include progressive neuropsychiatric distur-
bance and chorea (Montoya et al., 2006). Similarly to PD and
AD, HD has also been associated with mitochondrial dys-
function and oxidative stress as possible disease mechan-
isms (Arun et al., 2016).
To date, only 1 study has analyzed the antioxidant proper-
ties of curcumin in an animal (rat) model of HD (Table 3). In
this model, rats were injected with the ROS-producing neuro-
toxin, 3-nitropropionic acid (Sandhir et al., 2014). The rats
were subsequently treated by oral gavage with curcumin
nanoparticles (C-SLN), in which curcumin was encapsulated
in solid lipid nanoparticles. C-SLN prevented the increase in
MDA, ROS and protein carbonyls. Moreover, it protected
against the depletion of GSH, while increasing SOD activity.
Rats treated with C-SLN also showed an increase in the
expression of the antioxidant-inducing Nrf2.
Spinal muscular atrophy
The antioxidant effect of curcumin was investigated in 1 study
of an animal model (mouse) of SMA (Table 3). In the trans-
genic AR97Q mouse model, the ASC-JM17 curcumin analo-
gue was given via oral gavage for 6 weeks (Bott et al., 2016).
ASC-JM17 activated expression of both Nrf1 and Nrf2 which
led to increased expression of downstream genes coding for
proteasome subunits, molecular chaperones and antioxidant
enzymes; and thereby improved motor function in the trans-
genic mice.
Antioxidant effects of curcumin in models of
oxidative/nitrosative stress
Eleven studies tested the antioxidant effects of curcumin in
models of oxidative stress in animals treated with toxins,
metal ions and excitotoxic inducers (Table 4). No studies
were performed specifically on nitrosative stress. All of these
studies found that curcumin or curcumin derivatives showed
antioxidant protection in various animals including mice, rats
and rabbits. However, various assays or techniques were
used making it difficult to compare findings between studies.
Sodium nitroprusside-induced model
Sodium nitroprusside is a vasodilator which stimulates oxida-
tive stress (Nazari et al., 2012), and in a mouse model of
sodium nitroprusside-induced oxidative stress, animals were
orally pre-treated with curcumin and the curcumin derivative,
Theracumin (Nazari et al., 2014). Theracumin protected
against motor dysfunction and neuronal loss. No oxidative
markers or antioxidant agents were tested and therefore the
antioxidant effects of curcumin and Theracumin were inferred
from the prevention of sodium nitroprusside-induced apoptosis.
Lipopolysaccharide-induced model
In an LPS-induced mouse model, mice were orally treated
with curcumin for 7 days prior to LPS injection (Jangra et al.,
2016). Curcumin decreased levels of MDA and nitrates, and
increased GSH levels. All protective effects of curcumin had
a larger effect size when curcumin was co-administered
with piperine, to increase its bioavailability (Suresh and
Srinivasan, 2010).
Metal ion-induced model
In an aluminum-induced rat model of oxidative stress, rats
were intraperitoneally co-treated with curcumin and aluminum
(Sood et al., 2011). Curcumin prevented the depletion of GSH
levels and increased mRNA expression of the molecular
chaperone heat shock protein, HSP70. It was suggested that
the improvement in mitochondrial activity was due to the
antioxidant effect of curcumin. In a lead-induced rat model,
rats were co-treated with curcumin and lead intraperitoneally
for 8 weeks (Hosseinzadeh et al., 2013). Curcumin inhibited
 Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
lipid peroxidation, while also increasing the total antioxidant
capacity.
Excitotoxicity model
Six studies were performed using different neurotoxins
including dopamine, kainic acid, parathion, fluoride and
nicotine. In the dopamine-induced rat model of excitotoxicity
and oxidative stress, rats were pre-treated with curcumin
followed by dopamine exposure (Luo et al., 1999). Curcumin
protected against prolonged activation of activated protein
1 (AP-1) and therefore, it was proposed that oxidative stress
and apoptosis were suppressed. Kainic acid is an oxidative
agent which stimulates oxidative stress and leads to neuro-
toxicity. Two studies investigated a kainic acid-induced rat
model in which animals were intraperitoneally injected with
various curcuminoids and thereafter exposed to kainic acid
(Shin et al., 2007; Sumanont et al., 2007). Curcuminoids
reduced nitric oxide levels and expression of the iNOS gene.
A mouse model was treated with an intraperitoneal injection
of curcumin prior to kainic acid injection (Shin et al., 2007).
Curcumin reduced the number of heme oxygenase 1 positive
hippocampal cells. The authors proposed that the antioxidant
effects of curcumin played a role in the suppression of apop-
tosis. In a parathion model of neurotoxic-mediated oxidative
stress, rats were treated with curcumin for 1 week prior to
parathion exposure (Canales-Aguirre et al., 2012). Curcumin
inhibited the increase in MDA in the hippocampus. It should
be noted that curcumin's antioxidant ability may play a role
in curcumin preventing apoptosis and microgliosis in
parathion-induced rats. In a fluoride-exposed mouse model
of neurotoxic-mediated oxidative stress, curcumin and
fluoride were orally co-treated for 30 days (Sharma et al.,
2014). Curcumin protected against an increase in MDA in
the hippocampus. Finally, in a nicotine-induced rat model,
rats were intraperitoneally co-treated with curcumin and nico-
tine (Motaghinejad et al., 2017). Curcumin dose-dependently
prevented an increase in MDA, depletion of GSH, increase in
GSSG, and decrease in SOD, GPx and GR enzyme activities.
Neuroinflammatory-induced model
In a cholesterol-induced rabbit model of neuroinflammation to
elicit oxidative damage, rabbits were orally co-treated with
curcumin and a high fat diet (Manogaran et al., 2015). Curcu-
min increased SOD activity and prevented lipid peroxidation.
Curcumin also reduced plasma and brain cholesterol levels,
possibly due to increased antioxidant activity.
ANTIOXIDANT EFFECTS OF CURCUMIN IN
MODELS OF DEMENTIA AND AGING
Additionally, we included studies involving curcumin in
dementia and aging since these have both been linked to
an increase in the levels of oxido-nitrosative stress. The
etiology of the negative cellular effects of aging is unknown;
however, several hypotheses exist including accumulation
of induced DNA damage, mitochondrial dysfunction, cellular
aging, and oxidative stress (López-Otín et al., 2013). ROS
has been highlighted as an important role player in DNA
damage leading to aging.
17
To date, only studies on animal models on dementia and
aging have been performed, and these have been included
in Table 4. To summarize, all 9 studies showed an anti-
oxidant effect of curcumin against lipid and protein oxidation
in animals, including mice and rats. For these studies, only
streptozotocin was used to induce dementia, whereas D-
galactose, transgenic mice and natural aging were used to
induce features of aging.
To date, only 3 studies have investigated the antioxidant
properties of curcumin in a streptozotocin-induced rat model
of dementia (Table 4). Two of the studies only post-treated
rats with curcumin (Ishrat et al., 2009; Samy et al., 2016),
while the third study pre- and post-treated rats (Agrawal
et al., 2010). Both pre- and post-treatments of curcumin
suppressed the increase in MDA and depletion of GSH in
all 3 studies. Furthermore, Ishrat et al. (2009) showed that
curcumin prevented the increase in 4-hydroxy-2-nonenal,
TBARS, protein carbonyls and H2O2, while increasing the
activity of antioxidant enzymes GPx and GR.
Six studies have investigated animal models of aging and
the antioxidant effects of curcumin (Table 4). Four of the 6
studies used mouse and rat models of aging in which animals
were treated orally or by injection with curcumin and aging-
inducing D-galactose (Kumar et al., 2011; Banji et al., 2013,
2014; Fu et al., 2017). In these D-galactose studies, curcumin
prevented an increase in MDA, nitrites, and protein carbonyls
and thiols. Curcumin also protected against the reduction of
GSH levels, and SOD, GST, GPx and catalase enzyme
activities. In a transgenic SAMP8 mouse model of accelerated
aging, curcumin was administered intragastrically for 25 days
(Sun et al., 2013). Curcumin reduced MDA levels and
increased SOD activity in mice hippocampus. Nineteen-
month-old rats were used as a model for aging with the rats
fed curcuminoids for 3 months (Rastogi et al., 2014). The
curcuminoids lowered neuronal NOS levels in the aged rats.
The authors concluded that the improvement in aging-
induced mitochondrial impairments was partly influenced by
curcumin inhibition of neuronal NOS.
CURCUMIN-MEDIATED ANTIOXIDANT PATHWAYS
DERIVED FROM THE REVIEWED STUDIES
The studies which have been reviewed have shown that cur-
cumin acted via multiple pathways to block oxido-nitrosative
stress (Tables 1–4). Fig. 1 summarizes the information gath-
ered from the reviewed articles and depicts the main findings
from these studies. Curcumin was shown mainly to inhibit
lipid and protein oxidation with a reduction in levels of MDA,
as well as protein carbonyls, thiols and nitrotyrosines. Curcu-
min also inhibited unregulated DNA damage by stimulating
Akt and MAPK pathways (Fig. 1). The activities of the anti-
oxidant enzymes, specifically SOD, catalase, GPx, GST,
GR and iNOS enzymes, were also stimulated by curcumin.
Moreover, there was evidence for curcumin preventing the
inhibition of Nrf2, NFĸB translocation and IĸB degradation,
all processes which are involved in regulating antioxidant
activity in the body. Oxidative or nitrosative stressors
(e.g. rotenone, paraquat exposure) inhibit Nrf2 and stimulate
translocation of NFĸB in the cytosol and degradation of IĸB,
18 Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21

indicated by the low

plasma curcumin levels
with 1 of the trials
reporting approximately
7.32 ng/ml (Ringman
et al., 2012). Therefore,
the positive findings
from animal and cellular
models may not be
directly translatable to
humans, and this has
led to research on alter-
native formulations of
curcumin to improve
its bioavailability (Chen
et al., 2018; Squillaro
et al., 2018). Other
clinical trials showed
70- and 180-fold in-
creases in curcumin
plasma when using
micelles as a novel
carrier system com-
pared to free curcumin
(Schiborr et al., 2014;
Fig. 1. The Proposed Antioxidant Effects of Curcumin Against DNA damage, and Lipid and Protein Oxidation. This schematic
diagram summarizes the main findings of the 64 articles summarized in this review. The arrow with a plus sign above indicates
Kocher et al., 2015).
stimulation while the T-shaped line indicates inhibition. The cross indicates protein degradation while the dashed lines highlight
processes which cause adverse effects to the cells including cellular dysfunction, damage and death. The exact cellular signal-
ing targets for curcumin have yet to be identified. GR: Glutathione reductase; GPx: Glutathione Peroxidase; H2O2: hydrogen
DISCUSSION AND
peroxide; HNE: 4-hydroxy-2-nonenal; IĸB: inhibitors-of-kappa B; MDA: malondialdehyde; NFĸB: nuclear-factor κB; NO: nitric CONCLUSION
oxide; NO2: nitrogen dioxide; N2O3: dinitrogen trioxide; Nrf2: nuclear factor erythroid 2–related factor 2; O2−: superoxide anion;
There are a number of
O2−2: peroxide; OH: hydroxyl radical; PN: peroxynitrate; SOD: superoxide dismutase.
completed or ongoing
clinical trials using cur-
which in turn suppresses antioxidant enzyme activity and cumin or its formulations and for many of these positive out-
enables unregulated production of ROS and RNS. Curcumin comes have been observed (NIH, 2018). However, there is
treatment, alternatively, could promote Nrf2 activation, and also some concern that curcumin and derivatives thereof
inhibit NFĸB translocation and IĸB degradation. Therefore, cur- are highly reactive, and have poor structural stability leading
cumin could stimulate the activities of antioxidant enzymes, to rapid metabolism and excretion. These issues may give
and thereby reduce the levels of oxidized proteins and lipid rise to false signals in drug screening tests and have led to
radicals to achieve oxidative homeostasis in cells. concerns regarding the efficacy of curcumin as a potential
therapeutic (Baker, 2016; Nelson et al., 2017).
In the 64 articles reviewed here, majority of the studies
reported in Tables 1 to 4 have produced promising results
CLINICAL TRIALS
for curcumin as an antioxidant therapy in NDDs and oxido-
According to clinicaltrials.gov, there are 13 ongoing and com- nitrosative stress. These protective effects have been observed
pleted clinical trials involving curcumin treatment and NDDs, for both animal and cellular models of these disorders. Curcu-
including AD, mild cognitive impairment and amyloidosis min was shown to be effective across a wide range of different
(https://clinicaltrials.gov). Currently, only 2 of the 13 clinical concentrations, when used before or after induction of oxidative
trials have been published in peer-reviewed journals (Baum stress, across different cell types and for various toxins. How-
et al., 2008; Ringman et al., 2012). In 1 of these clinical trials, ever, a major conflicting issue when analyzing the articles is
curcumin capsules or powder was ingested daily by 27 patients determination of the “protective” effects of antioxidant agents
with mild cognitive impairment for 6 months. No change in and enzymes in response to oxidative stress and curcumin.
levels of isoprostane and no improvement in cognitive decline Some studies report increased levels of SOD and reduced
at 1 and 4 g/day curcumin dosages were observed (Baum catalase and GSH levels, while others showed the converse,
et al., 2008). In the second study, no difference in iso- however, all of these studies concluded that curcumin was pro-
prostane, amyloid-β and tau plasma levels, at both 2- and tective. Furthermore, the use of a variety of toxins to elicit the
4-g/day dosages of curcumin were reported in a 24-week trial same disease makes comparing analyses between articles
of AD patients (Ringman et al., 2012). A possible reason for challenging, as it is uncertain whether the toxin is eliciting the
these findings could be due to the poor absorption of curcumin relevant disease pathways.
 Shameemah Abrahams et al. / Neuroscience 406 (2019) 1–21
This review article is limited by the fact that only original
journal articles in English were included, and only 3 online
search databases, with a specific set of keywords, were
used. As a consequence of these filtering steps, relevant
research articles may not have been retrieved.
In conclusion, curcumin is a promising agent for antioxida-
tion (Fig. 1). However, further targeted experiments on curcu-
min are needed to identify its exact molecular targets and the
various pathways it is involved in before it can be used in the
design of novel therapeutics.
CONFLICTS OF INTEREST
All authors declare no conflict of interest.
ACKNOWLEDGMENTS
We would like to acknowledge Prof Helena Kuivaniemi
(Stellenbosch University) for assisting in setting up the litera-
ture search and critically reviewing the manuscript. This work
is based on the research supported wholly / in part by the
National Research Foundation of South Africa (Grant
Numbers: 111958, 106052, 96072), the South African
Medical Research Council (Self-Initiated Research Grant),
and Stellenbosch University. WH is supported by the Faculty
of Medicine and Health Sciences, Stellenbosch University.
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(Received 27 November 2018, Accepted 13 February 2019)
(Available online 28 February 2019)
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