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The neurotoxic effects of vitamin A and retinoids
"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, influence 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)."
"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 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′-dichlorohydrofluorescein 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."
"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 H2O2 production that may lead to hydroxyl radical (OH) formation through Fenton reaction (Halliwell 2006), since SOD converts O2 -• to H2O2, but this reactive specie probably accumulates due to decreased or unaltered CAT and unaltered GPx enzyme activities. Regarding the toxic effects of O2 -•, it was shown that O2 -• 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 field 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-1induced mitochondrial dysfunction and increased β-amyloid1-40 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 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 O2 -•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 H2O2 during the reaction of dismutation of O2 -• and degradation of dopamine, respectively (Halliwell 2006, Edmondson 2014). Then, mitochondria seem to be a potential source of H2O2 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 O2 -•, 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 O2 -• and NOl production (Squadrito and Pryor 1998, Radi 2013). Indeed, it was demonstrated that vitamin A intake increased mitochondrial O2 -• 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 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 (NO2 +), nitrogen diozide radical (•NO2), and hydroxyl radical (•OH) through a reaction called homolytic fission (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."
"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 O2 -• 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 O2 -• production due to electron leakage from the mitochondrial electron transfer chain (Halliwell 2006, Hüttemann et al. 2011). Then, O2 -• 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 deficiency 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 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 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 neuroinflammation-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."
"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 H2O2, β-amyloid peptide1-40, and CaCl2and 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 sufficient 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 mefloquine (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 find 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 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 inflammation. Some of the effects discussed here are summarized in Figure 1."
"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, influence 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)."
"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 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′-dichlorohydrofluorescein 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."
"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 H2O2 production that may lead to hydroxyl radical (OH) formation through Fenton reaction (Halliwell 2006), since SOD converts O2 -• to H2O2, but this reactive specie probably accumulates due to decreased or unaltered CAT and unaltered GPx enzyme activities. Regarding the toxic effects of O2 -•, it was shown that O2 -• 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 field 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-1induced mitochondrial dysfunction and increased β-amyloid1-40 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 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 O2 -•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 H2O2 during the reaction of dismutation of O2 -• and degradation of dopamine, respectively (Halliwell 2006, Edmondson 2014). Then, mitochondria seem to be a potential source of H2O2 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 O2 -•, 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 O2 -• and NOl production (Squadrito and Pryor 1998, Radi 2013). Indeed, it was demonstrated that vitamin A intake increased mitochondrial O2 -• 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 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 (NO2 +), nitrogen diozide radical (•NO2), and hydroxyl radical (•OH) through a reaction called homolytic fission (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."
"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 O2 -• 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 O2 -• production due to electron leakage from the mitochondrial electron transfer chain (Halliwell 2006, Hüttemann et al. 2011). Then, O2 -• 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 deficiency 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 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 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 neuroinflammation-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."
"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 H2O2, β-amyloid peptide1-40, and CaCl2and 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 sufficient 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 mefloquine (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 find 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 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 inflammation. Some of the effects discussed here are summarized in Figure 1."
