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Abstract

Vitamin A (retinol) and its congeners - the retinoids - participate in a panoply of biological events, as for instance cell differentiation, proliferation, survival, and death, necessary to maintain tissue homeostasis. Furthermore, such molecules may be applied as therapeutic agents in the case of some diseases, including dermatological disturbances, immunodeficiency, and cancer (mainly leukemia). In spite of this, there is a growing body of evidences showing that vitamin A doses exceeding the nutritional requirements may lead to negative consequences, including bioenergetics state dysfunction, redox impairment, altered cellular signaling, and cell death or proliferation, depending on the cell type. Neurotoxicity has long been demonstrated as a possible side effect of inadvertent consumption, or even under medical recommendation of vitamin A and retinoids at moderate to high doses. However, the exact mechanism by which such molecules exert a neurotoxic role is not clear yet. In this review, recent data are discussed regarding the molecular findings associated with the vitamin A-related neurotoxicity.
An Acad Bras Cienc (2015) 87 (2 Suppl.)
Anais da Academia Brasileira de Ciências (2015) 87(2 Suppl.): 1361-1373
(Annals of the Brazilian Academy of Sciences)
Printed version ISSN 0001-3765 / Online version ISSN 1678-2690
http://dx.doi.org/10.1590/0001-3765201520140677
www.scielo.br/aabc
The neurotoxic effects of vitamin A and retinoids
MARCOS ROBERTO DE OLIVEIRA
Departamento de Química, ICET, Universidade Federal de Mato Grosso (UFMT),
Av. Fernando Corrêa da Costa, 2367, 78060-900 Cuiabá, MT, Brasil
Manuscript received on December 10, 2014; accepted for publication on March 4, 2015
ABSTRACT
Vitamin A (retinol) and its congeners – the retinoids – participate in a panoply of biological events, as for
instance cell differentiation, proliferation, survival, and death, necessary to maintain tissue homeostasis.
Furthermore, such molecules may be applied as therapeutic agents in the case of some diseases, including
dermatological disturbances, immunodeciency, and cancer (mainly leukemia). In spite of this, there is
a growing body of evidences showing that vitamin A doses exceeding the nutritional requirements may
lead to negative consequences, including bioenergetics state dysfunction, redox impairment, altered
cellular signaling, and cell death or proliferation, depending on the cell type. Neurotoxicity has long been
demonstrated as a possible side effect of inadvertent consumption, or even under medical recommendation
of vitamin A and retinoids at moderate to high doses. However, the exact mechanism by which such
molecules exert a neurotoxic role is not clear yet. In this review, recent data are discussed regarding the
molecular ndings associated with the vitamin A-related neurotoxicity.
Key words: mitochondrial dysfunction, neurotoxicity, oxidative stress, retinoids, vitamin A.
INTRODUCTION
Increased access to vitamin A through fortified
foods and supplements is an important strategy
to avoid deciency of such fat-soluble vitamin to
humans. However, it is necessary to monitor the
impact of such practice on human health due to
the potential risk of several deleterious effects
classically induced by vitamin A, retinoids, and
carotenoids, which are vitamin A precursors from
vegetal diet (Snodgrass 1992, Napoli 1999, 2012,
Myhre et al. 2003). In addition to its origin from
diet, vitamin A is utilized therapeutically in cases
of dermatological disturbances, immunodeciency,
weight gain of preterm infants, and leukemia
(Tsunati et al. 1990, Ross 2002). It was previously
reported that vitamin A doses ranging from 150,000
to 300,000 IU/kg.day
-1
or more were being utilized
in the treatment of leukemic children of different
ages (Fenaux et al. 2001). Also, vitamin A at doses
that exceed 8500 IU/kg.day
-1
were administered
to very-low-weight-preterm infants during weight
gain therapy (Mactier and Weaver 2005). It was
previously reported the utilization of vitamin A
supplementation at 100,000 to 200,000 IU to treat
children in attempt to prevent mortality in Guinea-
Bissau (Fisker et al. 2014). Then, vitamin A may be
obtained from both diet and as a supplementation
with clinical use or even inadvertently.
E-mail: mrobioq@gmail.com
An Acad Bras Cienc (2015) 87 (2 Suppl.)
1362 MARCOS ROBERTO DE OLIVEIRA
Some authors discuss that it is rare to observe
toxicity resulting from excessive vitamin A intake
(Allen and Haskell 2002). However, the most
common parameters that are analyzed in cases
of vitamin A intoxication include observation
of acute signs and symptoms, among which are
nausea, vomiting, diarrhea, headache, bulging of
the fontanelle in infants (as a result of increased
intracranial pressure), and fever, to cite a few (Allen
and Haskell 2002, Lam et al. 2006). Disturbances
related to nervous functions also appear on the list
of side effects resulting from excessive vitamin
A intake, as for instance confusion, irritability,
anxiety, depression, and suicide ideation
(Snodgrass 1992). However, such central effects
are more commonly observed after chronic vitamin
A exposition. On the other hand, acute behavioral
impairment was reported in individuals that
experienced high vitamin A concentrations due to
consumption of bear liver. Such altered behavior
was called “polar hysteria” and was compared to
schizophrenia (Rodahl and Moore 1943, Restak
1972). Additionally, acute vitamin A intoxication
may lead to blurred vision and decreased muscular
coordination (Olson 1993).
Some aspects of vitamin A intoxication
may be easily assessed, as for example, through
analyses of liver and renal function (Penniston and
Tanumihardjo 2006). However, with the exception
of morphological observations or the consequent
behavior resulting from pain (as occurs during
headache), it is very difficult to affirm that the
acute vitamin A exposition will not lead to sequels
that may negatively affect the neuronal function
later. Gender, age, and nutritional quality, among
other factors, inuence the degree of intoxication
of almost all existing toxicants (or xenobiotics).
Therefore, caution must be taken when concluding
that previous vitamin A intake at higher than normal
concentrations not induce posterior dysfunction
mainly when analyzing neuronal environment,
since neurons did not divide during adulthood
(with exception to some hippocampal areas and
other regions) and its loss would lead to irreversible
alterations of brain function (Aimone et al. 2014).
In this review, the effects of vitamin A on
neuronal cells will be described and discussed
to show that vitamin A – and its derivatives, the
retinoids – may exert long-term effects on brain
areas that either facilitate (indirect effect) or induce
(direct effect) central malfunction.
VITAMIN A AND RETINOIDS: A BRIEF OVERVIEW
Vitamin A (retinol – a hydrocarbon chain-
containing isoprenoid with a hydroxyl group at one
end of the molecule) may be obtained from both
vegetal (provitamin A) and animal (preformed) diet
(Olson 1993, Napoli 1999, 2012). β-carotene is a
main source of vitamin A in vegetables, and retinol
esters occurs in animals (Castenmiller and West
1998, von Lintig 2012, Van Loo-Bouwman et al.
2014). After digestion, retinol and retinoids must
bind to proteins to be soluble in aqueous solutions
such as blood and cytosol (Noy 2000, Napoli 2012).
The cellular metabolism of retinol is as follows:
retinol is converted to retinal (an aldehyde) or to
retinoic acid (a carboxylic acid) through oxidation
of the hydroxyl group (Olson 1993). Furthermore,
retinol may be esteried by lecithin retinol acyl
transferase (LRAT) or acyl-Coa acyl transferase
(ARAT) leading to the formation of palmitate
retinol, as well as other chemical forms, as for
instance retinol oleate, retinol linoleate, and more
(Sauvant et al. 2003). Retinoic acids (mainly all-
trans-retinoic acid and 9-cis-retinoic acid) exert its
effects by binding to receptors that act as nuclear
factors when translocate to nucleus (Napoli 1996).
However, an increasing body of evidence shows
that retinol and retinoids may trigger specific
signals through non-genomic events (Piskunov et
al. 2014, Rochette-Egly 2015).
Vitamin A plays important roles during both
mammalian development and adulthood through
maintenance of several tissue functions, including
the central nervous system as a whole (Olson 1993,
Tanumihardjo 2004, Tafti and Ghyselinck 2007).
An Acad Bras Cienc (2015) 87 (2 Suppl.)
THE NEUROTOXIC EFFECTS OF VITAMIN A AND RETINOIDS 1363
This vitamin and its derivatives participate in the
regulation of cell proliferation, differentiation,
survival, and death (by triggering apoptosis),
leading to the formation of the normal shape of
the embryo, organogenesis, and tissue physiology,
for example (Das et al. 2014). Furthermore, some
biological processes including, for example, vision,
structure and function of skin and bones, immune
defenses, and neuronal activity will depend on
regular access to vitamin A during the entire human
life (Olson 1993, Napoli 1996, Huang et al. 2014).
The main site of vitamin A storage in mammals
is the liver, but it is also possible to nd vitamin
esters in adipose tissue (Napoli 1996, Van Loo-
Bouwman et al. 2014). Vitamin A content in the
liver of adult humans is about 100 µg/g (Furr et
al. 1989). It was suggested that a concentration of
vitamin A of roughly 300 µg/g in the liver reveals
intoxication (Olson 1993).
THE BIOLOGY OF VITAMIN A IN THE
CENTRAL NERVOUS SYSTEM
After hydrolysis of retinol esters, retinol binds to
retinol binding proteins (RBP) and is transported
through circulation. In the target organ, a
membrane receptor with high afnity for retinol
mediates its uptake (Kawaguchi et al. 2007).
All-trans-retinoic acid is produced from retinol
by retinol dehydrogenase (generating retinal)
and retinaldehyde dehydrogenase (producing
retinoic acid) (Napoli 1996). The synthesis of all-
trans-retinoic acid occurs in several brain areas
of mammals, including cerebrum, cerebellum,
meninges, basal ganglia, and hippocampus
(Lane and Bailey 2005). Interestingly, it was
demonstrated that retinal dehydrogenase enzyme
expression occurs in blood vessels of all brain
areas (Thompson Haskell et al. 2002). Recently,
it was published that astrocytes may participate in
the maintenance of the homeostasis of retinoids
levels in brain by regulating its synthesis (Shearer
et al. 2012a). Moreover, retinoid binding proteins
were detected throughout the entire brain (Lane
and Bailey 2005). Cellular retinol binding proteins
(CRBP-I and II) and cellular retinoic acid binding
proteins (CRABP-I and II) solubilize retinoids in
the cytoplasm and avoid non-specic interactions
and even oxidation of such molecules (Napoli
1996, 1999, 2012, Folli et al. 2001). The binding
of retinoic acids to cellular retinoic acid binding
protein (CRABP) forms a complex that it is thought
to migrates to the nucleus and induce different
effects through interacting with nuclear receptors
to retinoic acid (RAR and RXR) (Lane and Bailey
2005, Shearer et al. 2012b). Brain contains RAR
and RXR and its functions are better observed
during development. During adulthood, these
nuclear receptors are still found in neuronal cells,
but show a specic pattern of localization (Tafti
and Ghyselinck 2007). It was reported that RAR
binds with all-trans-retinoic acid and with 9-cis-
retinoic acid (with lower afnity for the later) and
RXR binds with 9-cis-retinoic acid (Napoli 1996,
Lane and Bailey 2005). There is a myriad of genes
that contain response elements to retinoids in adult
mammalian brain, as previously reviewed (Lane
and Bailey 2005). Then, retinoids are metabolized
in brain areas and exert its effects in nervous and
glial cells specically throughout all life.
However, even being a biological target of
vitamin A and its derivatives, the ability of vitamin
A to induce serious effects that may compromise
neuronal function has been described. Such effects
include impaired bioenergetic parameters related to
mitochondrial function, oxidative and nitrosative
stress, alterations of dopamine signaling, and
behavioral disturbances, to cite some examples.
MOLECULAR EVIDENCES OF VITAMIN
A-RELATED NEUROTOXICITY
Even though vitamin A and its derivatives
are essential during both development and
maintenance of central nervous system activity,
there is a considerable body of evidences showing
that vitamin A concentrations exceeding that
which is required for normal function of cells lead
An Acad Bras Cienc (2015) 87 (2 Suppl.)
1364 MARCOS ROBERTO DE OLIVEIRA
to deleterious effects including disruption of the
redox environment, mitochondrial dysfunction, and
induction of cell death, as discussed below (Napoli
1999, Myhre et al. 2003, Lane and Bailey 2005).
All-trans-retinoic acid, a retinoid originated
from retinol, is able to induce oxidative stress in
cultured Sertoli cells (Conte da Frota et al. 2006),
but not in PC12 cell line (Gelain and Moreira
2008), which is derived from pheochromocytoma
of rat adrenal medulla (which is, in turn,
originated from the neural crest) and produces
dopamine and norepinephrine. In PC12 cell line
treated with retinol, increased rates of reactive
oxygen species production through a real-time
2′,7′-dichlorohydrouorescein diacetate (DCFH-
DA) assay designed for live cells were observed
(Wang and Joseph 1999). Also, decreased viability
was reported in PC12 cells treated with retinol.
DCFH-DA serves as a probe to detection of
hydrogen peroxide, hydroxyl, and peroxyl radicals
(LeBel et al. 1992). Then, retinol, but not all-
trans retinoic acid may alter redox environment
of such catecholamine producing cells, possibly
leading to loss of viability by a mechanism that
may be associated to its ability to act as a pro-
oxidant. However, it remains to be determined
whether the loss of cell viability is really related
to the pro-oxidant effect of retinol in that cell
system. Recently, it was demonstrated that all-trans
retinoic acid modulates gene expression through
a redox mechanism during SH-SY5Y cell line
differentiation, since the effects seen were blocked
by an antioxidant that is analogue to α-tocopherol
(de Bittencourt Pasquali et al. in press). However,
it was not analyzed in that work whether retinoic
acid altered redox environment parameters, as
for instance by inducting oxidative damage or
increasing the rates of reactive species.
Vitamin A is necessary for both development
and maintenance of the nigrostriatal axis (substantia
nigra and striatum), which regulates dopamine
signaling in brain. However, as mentioned above,
such vitamin and its derivatives may cause oxidative
impairment of such brain areas by increasing
reactive oxidative species. Actually, it was reported
that vitamin A supplementation (in the form of
retinol palmitate) at doses commonly utilized
clinically (1,000 to 9,000 IU/kg.day
-1
for 3, 7, or
28 days) induced some redox disturbances in the
nigrostriatal axis of adult male rats. Increased lipid
peroxidation, protein carbonylation, and oxidation
of protein thiol groups were observed in the
substantia nigra and striatum of vitamin A-treated
rats (De Oliveira et al. 2007a, 2008). Moreover,
vitamin A modulated antioxidant enzyme activity,
as observed with superoxide dismutase (SOD)
and, in some cases, with catalase (CAT), but not
with glutathione peroxidase (GPx). It is interesting
to note that, in that experimental model, retinol
palmitate supplementation induced an increase in
SOD enzyme activity, but did not affect either CAT
or GPx enzyme activity or even decreased CAT
enzyme activity. Therefore, vitamin A is favoring
an increase in H
2
O
2
production that may lead to
hydroxyl radical (OH) formation through Fenton
reaction (Halliwell 2006), since SOD converts
O
2
-l
to H
2
O
2
, but this reactive specie probably
accumulates due to decreased or unaltered CAT and
unaltered GPx enzyme activities. Regarding the
toxic effects of O
2
-l
, it was shown that O
2
-l
is able
to inhibit CAT enzyme activity directly (Kono and
Fridovich 1982). Thus, it may be a mechanism by
which vitamin A modulates CAT enzyme activity in
vivo. Interestingly, vitamin A supplementation for
28 days decreased rat exploration of and locomotion
in an open eld arena (De Oliveira et al. 2007a,
2008). However, it was not analyzed whether such
behavioral abnormalities were associated with
impaired redox status observed in the brain areas
that participate in movement control.
More recently, De Oliveira et al. (2012a)
demonstrated that vitamin A supplementation at
500 to 2,500 IU/kg.day
-1
induced mitochondrial
dysfunction and increased β-amyloid
1–40
peptide
and tumor necrosis factor-alpha (TNF-α) contents
in substantia nigra and striatum of adult rats.
Additionally, increased monoamine oxidase
(MAO) enzyme activity was observed in that
An Acad Bras Cienc (2015) 87 (2 Suppl.)
THE NEUROTOXIC EFFECTS OF VITAMIN A AND RETINOIDS 1365
experimental model. Mitochondrial dysfunction
was found by assessing mitochondrial electron
transfer chain activity. Decreased complex I-III,
complex II, succinate dehydrogenase (SDH),
complex II-III, and complex IV enzyme activity
was reported, which may lead not only to decreased
rates of ATP production, but may favor electron
leakage from that system, which may lead to O
2
-l
formation (Halliwell 2006). In addition, it was
seen increased Mn-SOD (manganese SOD – the
mitochondrial SOD) enzyme activity, as well as
MAO enzyme activity was observed increased.
These two enzymes differ in location (Mn-SOD
is a mitochondrial matrix enzyme, and MAO is
located at the outer mitochondrial membrane),
but both produce H
2
O
2
during the reaction of
dismutation of O
2
-l
and degradation of dopamine,
respectively (Halliwell 2006, Edmondson 2014).
Then, mitochondria seem to be a potential
source of H
2
O
2
in the case of increased vitamin
A intake as a supplement. Interestingly, vitamin
A supplementation also induced a decrease in
the immunocontent of D2 receptor (D2R) in both
substantia nigra and striatum (De Oliveira et al.
2012a). Low levels of D2R may cause an increase of
dopamine release from catecholaminergic neurons,
which may lead to exceeding dopamine levels in
both extracellular and intracellular environments
of post-synaptic neurons (Lotharius and Brundin
2002, Jorg et al. 2014). Dopamine is very reactive
under physiologic pH, giving rise to semi-quinones
that may react with thiol groups in protein and affect
its structure and function (Graham 1978, Maker
et al. 1981, Lotharius and Brundin 2002). In fact,
increased concentration of oxidized protein thiol
groups was observed in that experimental model.
However, it remains to be investigated whether a
causative link between such effects really exists.
Carta et al. (2006) demonstrated that vitamin
A deficiency impaired locomotion and striatal
cholinergic function in rats. Even though vitamin
A is necessary to modulate signaling pathways
associated to dopamine and other neurotransmitters
(Lane and Bailey 2005), excessive vitamin A intake
may trigger several neuronal dysfunctions that
may be originated from its pro-oxidant ability, for
example.
It is interesting the fact that vitamin A
supplementation also increased glutathione-S
transferase (GST) enzyme activity in several
rat brain areas (De Oliveira et al. 2009f, 2011a,
2012a, c). GST conjugates reduced glutathione
(GSH) with apolar xenobiotics in order to increase
its solubility in aqueous solution, rendering its
excretion easy after biotransformation (Sheehan
et al. 2001). However, by increasing GST enzyme
activity during vitamin A metabolism, such
enzyme consumes greater amounts of GSH. GSH
is the major non-enzymatic antioxidant inside cells
and organelles such as mitochondria (Halliwell
2006). Thereby, vitamin A affects neuronal redox
status not by directly inducing the production of
O
2
-l
, for example, but also through increasing the
consumption and consequent excretion of GSH,
weakening the antioxidant power of cells.
Sub acute vitamin A supplementation
also increased both 3-nitrotyrosine (total and
mitochondrial) and α-synuclein contents in the
rat substantia nigra and striatum (De Oliveira et
al. 2012a). Increased 3-nitrotyrosine levels may
result from high rates of O
2
-l
and NO
l
production
(Squadrito and Pryor 1998, Radi 2013). Indeed, it
was demonstrated that vitamin A intake increased
mitochondrial O
2
-l
production in different rat tissues
including brain (De Oliveira and Moreira 2007,
2008, De Oliveira et al. 2009a, b, c, d, e, f, 2011a,
2012b). The protein α-synuclein may be a target
of 3-nitrotyrosine, as previously demonstrated
(Giasson et al. 2000, Souza et al. 2000). Aggregated
α-synuclein may lead to proteasome inhibition, a
step towards accumulation of protein aggregates
inside cells (Snyder et al. 2003). Nagl et al. (2009)
published the mechanism by which all-trans-retinoic
acid induced the expression of neuronal nitric oxide
synthase (nNOS) in TGW-nu-I, a neuroblastoma
cell line. They found that all-trans-retinoic acid
induced nNOS expression through activation of
the phosphatidylinositol 3-kinase (PI3K)/Akt
An Acad Bras Cienc (2015) 87 (2 Suppl.)
1366 MARCOS ROBERTO DE OLIVEIRA
signaling pathway and the orphan nuclear receptor
DAX1 (NR0B1). All-trans-retinoic acid, among
other retinoids, as for example, 9-cis-retinoic
acid, are originated from vitamin A intake in vivo
(Napoli 1996, 1999, 2012), and increased access
to retinoids may lead to an increased expression
of nNOS and augmented rates of NO production,
which favors increased production of peroxynitrite
(ONOO
-
), a reactive specie that give rise to nitryl
cation (NO
2
+
), nitrogen diozide radical (
l
NO
2
), and
hydroxyl radical (
l
OH) through a reaction called
homolytic ssion (Radi 2013, Carballal et al. 2014).
In spite of this evidences, the effects of vitamin
A supplementation on NOS enzyme activity and
expression in the mammalian brain remain to be
investigated.
Even though NO may play an important role
in the neurotoxicity elicited by vitamin A, the co-
treatment with NG-nitro-L-arginine methyl ester
(L-NAME) did not affect either mitochondrial
dysfunction or other redox-related parameters in the
experimental model of vitamin A supplementation
at clinical doses (1,000 9,000 IU/kg.day
-1
for
28 days) (De Oliveira et al. 2012c). Furthermore,
L-NAME co-treatment did not prevent behavioral
disturbances induced by vitamin A. Taken together,
these data suggest that the neurotoxicity of vitamin
A is not dependent on the formation of NO
l
,
ONOO
-
, and/or 3-nitrotyrosine. However, the
experimental model utilized has some limitations,
since only one dose of L-NAME was tested. For a
better conclusion, two or even three concentrations
of L-NAME should be applied.
In cerebral cortex and cerebellum, retinol
palmitate supplementation at clinical doses (1,000
to 9,000 IU/kg.day
-1
) for 3, 7, or 28 days induced
oxidative stress and mitochondrial dysfunction,
as assessed through quantification of lipid
peroxidation, protein carbonylation, and oxidation
of protein thiol groups (De Oliveira and Moreira
2007). Similar results were obtained in vitro by
exposing isolated rat liver mitochondria to retinol.
It was observed that 20-40 µM retinol increased
O
2
-l
production and lipid peroxidation levels
(Klamt et al. 2005). It has been reported that higher
than normal mitochondrial lipid peroxidation
levels may lead to cytochrome c release through
oxidation of cardiolipin (Hüttemann et al. 2011). In
the cytoplasm, cytochrome c may trigger apoptosis
(Green et al. 2014). However, release of cytochrome
c from mitochondria is associated with increased
rates of O
2
-l
production due to electron leakage
from the mitochondrial electron transfer chain
(Halliwell 2006, Hüttemann et al. 2011). Then, O
2
-l
is able to increase its own production by favoring
cytochrome c release through cardiolipin oxidation.
Vitamin A (retinol) alters mitochondrial function
and may induce cell death by a mitochondrial
dependent route, as demonstrated (Klamt et al.
2008). Vitamin A supplementation did not induce
cell death in any rat brain region investigated, but
increased caspase-3 enzyme activity was found in
the rat cerebral cortex after sub acute treatment
the vitamin (De Oliveira et al. 2010). However, it
was not analyzed whether such enzyme activation
participates in the mechanism of cell death in such
rat brain region. It is known that 13-cis-retinoic
acid may suppress cell survival in the hippocampus
of mice (Sakai et al. 2004). Additionally, cell
division may be inhibited in vivo by the same
retinoid (Crandall et al. 2004). Indeed, such cellular
impairments may be the cause of depressive
behavior previously reported in mice exposed to
13-cis-retinoic acid (O’Reilly et al. 2006), as well
as explain, at least in part, the decreased capacity in
animals to learn after receiving such drug (Crandall
et al. 2004). Actually, anxiety-like behavior was
observed in adult rats maintained under vitamin
A supplementation at pharmacological doses
administered sub acutely (De Oliveira et al. 2007b).
On the other hand, vitamin A deciency impaired
cognitive functions, as for instance learning and
memory in different experimental models (Jiang
et al. 2012, Navigatore-Fonzo et al. 2014, Hou et
al. 2015).
Vitamin A supplementation also affected the
levels of one of the most important neurotrophins
in the mammalian brain experimentally. It was
An Acad Bras Cienc (2015) 87 (2 Suppl.)
THE NEUROTOXIC EFFECTS OF VITAMIN A AND RETINOIDS 1367
reported that retinol palmitate supplementation
(1,000 to 9,000 IU/day
-1
) for 28 days decreased
brain-derived neurotrophic factor (BDNF) in
the rat hippocampus (De Oliveira et al. 2011a).
BDNF regulates neuronal plasticity, bioenergetics,
mitochondrial biogenesis, and neuronal survival, to
cite a few (Cheng et al. 2010, Agrawal et al. 2014,
Marosi and Mattson 2014). Decreased BDNF
may lead to limited mitochondrial biogenesis
and mitochondrial dysfunction during events of
neurotoxicity. By decreasing BDNF levels, vitamin
A impairs not only neuronal plasticity that is
necessary to the learning and memory processes,
but also the ability of this organelle to produce
Figure 1 - A summary of possible effects elicited by vitamin A (either retinol or retinol palmitate) on the
mammalian central nervous system. It has been demonstrated that vitamin A supplementation (in the form
of retinol palmitate or retinol) is able to induce an increase in the immunocontent of RAGE, which mediates
neuroinammation in some experimental models. Additionally, such supplementation may lead to altered redox
environment parameters, which has been evidenced as oxidative and nitrosative stress. Moreover, vitamin A
supplementation induces mitochondrial dysfunction in vitro and in vivo. Increased levels of O
2
-l
may affect
the function of several enzymes, including catalase (CAT) and Mn-superoxide dismutase (Mn-SOD, the
mitochondrial isoform of SOD). Furthermore, O
2
-l
may be a consequence of impaired electron transfer chain
due to vitamin A-dependent electron leakage from that complex system. Vitamin A, which is liposoluble,
may interact with mitochondrial membranes disrupting the normal ow of electrons between mitochondrial
complexes, which in turn may favor abnormal electron ux. Alternatively, increased activity of this system may
be due to an augmentation in the need for adenosine triphosphate (ATP) in acute phases of intoxication with
vitamin A. Both Mn-SOD and monoamine oxidase (MAO) enzyme activities may lead to increased hydrogen
peroxide (H
2
O
2
) production, which may diffuse from mitochondria to other organelles. Increased levels of
oxidative and nitrosative stress markers may induce α-synuclein aggregation, which may interact negatively
with mitochondria (please see text for details). General cell dysfunction and cell death may result if vitamin A
concentration remains elevated. Other effects may be induced by vitamin A and/or retinoids on neuronal cells.
This gure represents just a summary of some of them.
VitaminA
supplementaon
Oxidave
stress
Nitrosave
stress
RAGE
immunocontent
Neuroinflammaon?
Mitochondrial
dysfuncon
- O
2
-
producon
- altered Mn-SOD enzyme acvity
H
2
O
2
producon
-
lipidperoxidaon in
mitochondrialmembranes
- impaired electron transfer chain
acvity
reacveoxygen
speciesproducon(O
2
-
,H
2
O
2
,
other)
-
MAOenzymeacvity
H
2
O
2
producon
- increasedsuscepbility to
chemical challengesincluding
H
2
O
2
,CaCl
2
,and amyloid-beta
pepdes
- mitochondrial swelling
-
cytochrome crelease
- caspase3acvaon
-
proteincarbonylaon
-
lipid peroxidaon
- alteredenzymacanoxidant
defenses
-
non-enzymac anoxidant
defenses
-
3-nitrotyrosinecontent
α-synuclein
aggregaon
General cellular
dysfuncon
Cell death
An Acad Bras Cienc (2015) 87 (2 Suppl.)
1368 MARCOS ROBERTO DE OLIVEIRA
adequate amounts of ATP needed to counteract acute
and chronic stress. In fact, it was demonstrated that
vitamin A affects mitochondrial function in vitro
and in vivo, as discussed above.
In another study, it was observed that vitamin
A daily administrated to rats is able to increase
receptor for advanced glycation endproducts
(RAGE) immunocontent in rat cerebral cortex (De
Oliveira et al. 2009e). This receptor is implicated
in the amplification of oxidative stress by a
neuroinammation-related mechanism (Brownlee
2000, Schmidt et al. 2001, Bierhaus et al. 2005).
Moreover, RAGE may play a crucial role in the
onset and progression of Alzheimers disease, as
previously postulated (Sato et al. 2006). In fact,
RAGE mediates the transport of β-amyloid peptides
from blood to brain across the blood-brain barrier
(Deane et al. 2003) and possibly plays a crucial
role in the onset of Alzheimers disease in diabetic
patients. Additionally, sustained RAGE activation
may trigger cell death and tissue dysfunction
(Bierhaus et al. 2005). More investigations are
needed to better address the role of vitamin A on
inducing RAGE activation in brain.
It was recently demonstrated that retinol
palmitate supplementation at 100, 200, or 500 IU/
kg.day
-1
for 2 months did not induce any antioxidant
effect in frontal cortex, hippocampus, striatum,
and cerebellum of adult female rats (De Oliveira
et al. 2011b). Retinol palmitate at 100 IU/kg is
equivalent to 7000 IU/day for a human weighing
70-kg. Such dosage is far below the approximate
25,000 IU/day that some vitamin A supplements
users ingest. Additionally, such supplementation
did not decrease endoplasmic reticulum stress,
as assessed through quantication of BiP/GRP78
protein level. In addition, vitamin A did not affect
either TNF-α or RAGE immunocontent, showing
that vitamin A may not be the best choice to prevent
inammation in such brain areas.
Interestingly, it was reported that in vivo
retinol palmitate supplementation increased in
vitro susceptibility of mitochondrial to different
challenges. Mitochondria were isolated from
substantia nigra, striatum, frontal cortex, and
hippocampus and challenged with H
2
O
2
, β-amyloid
peptide
1-40
, and CaCl
2
and it was observed an
increased impact of each challenge on mitochondria
that were isolated from retinol palmitate-treated
rats (De Oliveira et al. 2012a, b). It suggests that
prior vitamin A supplementation may increase
vulnerability of mitochondria to posterior chemical
insult that affect mitochondrial electron transfer
chain activity, for example, as demonstrated. Thus,
excessive intake of vitamin A may, at least in part,
facilitate neuronal abnormalities (including both
redox and bioenergetics states) that may appear
from other pathological event, as for instance
increased rates of β-amyloid peptides production
in the case of Alzheimer disease. However, the data
obtained with animal research are not sufcient to
conclude that vitamin A supplementation is a risk
factor for neurodegenerative diseases in humans.
Nonetheless, it has been demonstrated that vitamin
A intake among well-nourished subjects may lead
to decreased life quality and increased mortality
rates (Bjelakovic et al. 2007, 2008, 2012, 2014).
Recently, it was suggested that meoquine (a drug
used to prevent and treat malaria) may elicit its
deleterious effects by altering the concentrations
of retinoids in circulation, leading to cognitive
disturbances, as for example, anxiety, depression,
psychosis, and violence (Mawson 2013). The
author suggests that mefloquine would be able
to impair retinoid metabolism in liver, causing
posterior spillage of retinoids from liver to blood
at toxic concentrations. Takeda et al. (2014) did not
nd any association between blood levels or dietary
intake of retinoids and the risk of Parkinson’s
disease, i.e. whether decreased levels of retinoids
may favor PD is not known, but it did not prevent
individuals from such neurodegenerative disease.
In spite of this, some authors have reported that
vitamin A derivatives may reduce chemotherapy-
associated neuropathy in both animal model and
patients under lung cancer therapy (Arrietá et al.
2011). Furthermore, retinol and retinoids possess
antioxidant ability, since such effects have been
An Acad Bras Cienc (2015) 87 (2 Suppl.)
THE NEUROTOXIC EFFECTS OF VITAMIN A AND RETINOIDS 1369
demonstrated in different experimental models.
However, it is mainly an issue of dosage. Depending
on retinoid concentration, but also other factors,
as for instance age, gender, and some nutritional
parameters, as well as exposition to environmental
toxicants, retinoids may favor a pro-oxidant state
and cell damage with consequent increased rates
of cell death and inammation. Some of the effects
discussed here are summarized in Figure 1.
CONCLUSIONS
Overall, even though vitamin A is an essential
micronutrient to normal brain development and
function, caution must be taken when administering
such vitamin to individuals without any sign of
deciency and/or with history of neurodegenerative
diseases in the family, for example, since central
nervous system is a clear target of vitamin
A-associated toxicity. The utilization of vitamin
A or retinoids in the treatment of some types of
cancer and dermatological disturbances is based
on the fact that such molecules may trigger cell
death or slow cell cycle progression, leading
to decreased rates of tumor growth. However, it
would be catastrophic if an individual with history
of neurodegenerative disease in the family exceeds
vitamin A intake through either supplement use
or clinical administration, for example. More
investigations are needed to clarify the mechanisms
by which vitamin A and its derivatives affect
neuronal function, as well as the glial network.
ACKNOWLEDGMENTS
I would like to thank MSc. Fernanda Rafaela
Jardim for the help with English grammar revision.
RESUMO
A vitamina A (retinol) e seus congêneres – os retinoides
– participam de um vasto número de eventos biológicos,
como por exemplo, diferenciação, proliferação,
sobrevivência, e morte da célula necessários para manter
a homeostasia tecidual. Além disso, tais moléculas podem
ser aplicadas como agentes terapêuticos no caso de
algumas doenças, incluindo distúrbios dermatológicos,
imunodeciência, e câncer (principalmente, leucemia).
Apesar disto, há um crescente corpo de evidências
mostrando que doses de vitamina A que excedem as
necessidades nutricionais podem levar a consequências
negativas, incluindo disfunção do estado bioenergético,
prejuízo redox, sinalização celular alterada, e morte
ou proliferação celulares, dependendo do tipo celular.
Neurotoxicidade tem sido demonstrada há bastante
tempo como um possível efeito colateral do consumo
inadvertido ou mesmo sob recomendação médica
de vitamina A e de retinoides em doses moderadas
e altas. No entanto, o mecanismo exato pelo qual tais
moléculas exercem um papel neurotóxico ainda não é
claro. Nesta revisão, dados recentes em relação aos
achados moleculares associados com a neurotoxicidade
relacionada à vitamina A são discutidos.
Palavras-chave: disfunção mitocondrial, neurotoxicidade,
estresse oxidativo, retinoides, vitamina A.
REFERENCES
A
GRAWAL R, TYAGI E, VERGNES L, REUE K AND GOMEZ-
P
INILLA F. 2014. Coupling energy homeostasis with a
mechanism to support plasticity in brain trauma. Biochim
Biophys Acta 1842: 535-546.
A
IMONE JB, LI Y, L EE SW, CLEMENSON GD, DENG W
AND GAGE FH. 2014. Regulation and function of adult
neurogenesis: from genes to cognition. Physiol Rev 94:
991-1026.
A
LLEN LH AND HASKELL M. 2002. Estimating the potential
for vitamin A toxicity in women and young children. J
Nutr 132: 2907S-2919S.
A
RRIETA Ó ET AL. 2011. Retinoic acid reduces chemotherapy-
induced neuropathy in an animal model and patients with
lung cancer. Neurology 77: 987-995.
B
IERHAUS A, HUMPERT PM, MORCOS M, WENDT T, CHAVAKIS
T, A
RNOLD B, STERN DM AND NAWROTH PP. 2005.
Understanding RAGE, the receptor for advanced glycation
end products. J Mol Med (Berl) 83: 876-886.
B
JELAKOVIC G, NIKOLOVA D AND GLUUD C. 2014. Antioxidant
supplements and mortality. Curr Opin Clin Nutr Metab
Care 17: 40-44.
B
JELAKOVIC G, NIKOLOVA D, GLUUD LL, SIMONETTI RG
AND GLUUD C. 2007. Mortality in randomized trials of
antioxidant supplements for primary and secondary
prevention: systematic review and meta-analysis. JAMA
297: 842-857.
An Acad Bras Cienc (2015) 87 (2 Suppl.)
1370 MARCOS ROBERTO DE OLIVEIRA
BJELAKOVIC G, NIKOLOVA D, GLUUD LL, SIMONETTI RG AND
G
LUUD C. 2008. Antioxidant supplements for prevention of
mortality in healthy participants and patients with various
diseases. Cochrane Database Syst Rev 2: CD007176.
B
JELAKOVIC G, NIKOLOVA D, GLUUD LL, SIMONETTI RG AND
G
LUUD C. 2012. Antioxidant supplements for prevention of
mortality in healthy participants and patients with various
diseases. Cochrane Database Syst Rev 3: CD007176.
B
ROWNLEE M. 2000. Negative consequences of glycation.
Metabolism 49: 9-13.
C
ARBALLAL S, BARTESAGHI S AND RADI R. 2014. Kinetic and
mechanistic considerations to assess the biological fate of
peroxynitrite. Biochim Biophys Acta 1840: 768-780.
C
ARTA M, STANCAMPIANO R, TRONCI E, COLLU M, USIELLO
A, M
ORELLI M AND FADDA F. 2006. Vitamin A deficiency
induces motor impairments and striatal cholinergic
dysfunction in rats. Neuroscience 139: 1163-1172.
C
ASTENMILLER JJN AND WEST CE. 1998. Bioavailability and
bioconversion of carotenoids. Annu Rev Nutr 18: 19-38.
C
HENG A, HOU Y AND MATTSON MP. 2010. Mitochondria and
neuroplasticity. ASN Neuro 2: e00045.
C
ONTE DA FROTA JR ML, GOMES DA SILVA E, BEHR GA,
R
OBERTO DE OLIVEIRA M, DAL-PIZZOL F, KLAMT F
AND MOREIRA JC. 2006. All-trans retinoic acid induces
free radical generation and modulate antioxidant enzyme
activities in rat Sertoli cells. Mol Cell Biochem 285: 173-
179.
C
RANDALL J, SAKAI Y, Z HANG J, KOUL O, MINEUR Y, C RUSIO
WE
AND MCCAFFERY P. 2004. 13-cis-retinoic acid
suppresses hippocampal cell division and hippocampal-
dependent learning in mice. Proc Natl Acad Sci USA 101:
5111-5116.
D
AS BC ET AL. 2014. Retinoic acid signaling pathways in
development and diseases. Bioorg Med Chem 22: 673-683.
D
E BITTENCOURT PASQUALI MA, DE RAMOS VM, ALBANUS
RD, K
UNZLER A, DE SOUZA LH, DALMOLIN RJ, GELAIN
DP, R
IBEIRO L, CARRO L AND MOREIRA JC. In press. Gene
Expression Profile of NF-κB, Nrf2, Glycolytic, and p53
Pathways During the SH-SY5Y Neuronal Differentiation
Mediated by Retinoic Acid.
D
E OLIVEIRA MR, DA ROCHA RF AND MOREIRA JC. 2012b.
Increased susceptibility of mitochondria isolated from
frontal cortex and hippocampus of vitamin A-treated rats
to non-aggregated amyloid-β peptides 1–40 and 1–42.
Acta Neuropsychiatr 24: 101-108.
D
E OLIVEIRA MR, DA ROCHA RF, PASQUALI MA AND MOREIRA
JC. 2012a. The effects of vitamin A supplementation for 3
months on adult rat nigrostriatal axis: increased monoamine
oxidase enzyme activity, mitochondrial redox dysfunction,
increased β-amyloid(1-40) peptide and TNF contents,
and susceptibility of mitochondria to an in vitro H
2
O
2
challenge. Brain Res Bull 87: 432-444.
D
E OLIVEIRA MR, DA ROCHA RF, SCHNORR CE AND MOREIRA
JC. 2012c. L-NAME cotreatment did prevent neither
mitochondrial impairment nor behavioral abnormalities in
adult Wistar rats treated with vitamin A supplementation.
Fundam Clin Pharmacol 26: 513-529.
D
E OLIVEIRA MR, DA ROCHA RF, STERTZ L, FRIES GR, DE
O
LIVEIRA DL, KAPCZINSKI F AND MOREIRA JC. 2011a.
Total and mitochondrial nitrosative stress, decreased brain-
derived neurotrophic factor (BDNF) levels and glutamate
uptake, and evidence of endoplasmic reticulum stress in
the hippocampus of vitamin A-treated rats. Neurochem
Res 36: 506-517.
D
E OLIVEIRA MR, DE BITTENCOURT PASQUALI MA,
S
ILVESTRIN RB, MELLO E SOUZA T AND MOREIRA JC.
2007a. Vitamin A supplementation induces a prooxidative
state in the striatum and impairs locomotory and
exploratory activity of adult rats. Brain Res 1169: 112-119.
D
E OLIVEIRA MR, LORENZI R, SCHNORR CE, MORRONE M AND
M
OREIRA JC. 2011b. Increased 3-nitrotyrosine levels in
mitochondrial membranes and impaired respiratory chain
activity in brain regions of adult female rats submitted to
daily vitamin A supplementation for 2 months. Brain Res
Bull 86: 246-253.
D
E OLIVEIRA MR AND MOREIRA JC. 2007. Acute and chronic
vitamin A supplementation at therapeutic doses induces
oxidative stress in submitochondrial particles isolated
from cerebral cortex and cerebellum of adult rats. Toxicol
Lett 173: 145-150.
D
E OLIVEIRA MR AND MOREIRA JC. 2008. Impaired redox
state and respiratory chain enzyme activities in the
cerebellum of vitamin A-treated rats. Toxicology 253:
125-130.
D
E OLIVEIRA MR, OLIVEIRA MW, BEHR GA, DE
B
ITTENCOURT PASQUALI MA AND MOREIRA JC. 2009e.
Increased receptor for advanced glycation endproducts
immunocontent in the cerebral cortex of vitamin A-treated
rats. Neurochem Res 34: 1410-1416.
D
E OLIVEIRA MR, OLIVEIRA MW, BEHR GA, HOFF ML,
D
A ROCHA RF AND MOREIRA JC. 2009f. Evaluation
of the effects of vitamin A supplementation on adult rat
substantia nigra and striatum redox and bioenergetic states:
mitochondrial impairment, increased 3-nitrotyrosine and
alpha-synuclein, but decreased D2 receptor contents. Prog
Neuropsychopharmacol Biol Psychiatry 33: 353-362.
D
E OLIVEIRA MR, OLIVEIRA MW, BEHR GA AND MOREIRA
JC. 2009a. Vitamin A supplementation at clinical doses
induces a dysfunction in the redox and bioenergetics states,
but did change neither caspases activities nor TNF-alpha
levels in the frontal cortex of adult Wistar rats. J Psychiatr
Res 43: 754-762.
D
E OLIVEIRA MR, OLIVEIRA MW, DA ROCHA RF AND
M
OREIRA JC. 2009d. Vitamin A supplementation at
pharmacological doses induces nitrosative stress on the
An Acad Bras Cienc (2015) 87 (2 Suppl.)
THE NEUROTOXIC EFFECTS OF VITAMIN A AND RETINOIDS 1371
hypothalamus of adult Wistar rats. Chem Biol Interact 180:
407-413.
D
E OLIVEIRA MR, OLIVEIRA MW, LORENZI R, FAGUNDES
D
A ROCHA R AND FONSECA MOREIRA JC. 2009b. Short-
term vitamin A supplementation at therapeutic doses
induces a pro-oxidative state in the hepatic environment
and facilitates calcium-ion-induced oxidative stress in
rat liver mitochondria independently from permeability
transition pore formation: detrimental effects of vitamin A
supplementation on rat liver redox and bioenergetic states
homeostasis. Cell Biol Toxicol 25: 545-560.
D
E OLIVEIRA MR, OLIVEIRA MW AND MOREIRA JC. 2010.
Pharmacological doses of vitamin A increase caspase-3
activity selectively in cerebral cortex. Fundam Clin
Pharmacol 24: 445-450.
D
E OLIVEIRA MR, SILVESTRIN RB, MELLO E SOUZA T AND
M
OREIRA JC. 2007b. Oxidative stress in the hippocampus,
anxiety-like behavior and decreased locomotory and
exploratory activity of adult rats: effects of sub acute
vitamin A supplementation at therapeutic doses.
Neurotoxicology 28: 1191-1199.
D
E OLIVEIRA MR, SILVESTRIN RB, MELLO E SOUZA T AND
M
OREIRA JC. 2008. Therapeutic vitamin A doses increase
the levels of markers of oxidative insult in substantia nigra
and decrease locomotory and exploratory activity in rats
after acute and chronic supplementation. Neurochem Res
33: 378-383.
D
E OLIVEIRA MR, SOARES OLIVEIRA MW, MÜLLER HOFF
ML, B
EHR GA, DA ROCHA RF AND FONSECA MOREIRA
JC. 2009c. Evaluation of redox and bioenergetics states in
the liver of vitamin A-treated rats. Eur J Pharmacol 610:
99-105.
D
EANE R ET AL. 2003. RAGE mediates amyloid-beta peptide
transport across the blood-brain barrier and accumulation
in brain. Nat Med 9: 907-913.
E
DMONDSON DE. 2014. Hydrogen peroxide produced by
mitochondrial monoamine oxidase catalysis: biological
implications. Curr Pharm Des 20: 155-160.
F
ENAUX P, CHOMIENNE C AND DEGOS L. 2001. Treatment
of acute promyelocytic leukaemia. Best Pract Res Clin
Haematol 14: 153-174.
F
ISKER AB ET AL. 2014. High-dose vitamin A with vaccination
after 6 months of age: a randomized trial. Pediatrics 134:
e739-748.
F
OLLI C, CALDERONE V, O TTONELLO S, BOLCHI A, ZANOTTI
G, S
TOPPINI M AND BERNI R. 2001. Identification, retinoid
binding, and x-ray analysis of a human retinol-binding
protein. Proc Natl Acad Sci USA 98: 3710-3715.
F
URR HC, AMEDEE-MANESME O, CLIFFORD AJ, BERGEN HR
3
RD, JONES AD, ANDERSON DP AND OLSON JA. 1989.
Vitamin A concentrations in liver determined by isotope
dilution assay with tetradeuterated vitamin A and by
biopsy in generally healthy adult humans. Am J Clin Nutr
49: 713-716.
G
ELAIN DP AND MOREIRA JC. 2008. Evidence of increased
reactive species formation by retinol, but not retinoic acid,
in PC12 cells. Toxicol In Vitro 22: 553-558.
G
IASSON BI, DUDA JE, MURRAY IV, CHEN Q, SOUZA JM,
H
URTIG HI, ISCHIROPOULOS H, TROJANOWSKI JQ AND LEE
VM. 2000. Oxidative damage linked to neurodegeneration
by selective alpha-synuclein nitration in synucleinopathy
lesions. Science 290: 985-989.
G
RAHAM DG. 1978. Oxidative pathways for catecholamines in
the genesis of neuromelanin and cytotoxic quinones. Mol
Pharmacol 14: 633-643.
G
REEN DR, GALLUZZI L AND KROEMER G. 2014. Cell biology.
M
etabolic control of cell death. Science 345(6203):
1250256.
H
ALLIWELL B. 2006. Oxidative stress and neurodegeneration:
where are we now? J Neurochem 97: 1634-1658.
H
OU N, REN L, GONG M, BI Y, G U Y, D ONG Z, LIU Y, C HEN
J
AND LI T. 2015. Vitamin A Deficiency Impairs Spatial
Learning and Memory: The Mechanism of Abnormal CBP-
Dependent Histone Acetylation Regulated by Retinoic
Acid Receptor Alpha. Mol Neurobiol 51: 633-647.
H
UANG P, CHANDRA V AND RASTINEJAD F. 2014. Retinoic
acid actions through mammalian nuclear receptors. Chem
Rev 114: 233-254.
H
ÜTTEMANN M, PECINA P, RAINBOLT M, SANDERSON TH,
K
AGAN VE, SAMAVATI L, DOAN JW AND LEE I. 2011. The
multiple functions of cytochrome c and their regulation
in life and death decisions of the mammalian cell: From
respiration to apoptosis. Mitochondrion 11: 369-381.
J
IANG W ET AL. 2012. Vitamin A deficiency impairs postnatal
cognitive function via inhibition of neuronal calcium
excitability in hippocampus. J Neurochem 121: 932-943.
J
ORG M, SCAMMELLS PJ AND CAPUANO B. 2014. The
dopamine D2 and adenosine A2A receptors: past, present
and future trends for the treatment of Parkinson’s disease.
Curr Med Chem 21: 3188-3210.
K
AWAGUCHI R, YU J, HONDA J, HU J, WHITELEGGE J, PING P,
W
IITA P, BOK D AND SUN H. 2007. A membrane receptor
for retinol binding protein mediates cellular uptake of
vitamin A. Science 315: 820-825.
K
LAMT F, DAL-PIZZOL F, GELAIN DP, DALMOLIN RS,
B
IRNFELD DE OLIVEIRA R, BASTIANI M, HORN F AND
F
ONSECA MOREIRA JC. 2008. Vitamin A treatment induces
apoptosis through an oxidant-dependent activation of the
mitochondrial pathway. Cell Biol Int 32: 100-106.
K
LAMT F, ROBERTO DE OLIVEIRA M AND MOREIRA JC. 2005.
Retinol induces permeability transition and cytochrome c
release from rat liver mitochondria. Biochim Biophys Acta
1726: 14-20.
K
ONO Y AND FRIDOVICH I. 1982. Superoxide radical inhibits
catalase. J Biol Chem 257: 5751-5754.
An Acad Bras Cienc (2015) 87 (2 Suppl.)
1372 MARCOS ROBERTO DE OLIVEIRA
LAM HS, CHOW CM, POON WT, LAI CK, CHAN KC, YEUNG
WL, H
UI J, CHAN AY AND NG PC. 2006. Risk of vitamin
A toxicity from candy-like chewable vitamin supplements
for children. Pediatrics 118: 820-824.
L
ANE MA AND BAILEY SJ. 2005. Role of retinoid signalling in
the adult brain. Prog Neurobiol 75: 275-293.
L
EBEL CP, ISCHIROPOULOS H AND BONDY SC. 1992.
Evaluation of the probe 2’,7’-dichlorofluorescin as
an indicator of reactive oxygen species formation and
oxidative stress. Chem Res Toxicol 5: 227-231.
L
OTHARIUS J AND BRUNDIN P. 2002. Pathogenesis of
Parkinson’s disease: dopamine, vesicles and alpha-
synuclein. Nat Rev Neurosci 3: 932-942.
M
ACTIER H AND WEAVER LT. 2005. Vitamin A and preterm
infants: what we know, what we don’t know, and what
we need to know. Arch Dis Child Fetal Neonatal Ed 90:
F103-108.
M
AKER HS, WEISS C, SILIDES DJ AND COHEN G. 1981.
Coupling of dopamine oxidation (monoamine oxidase
activity) to glutathione oxidation via the generation of
hydrogen peroxide in rat brain homogenates. J Neurochem
36: 589-593.
M
AROSI K AND MATTSON MP. 2014. BDNF mediates adaptive
brain and body responses to energetic challenges. Trends
Endocrinol Metab 25: 89-98.
M
AWSON A. 2013. Mefloquine use, psychosis, and violence: a
retinoid toxicity hypothesis. Med Sci Monit 19: 579-583.
M
YHRE AM, CARLSEN MH, BOHN SK, WOLD HL, LAAKE P
AND BLOMHOFF R. 2003. Water-miscible, emulsified, and
solid forms of retinol supplements are more toxic than oil-
based preparations. Am J Clin Nutr 78: 1152-1159.
N
AGL F, SCHÖNHOFER K, SEIDLER B, MAGES J, ALLESCHER
HD, S
CHMID RM, SCHNEIDER G AND SAUR D. 2009.
Retinoic acid-induced nNOS expression depends on a
novel PI3K/Akt/DAX1 pathway in human TGW-nu-I
neuroblastoma cells. Am J Physiol Cell Physiol 297:
C1146-C1156.
N
APOLI JL. 1996. Retinoic acid biosynthesis and metabolism.
FASEB J 10: 993-1001.
N
APOLI JL. 1999. Retinoic acid: its biosynthesis and
metabolism. Prog Nucleic Acid Res Mol Biol 63: 139-188.
N
APOLI JL. 2012. Physiological insights into all-trans-retinoic
acid biosynthesis. Biochim Biophys Acta 1821: 152-167.
N
AVIGATORE-FONZO LS, DELGADO SM, GOLINI RS
AND ANZULOVICH AC. 2014. Circadian rhythms of
locomotor activity and hippocampal clock genes
expression are dampened in vitamin A-deficient rats.
Nutr Res 34: 326-335.
N
OY N. 2000. Retinoid-binding proteins: Mediators of retinoid
action. Biochem J 348: 481-495.
O’R
EILLY KC, SHUMAKE J, GONZALEZ-LIMA F, LANE MA
AND BAILEY SJ. 2006. Chronic administration of 13-cis-
retinoic acid increases depression-related behavior in
mice. Neuropsychopharmacology 31: 1919-1927.
O
LSON J. 1993. Vitamin A. Present Knowledge in Nutrition.
The Nutrition Foundation, Washington, DC, p. 176-191.
P
ENNISTON KL AND TANUMIHARDJO SA. 2006. The acute and
chronic toxic effects of vitamin A. Am J Clin Nutr 83: 191-
201.
P
ISKUNOV A, AL TANOURY Z AND ROCHETTE-EGLY C.
2014. Nuclear and extra-nuclear effects of retinoid acid
receptors: how they are interconnected. Subcell Biochem
70: 103-127.
R
ADI R. 2013. Peroxynitrite, a stealthy biological oxidant. J
Biol Chem 288: 26464-26472
R
ESTAK RM. 1972. Pseudotumor cerebri, psychosis, and
hypervitaminosis A. J Nerv Ment Dis 155: 72-75.
R
OCHETTE-EGLY C. 2015. Retinoic acid signaling and mouse
embryonic stem cell differentiation: Cross talk between
genomic and non-genomic effects of RA. Biochim
Biophys Acta 1851: 66-75.
R
ODAHL K AND MOORE T. 1943. The vitamin A content and
toxicity of bear and seal liver. Biochem J 37: 166-168.
R
OSS DA. 2002. Recommendations for vitamin A
supplementation. J Nutr 131: 2902S-2906S.
S
AKAI Y, C RANDALL JE, BRODSKY J AND MCCAFFERY P. 2004.
13-cis Retinoic acid (accutane) suppresses hippocampal
cell survival in mice. Ann NY Acad Sci 1021: 436-440.
S
ATO T, SHIMOGAITO N, WU X, KIKUCHI S, YAMAGISHI S
AND TAKEUCHI M. 2006. Toxic advanced glycation end
products (TAGE) theory in Alzheimers disease. Am J
Alzheimers Dis Other Demen 21: 197-208.
S
AUVANT P, MEKKI N, CHARBONNIER M, PORTUGAL H,
L
AIRON D AND BOREL P. 2003. Amounts and types of fatty
acids in meals affect the pattern of retinoids secreted in
human chylomicrons after a high-dose preformed vitamin
A intake. Metabolism 52: 514-519.
S
CHMIDT AM, YAN SD, YAN SF AND STERN DM. 2001.
The multiligand receptor RAGE
as a progression factor
amplifying immune and inflammatory responses. J Clin
Invest 108: 949-955.
S
HEARER KD, FRAGOSO YD, CLAGETT-DAME M AND
M
CCAFFERY PJ. 2012a. Astrocytes as a regulated source
of retinoic acid for the brain. Glia 60: 1964-1976.
S
HEARER KD, STONEY PN, MORGAN PJ AND MCCAFFERY
PJ. 2012b. A vitamin for the braib. Trends Neurosci 35:
733-741.
S
HEEHAN D, MEADE G, FOLEY VM AND DOWD CA.
2001. Structure, function and evolution of glutathione
transferases: implications for classification of non-
mammalian members of an ancient enzyme superfamily.
Biochem J 360: 1-16.
S
NODGRASS SR. 1992. Vitamin neurotoxicity. Mol
Neurobiol 6: 41-73.
An Acad Bras Cienc (2015) 87 (2 Suppl.)
THE NEUROTOXIC EFFECTS OF VITAMIN A AND RETINOIDS 1373
SNYDER H, MENSAH K, THEISLER C, LEE J, MATOUSCHEK A
AND WOLOZIN B. 2003. Aggregated and monomeric alpha-
synuclein bind to the S6’ proteasomal protein and inhibit
proteasomal function. J Biol Chem 278: 11753-11759.
S
OUZA JM, GIASSON BI, CHEN Q, LEE VM AND ISCHIROPOULOS
H. 2000. Dityrosine cross-linking promotes formation
of stable alpha-synuclein polymers. Implication of
nitrative and oxidative stress in the pathogenesis of
neurodegenerative synucleinopathies. J Biol Chem 275:
18344-18349.
S
QUADRITO GL AND PRYOR WA. 1998. Oxidative chemistry
of nitric oxide: the roles of superoxide, peroxynitrite, and
carbon dioxide. Free Radic Biol Med 25: 392-403.
T
AFTI M AND GHYSELINCK NB. 2007. Functional implication
of the vitamin A signaling pathway in the brain. Arch
Neurol 64: 1706-1711.
T
AKEDA A, NYSSEN OP, SYED A, JANSEN E, BUENO-DE-
M
ESQUITA B AND GALLO V. 2014. Vitamin A and
carotenoids and the risk of Parkinson’s disease: a
systematic review and meta-analysis. Neuroepidemiology
42: 25-38.
T
ANUMIHARDJO SA. 2004. Assessing vitamin A status: past,
present and future. J Nutr 134: 290S-293S.
T
HOMPSON HASKELL G, MAYNARD TM, SHATZMILLER RA
AND LAMANTIA AS. 2002. Retinoic acid signaling at sites
of plasticity in the mature central nervous system. J Comp
Neurol 452: 228-241.
T
SUNATI H, IWASAKI H, KAWAI Y, TANAKA T, UEDA
T, U
CHIDA M AND NAKAMURA T. 1990. Reduction
of leukemia cell growth in a patient with acute
promyelocytic leukemia treated by retinol palmitate.
Leukemia Res 14: 595-600.
V
AN LOO-BOUWMAN CA, NABER TH AND SCHAAFSMA G.
2014. A review of vitamin A equivalency of β-carotene in
various food matrices for human consumption. Br J Nutr
111: 2153-2166.
V
ON LINTIG J. 2012. Provitamin A metabolism and functions
in mammalian biology. Am J Clin Nutr 96: 1234S-1244S.
W
ANG H AND JOSEPH JA. 1999. Quantifying cellular oxidative
stress by dichlorofluorescein assay using microplate
reader. Free Radic Biol Med 27: 612-616.
... Vitamin A (carotenoids and trans-retinol and its esters) is a group of fat-soluble substances that enter the body with food in the form of retinol esters and carotenoids, which are then metabolized into active compounds and are involved in many physiological processes, such as the neutralization of free radicals, regulation of protein synthesis, regulation of cell growth, and differentiation [7,8] (Table 1). Due to the variety of functions vitamin A performs, a lot of research has been devoted to its role in recent years, including the study of the relationship between the serum vitamin A level and the risk of ALS. ...
... Is likely to reduce the risk of ALS [7][8][9][10] Vitamin B1 (thiamine) Participation in oxidative metabolism; neuroprotection (reduction of neuroinflammation and neurodegeneration); participation in carbohydrate metabolism and associated energy, fat, protein, and water-salt metabolism; regulation of the activity of the central nervous system; optimization of the impact on cognitive activity; participation in the neutralization of xenobiotics (protection from the toxic effects of alcohol and nicotine); slowing down the aging process; imitation of the action of acetylcholine on neurons; participation in the exchange of zinc and manganese. ...
... At the same time, the approach to the choice of nutrients for patients with ALS should be careful and personalized; it should be negotiated with the consulting physician. Self-medication with multivitamins and dietary supplements is unacceptable [8]. ...
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Amyotrophic lateral sclerosis (ALS) is an incurable chronic progressive neurodegenerative disease with the progressive degeneration of motor neurons in the motor cortex and lower motor neurons in the spinal cord and the brain stem. The etiology and pathogenesis of ALS are being actively studied, but there is still no single concept. The study of ALS risk factors can help to understand the mechanism of this disease development and, possibly, slow down the rate of its progression in patients and also reduce the risk of its development in people with a predisposition toward familial ALS. The interest of researchers and clinicians in the protective role of nutrients in the development of ALS has been increasing in recent years. However, the role of some of them is not well-understood or disputed. The objective of this review is to analyze studies on the role of nutrients as environmental factors affecting the risk of developing ALS and the rate of motor neuron degeneration progression. Methods: We searched the PubMed, Springer, Clinical keys, Google Scholar, and E-Library databases for publications using keywords and their combinations. We analyzed all the available studies published in 2010-2020. Discussion: We analyzed 39 studies, including randomized clinical trials, clinical cases, and meta-analyses, involving ALS patients and studies on animal models of ALS. This review demonstrated that the following vitamins are the most significant protectors of ALS development: vitamin B12, vitamin E > vitamin C > vitamin B1, vitamin B9 > vitamin D > vitamin B2, vitamin B6 > vitamin A, and vitamin B7. In addition, this review indicates that the role of foods with a high content of cholesterol, polyunsaturated fatty acids, urates, and purines plays a big part in ALS development. Conclusion: The inclusion of vitamins and a ketogenic diet in disease-modifying ALS therapy can reduce the progression rate of motor neuron degeneration and slow the rate of disease progression, but the approach to nutrient selection must be personalized. The roles of vitamins C, D, and B7 as ALS protectors need further study.
... In addition to this, Vitamin E administration during radiation therapy to bone marrow polychromatic erythrocytes, reduced oxidative stress-induced micronucleus development. These inhibitory effects were reportedly due to the antioxidant potential as well as the modulation of DNA repair structures and exclusion of damaged DNA from host cells [50]. In another study, it was observed that Vitamin A or retinol exhibited antimutagenic activity due to its antioxidant properties. ...
... The important phytoconstituents known to produce antioxidant activity are phenolic compounds, flavonoids, tannins, carotenoids, diterpenoids, coumarins, anthraquinones, saponins, and xanthones [54,55]. Evidence from previous studies suggest a strong relationship between antioxidant property and antimutagenic potential [50][51][52][53]. Interestingly, some dietary components, such as tomatoes, carrots, spinach, turmeric, mustard oil, and guava, were found to possess anti-mutagenic potential due to antioxidant action [56]. ...
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Mutagenic complications can cause disease in both present as well as future generations. The disorders are caused by exogenous and endogenous agents that damage DNA beyond the normal repair mechanism. Rapid industrialization and the population explosion have contributed immensely to changes in the environment, leading to unavoidable exposure to mutagens in our daily life. As it is impossible to prevent exposure, one of the better approaches is to increase the intake of anti-mutagenic substances derived from natural resources. This review summarizes some of the important plants in Saudi Arabia that might have the potential to exhibit anti-mutagenic activity. The data for the review were retrieved from Google scholar, NCBI, PUBMED, EMBASE and the Web of Science. The information in the study has importance since one of the major reasons for mutation is viral infection. Considering the pandemic situation due to novel coronavirus and its aftermath, the native plants of Saudi Arabia could become an important source for reducing mutagenic complications associated with exogenous agents, including viruses.
... Vitamin A (retinol) is a lipid-soluble essential vitamin that plays important roles in several biological cellular events, including differentiation, proliferation, survival, and death, and it plays also a role in maintaining tissue homeostasis [67]. It can be supplied to the human body in two different forms: as β-carotene taken from a vegetable source or as retinol esters taken from an animal source [67]. ...
... Vitamin A (retinol) is a lipid-soluble essential vitamin that plays important roles in several biological cellular events, including differentiation, proliferation, survival, and death, and it plays also a role in maintaining tissue homeostasis [67]. It can be supplied to the human body in two different forms: as β-carotene taken from a vegetable source or as retinol esters taken from an animal source [67]. Then, both forms are converted to retinal or to retinoic acid (a carboxylic acid) through oxidation of the hydroxyl group [68,69]. ...
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Peripheral nerves are highly susceptible to injuries induced from everyday activities such as falling or work and sport accidents as well as more severe incidents such as car and motorcycle accidents. Many efforts have been made to improve nerve regeneration, but a satisfactory outcome is still unachieved, highlighting the need for easy to apply supportive strategies for stimulating nerve growth and functional recovery. Recent focus has been made on the effect of the consumed diet and its relation to healthy and well-functioning body systems. Normally, a balanced, healthy daily diet should provide our body with all the needed nutritional elements for maintaining correct function. The health of the central and peripheral nervous system is largely dependent on balanced nutrients supply. While already addressed in many reviews with different focus, we comprehensively review here the possible role of different nutrients in maintaining a healthy peripheral nervous system and their possible role in supporting the process of peripheral nerve regeneration. In fact, many dietary supplements have already demonstrated an important role in peripheral nerve development and regeneration; thus, a tailored dietary plan supplied to a patient following nerve injury could play a non-negotiable role in accelerating and promoting the process of nerve regeneration.
... In addition, we found that most of the vitamins belong to antioxidants, and in addition to studying the value of vitamins in cancer, the relationship between other antioxidants and cancer can be explored, such as melatonin, anthocyanins, astaxanthin, and quercetin. Finally, it should be noted that excessive use of vitamins will produce corresponding toxic side effects, such as excessive intake of carotenoids will cause loss of appetite, yellow skin, poor sleep, affecting female ovulation and so on (50)(51)(52). Therefore, we recommend an appropriate increase in vitamin A intake within a safe dose range, especially an increase in dietary intake of vegetables, fruits, and animal products. ...
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Background Colorectal cancer (CRC) risk is linked to serum and dietary retinol and carotenoids, according to clinical and epidemiological research. However, the findings are not consistent. As a result, we did this meta-analysis to determine the link between them. Methods From 2000 through 2022, the PubMed, Web of Science, and Embase databases, as well as pertinent article references, were searched and filtered based on inclusion and exclusion criteria and literature quality ratings. High and low intake were used as controls, and OR (odds ratio) or RR (relative risk) and 95% confidence interval were extracted. The extracted data were plotted and analyzed using Stata12.0 software. Results A total of 22 relevant studies were included, including 18 studies related to diet and 4 studies related to serum. For high and low intake or concentration controls, the pooled OR was as follows: β-carotene (OR = 0.89, 95% CI: 0.78–1.03), α-carotene (OR = 0.87, 95% CI: 0.72–1.03), lycopene (OR = 0.93, 95% CI: 0.81–1.07), lutein/zeaxanthin (OR = 0.96, 95% CI: 0.87–1.07), β-cryptoxanthin (OR = 0.70, 95% CI: 0.48–1.01), total carotenoids (OR = 0.97, 95% CI: 0.81–1.15), retinol (OR = 0.99, 95% CI: 0.89–1.10), serum carotenoids (OR = 0.73, 95% CI: 0.58–0.93), serum retinol (OR = 0.62, 95% CI: 0.26–1.49). Subgroup analysis was performed according to tumor type, study type and sex. Conclusion Total carotenoid intake and Lutein/Zeaxanthin intake were not associated with CRC risk. High β-carotene, α-carotene, lycopene, and β-cryptoxanthin all tended to reduce CRC risk. Serum carotenoid concentrations were significantly inversely associated with CRC risk.
... Previous studies have indicated that retinoids and vitamin A derivatives cause mitochondrial dysfunction, and trigger reactive oxygen species (ROS) production to induce cellular damage and apoptosis (24,25). Additionally, ATRA has been reported to induce ROS production in Sertoli cells and NB4 cells (26,27). ...
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All-trans-retinoic acid (ATRA) has been clinically used to treat acute promyelocytic leukemia and is being studied to treat other types of cancer; however, the therapeutic role and mechanism of ATRA against cholangiocarcinoma (CCA) remain unclear. The present study investigated the cytotoxic effect and underlying mechanisms of ATRA on CCA cell lines. Cell viability was evaluated by sulforhodamine B assay. Intracellular reactive oxygen species (ROS) levels were assessed by dihydroethidium assay. Apoptosis analysis was performed by flow cytometry. The pathways of apoptotic cell death induction were examined using enzymatic caspase activity assay. Proteins associated with apoptosis were evaluated by western blotting. The effects on gene expression were analyzed by reverse transcription-quantitative PCR analysis. ATRA induced a concentration- and time-dependent toxicity in CCA cells. Furthermore, when the cytotoxicity of ATRA against retinoic acid receptor (RAR)-deficient cells was assessed, it was revealed that ATRA cytotoxicity was RARB-dependent. Following ATRA treatment, there was a significant accumulation of cellular ROS and ATRA-induced ROS generation led to an increase in the expression levels of apoptosis-inducing proteins and intrinsic apoptosis. Pre-treatment with ROS scavengers could diminish the apoptotic effect of ATRA, suggesting that ROS and mitochondria may have an essential role in the induction of apoptosis. Furthermore, following ATRA treatment, an increase in cellular ROS content was associated with suppressing nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2) and NRF2-downstream active genes. ATRA also suppressed cisplatin-induced NRF2 expression, suggesting that the enhancement of cisplatin cytotoxicity by ATRA may be associated with the downregulation of NRF2 signaling. In conclusion, the results of the present study demonstrated that ATRA could be repurposed as an alternative drug for CCA therapy.
... The most common forms of food-derived vitamin A are retinol (vitamin A1) and carotenoids (provitamin A) which are transferred to hepatic stellate cells (HSCs) and then stored as retinyl ester [113]. Retinol, especially found in animal foods including dairy, fish, egg yolks, and meat, is converted to retinal by retinyl ester and thereby plays a key role in low-light and color vision and mitochondrial oxidative phosphorylation [114,115]. By being converted to retinoic acid (RA), a hormone-like growth factor, retinol stimulates the differentiation and growth of epithelial cells and maintains the homeostasis of the skin and bone [116,117]. ...
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Helicobacter pylori as a class I carcinogen is correlated with a variety of severe gastroduodenal diseases; therefore, H. pylori eradication has become a priority to prevent gastric carcinogenesis. However, due to the emergence and spread of multidrug and single drug resistance mechanisms in H. pylori, as well as serious side effects of currently used antibiotic interventions, achieving successful H. pylori eradication has become exceedingly difficult. Recent studies expressed the intention of seeking novel strategies to improve H. pylori management and reduce the risk of H. pylori-associated intestinal and extragastrointestinal disorders. For which, vitamin supplementation has been demonstrated in many studies to have a tight interaction with H. pylori infection, either directly through the regulation of the host inflammatory pathways or indirectly by promoting the host immune response. On the other hand, H. pylori infection is reported to result in micronutrient malabsorption or deficiency. Furthermore, serum levels of particular micronutrients, especially vitamin D, are inversely correlated to the risk of H. pylori infection and eradication failure. Accordingly, vitamin supplementation might increase the efficiency of H. pylori eradication and reduce the risk of drug-related adverse effects. Therefore, this review aims at highlighting the regulatory role of micronutrients in H. pylori-induced host immune response and their potential capacity, as intrinsic antioxidants, for reducing oxidative stress and inflammation. We also discuss the uncovered mechanisms underlying the molecular and serological interactions between micronutrients and H. pylori infection to present a perspective for innovative in vitro investigations, as well as novel clinical implications.
... [25] [26][27] [28] Concentrations up to 220 µM can also be reached for a short time, but this requires a maximum tolerable dose of 3 g every 4 hours [17]. It is well known that smoking affects ascorbate plasma levels negatively [10] [11]. ...
Article
Ascorbic acid (vitamin C) is a vital nutrient that belongs to the group of antioxidants. Vitamin C plays an important role in the functioning of the central (CNS) and peripheral nervous system (PNS), including maturation and differentiation of neurons, formation of myelin, synthesis of catecholamines, modulation of neurotransmission and antioxidant protection. Neurological diseases and mental disorders are characterized by increased generation of free radicals. At the same time, the highest concentrations of vitamin C are found in the brain and neuroendocrine tissues. It is believed that vitamin C can affect the age of debut and the course of many neurological diseases and mental disorders. However, its potential therapeutic role continues to be studied. The efficacy and safety of vitamin C is likely influenced by the pharmacogenetic profile of the patient, including the carriage of single-nucleotide variants (SNVS), candidate genes associated with vitamin C metabolism in the human body in normal and neuropsychic disorders. The purpose of this thematic review is to update current knowledge about the role of vitamin C pharmacogenetics in the efficacy and safety of its use in neurological diseases (amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, etc.) and mental disorders (depression, anxiety, schizophrenia, etc.). Special attention is paid to the possibility of translating the results of pharmacogenetic studies into real clinical practice in neurology and psychiatry.
Thesis
La vitamine A (VA), ou rétinol, est une molécule essentielle au maintien des processus neurobiologiques de la mémoire tout au long de la vie. Dans le cerveau, le rétinol est métabolisé en acide rétinoïque (AR), le métabolite actif de la VA, qui se lie alors à ses récepteurs, membres de la superfamille des récepteurs nucléaires, et le complexe ainsi formé active la transcription de gènes codant pour des protéines impliquées dans la mémoire.Des données obtenues chez l’Homme et l’animal plaident en faveur d’un affaissement de la voie de signalisation de l’AR survenant au cours du vieillissement, associé à des perturbations mnésiques. Par ailleurs, la diminution de l’activité de la signalisation de l’ar a également été associé à l’accumulation dans le cerveau de peptides amyloïdes-β (Aβ). Or, l’accumulation de ces peptides et l’hyperphosphorylation anormale de la protéine tau sont les deux lésions caractéristiques de la maladie d’Alzheimer (MA). La MA associe des troubles cognitifs importants, de mémoire principalement, conduisant inexorablement à la perte d’autonomie des malades. Son étiologie est encore mal connue, mais son facteur de risque majeur est l’âge avancé. Ainsi, nous avons formulé l’hypothèse qu'une diminution de l’activité de la signalisation de l’AR dans le cerveau au cours du vieillissement favorise le développement des lésions caractéristiques de la MA, et contribue au développement de la maladie.L’objectif de cette thèse était d’évaluer si une supplémentation nutritionnelle en VA au cours du vieillissement, en maintenant une activité optimale de sa signalisation cérébrale, pouvait prévenir la mise en place des lésions caractéristiques de la MA chez deux modèles complémentaires. Le premier modèle murin (injection intra-cérébro-ventriculaire aiguë de peptides amyloïdes) développe une neurotoxicité induite par le peptide Aβ25-35 et est mis en œuvre rapidement (semaines). Le second modèle est la souris 3xTg-AD, qui exprime les transgènes responsables du développement progressif de la neuropathologie de type Alzheimer au cours du vieillissement (mois).Chez les deux modèles, la supplémentation en VA a permis de préserver la mémoire spatiale à court-terme dépendante de l’hippocampe. Chez le modèle Aβ25-35, les mécanismes sous-jacents n’ont pas pu être déterminés de façon univoque. Cependant, ils impliquent une augmentation de la production d’AR dans l’hippocampe par la supplémentation. Chez le modèle de souris 3xTg-AD, l’effet protecteur de la VA s'accompagne d’une diminution de la production de peptides Aβ dans l’hippocampe, ainsi que de la diminution de la phosphorylation de tau chez les mâles uniquement. Chez les femelles, l’apport de VA n’a pas eu de conséquence sur la phosphorylation de tau, mais a accentué leur production de peptides Aβ, qui était déjà initialement plus prononcée que chez les mâles. Cependant, l’expression hippocampique des récepteurs de l’AR, qui témoignent de l’activité de sa voie de signalisation, variait négativement avec la quantité de peptides Aβ chez les deux sexes, mais de façon plus marquée chez les mâles. Ainsi, la baisse d’activité de la signalisation de l’AR serait aussi néfaste pour les femelles que les mâles. Toutefois, le régime enrichi en VA s’est avéré inefficace pour prévenir les lésions caractéristiques de la MA, voire délétère chez les femelles.Ainsi, nos travaux renforcent l’idée que le maintien d’un bon statut en VA, par voie nutritionnelle, au cours du vieillissement, est une stratégie de prévention de la MA à considérer chez les hommes. Cependant, pour les femmes, une autre stratégie plus efficace que l’intervention nutritionnelle devrait être envisagée.Enfin, ces résultats confirment l’intérêt de poursuivre les liens entre vitamine A et MA soulignent la nécessité d’encourager l’étude des effets du sexe dans les investigations précliniques portant sur la MA, sachant de plus que cette maladie affecte plus de femmes que d’hommes.
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Background Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of β-amyloid peptides (Aβ), and could thus contribute to the onset of AD. Methods We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4–6 females and 7–8 males). We also measured protein levels of Retinoic Acid Receptor β (RARβ) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20). Results The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aβ40 and Aβ42, as well as the phosphorylation of Tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal amyloid load. However, the expression of Rxr-β in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aβ in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARβ levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex. Conclusion Our data suggest that (i) an altered expression of RXRs receptors is a contributor to β-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females.
Chapter
Carotenoids possess strong anti-inflammatory and antioxidant actions in addition to a plethora of other properties. These actions of carotenoids are primarily due to their structure which dictate their functions. Because of their protective potential in disease states, carotenoids are associated with prevention and/or treatment of various neurological diseases. In this chapter, the role(s) of carotenoids in various neurological diseases such as Alzheimer’s disease, vascular dementia, Lewy body dementia, mild cognitive impairment, neurological trauma, brain tumor, schizophrenia, depression, Parkinson’s disease and multiple sclerosis, have been reviewed. A number of studies report associations of low levels of carotenoids with higher likelihood of neurological diseases. Other investigations describe beneficial and protective effects of pharmacological or dietary interventions which lead to enhancement of carotenoids levels in the body. However, further validation of these beneficial actions is required both in clinical and animal studies. Development of good animal models of neurological diseases will help.
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BACKGROUND: Our previous systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review. OBJECTIVES: To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults. METHODS: Search methods: We searched The Cochrane Library, Medline, Embase, Lilacs, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to February 2011. We scanned bibliographies of relevant publications and asked pharmaceutical companies for additional trials. Selection criteria: We included all primary and secondary prevention randomized clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention. Data collection and analysis: Three authors extracted data. Random-effects and fixed-effect model meta-analyses were conducted. Risk of bias was considered in order to minimize the risk of systematic errors. Trial sequential analyses were conducted to minimize the risk of random errors. Random effects model meta-regression analyses were performed to assess sources of intertrial heterogeneity. MAIN RESULTS: Seventy-eight randomized trials with 296,707 participants were included. Fifty-six trials including 244,056 participants had low risk of bias. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase. The mean age was 63 years (range 18 to 103 years). The mean proportion of women was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the factorial design, and 2 the cross-over design. All antioxidants were administered orally, either alone or in combination with vitamins, minerals, or other interventions. The duration of supplementation varied from 28 days to 12 years (mean duration 3 years; median duration 2 years). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (21,484 dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials, relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but significantly increased mortality in a fixed-effect model (RR 1.03, 95% CI 1.01 to 1.05). Heterogeneity was low with an I2- of 12%. In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertribal heterogeneity. Meta-regression analysis did not find a significant difference in the estimated intervention effect in the primary prevention and the secondary prevention trials. In the 56 trials with a low risk of bias, the antioxidant supplements significantly increased mortality (18,833 dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was confirmed by trial sequential analysis. Excluding factorial trials with potential confounding showed that 38 trials with low risk of bias demonstrated a significant increase in mortality (2822 dead/26,903 (10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15). In trials with low risk of bias, beta-carotene (13,202 dead/96,003 (13.8%) versus 8556 dead/ 77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01 to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561 dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05) significantly increased mortality, whereas vitamin A (3444 dead/24,596 (14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97 to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/ 29,283 (9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670 dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97, 95% CI 0.91 to 1.03) did not significantly affect mortality. In univariate meta-regression analysis, the dose of vitamin A was significantly associated with increased mortality (RR 1.0006, 95% CI 1.0002 to 1.001, P = 0.002). AUTHORS' CONCLUSIONS: We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.
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Catalase was inhibited by a flux of O2- generated in situ by the aerobic xanthine oxidase reaction. Two distinct types of inhibition could be distinguished. One of these was rapidly established and could be as rapidly reversed by the addition of superoxide dismutase. The second developed slowly and was reversed by ethanol, but not by superoxide dismutase. The rapid inhibition was probably due to conversion of catalase to the ferrooxy state (compound III), while the slow inhibition was due to conversion to the ferryl state (compound II). Since neither compound III nor compound II occurs in the catalatic reaction pathway, they are inactive. This inhibition of catalase by O2- provides the basis for a synergism between superoxide dismutase and catalase. Such synergisms have been observed in vitro and may be significant in vivo.
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The glutathione transferases (GSTs; also known as glutathione S-transferases) are major phase II detoxification enzymes found mainly in the cytosol. In addition to their role in catalysing the conjugation of electrophilic substrates to glutathione (GSH), these enzymes also carry out a range of other functions. They have peroxidase and isomerase activities, they can inhibit the Jun N-terminal kinase (thus protecting cells against H(2)O(2)-induced cell death), and they are able to bind non-catalytically a wide range of endogenous and exogenous ligands. Cytosolic GSTs of mammals have been particularly well characterized, and were originally classified into Alpha, Mu, Pi and Theta classes on the basis of a combination of criteria such as substrate/inhibitor specificity, primary and tertiary structure similarities and immunological identity. Non-mammalian GSTs have been much less well characterized, but have provided a disproportionately large number of three-dimensional structures, thus extending our structure-function knowledge of the superfamily as a whole. Moreover, several novel classes identified in non-mammalian species have been subsequently identified in mammals, sometimes carrying out functions not previously associated with GSTs. These studies have revealed that the GSTs comprise a widespread and highly versatile superfamily which show similarities to non-GST stress-related proteins. Independent classification systems have arisen for groups of organisms such as plants and insects. This review surveys the classification of GSTs in non-mammalian sources, such as bacteria, fungi, plants, insects and helminths, and attempts to relate them to the more mainstream classification system for mammalian enzymes. The implications of this classification with regard to the evolution of GSTs are discussed.
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Active vitamin A metabolites, known as retinoids, are essential for multiple physiological processes, ranging from vision to embryonic development. These small hydrophobic compounds associate in vivo with soluble proteins that are present in a variety of cells and in particular extracellular compartments, and which bind different types of retinoids with high selectivity and affinity. Traditionally, retinoid-binding proteins were viewed as transport proteins that act by solubilizing and protecting their labile ligands in aqueous spaces. It is becoming increasingly clear, however, that, in addition to this general role, retinoid-binding proteins have diverse and specific functions in regulating the disposition, metabolism and activities of retinoids. Some retinoid-binding proteins appear to act by sequestering their ligands, thereby generating concentration gradients that allow cells to take up retinoids from extracellular pools and metabolic steps to proceed in energetically unfavourable directions. Other retinoid-binding proteins regulate the metabolic fates of their ligands by protecting them from some enzymes while allowing metabolism by others. In these cases, delivery of a bound retinoid from the binding protein to the 'correct' enzyme is likely to be mediated by direct and specific interactions between the two proteins. One retinoid-binding protein was reported to enhance the ability of its ligand to regulate gene transcription by directly delivering this retinoid to the transcription factor that is activated by it. 'Channelling' of retinoids between their corresponding binding protein and a particular protein target thus seems to be a general theme through which some retinoid-binding proteins exert their effects.
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Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.
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Herein, we present an overview of the historic development of drugs for the treatment of Parkinson’s disease as well as prospective novel treatment forms based on targeting the dopamine and adenosine receptors. The review includes the development of levodopa, a precursor of the neurotransmitter dopamine, which to date is the most commonly prescribed and most effective drug for controlling the motor symptoms of Parkinson's disease, to more recent studies of the adenosine receptor; a promising target for the treatment of Parkinson’s disease due to its intrinsic neuroprotective nature. Ongoing and future drug-based research on the dopamine and adenosine receptors has the advantage of being guided by the improved understanding of receptor topography as well as their functional roles. Breakthroughs such as the first ligand-bound X-ray structure of a selective adenosine A 2A receptor antagonist in complex with the adenosine A 2A receptor, the discovery of the existence of dopamine D 2 homodimers, dopamine D 2 - adenosine A 2A heterodimers and higher order oligomers in addition to technological progress have changed the direction of research in academia and industry and form the pillars for novel and exciting discoveries in this field.
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Beyond their contribution to basic metabolism, the major cellular organelles, in particular mitochondria, can determine whether cells respond to stress in an adaptive or suicidal manner. Thus, mitochondria can continuously adapt their shape to changing bioenergetic demands as they are subjected to quality control by autophagy, or they can undergo a lethal permeabilization process that initiates apoptosis. Along similar lines, multiple proteins involved in metabolic circuitries, including oxidative phosphorylation and transport of metabolites across membranes, may participate in the regulated or catastrophic dismantling of organelles. Many factors that were initially characterized as cell death regulators are now known to physically or functionally interact with metabolic enzymes. Thus, several metabolic cues regulate the propensity of cells to activate self-destructive programs, in part by acting on nutrient sensors. This suggests the existence of “metabolic checkpoints” that dictate cell fate in response to metabolic fluctuations. Here, we discuss recent insights into the intersection between metabolism and cell death regulation that have major implications for the comprehension and manipulation of unwarranted cell loss.
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Background: The World Health Organization recommends vitamin A supplementation (VAS) at routine vaccination contacts after 6 months of age based on the assumption that it reduces mortality by 24%. The policy has never been evaluated in randomized controlled trials for its effect on overall mortality. We conducted a randomized double-blind trial to evaluate the effect of VAS with vaccines. Methods: We randomized children aged 6 to 23 months 1:1 to VAS (100000 IU if aged 6-11 months, 200000 IU if aged 12-23 months) or placebo at vaccination contacts in Guinea-Bissau. Mortality rates were compared in Cox proportional-hazards models overall, and by gender and vaccine. Results: Between August 2007 and November 2010, 7587 children were enrolled. Within 6 months of follow-up 80 nonaccident deaths occurred (VAS: 38; placebo: 42). The mortality rate ratio (MRR) comparing VAS versus placebo recipients was 0.91 (95% confidence interval 0.59-1.41) and differed significantly between boys (MRR 1.92 [0.98-3.75]) and girls (MRR 0.45 [0.24-0.87]) (P = .003 for interaction between VAS and gender). At enrollment, 42% (3161/7587) received live measles vaccine, 29% (2154/7587) received inactivated diphtheria-tetanus-pertussis-containing vaccines, and 21% (1610/7587) received both live and inactivated vaccines. The effect of VAS did not differ by vaccine group. Conclusions: This is the first randomized controlled trial to assess the effect of the policy on overall mortality. VAS had no overall effect, but the effect differed significantly by gender. More trials to ensure an optimal evidence-based vitamin A policy are warranted.