The neurotoxic effects of vitamin A and retinoids

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.

Full text

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 Alzheimer’s 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 Alzheimer’s 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.
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