Suppression of Mitochondria-Related Bioenergetics Collapse and Redox Impairment by Tanshinone I, a Diterpenoid Found in Salvia miltiorrhiza Bunge (Danshen), in the Human Dopaminergic SH-SY5Y Cell Line Exposed to Chlorpyrifos.

Tanshinone I (T-I, C18H12O3) is a diterpene found in Salvia miltiorrhiza Bunge (Danshen) and promotes cytoprotection in several experimental models. Chlorpyrifos (CPF) is an agrochemical that causes bioenergetics failure, redox impairment, inflammation, and cell death in animal tissues. Here, we investigated whether T-I would be able to prevent the consequences resulting from the exposure of the human dopaminergic SH-SY5Y cells to CPF. We found that a pretreatment with T-I at 2.5 µM for 2 h suppressed lipid peroxidation and protein carbonylation and nitration on the membranes of mitochondria extracted from the CPF-treated cells. Also, T-I reduced the production of radical superoxide (O2-•) by the mitochondria of the CPF-challenged cells. The production of nitric oxide (NO•) and hydrogen peroxide (H2O2) was also decreased by T-I in the cells exposed to CPF. The CPF-induced decrease in the activity of the complexes I-III, II-III, and V was abolished by a pretreatment with T-I. Loss of mitochondrial membrane potential (ΔΨm) and reduction in the production of adenosine triphosphate (ATP) were also prevented by T-I in the CPF-treated cells. T-I also induced anti-inflammatory effects in the CPF-treated cells by decreasing the levels of interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) and the activity of the nuclear factor-κB (NF-κB). Inhibition of heme oxygenase-1 (HO-1) or silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) blocked the T-I-promoted mitochondrial protection and anti-inflammatory action. Overall, T-I depended on the Nrf2/HO-1 axis to prevent the deleterious effects caused by CPF in this experimental model.

The effects of kahweol, a diterpene present in coffee, on the mitochondria of the human neuroblastoma SH-SY5Y cells exposed to hydrogen peroxide.

The oxidative phosphorylation (OXPHOS) system located in the mitochondria is the main source of adenosine triphosphate (ATP) in mammals. The mitochondria are also the main site of reactive oxygen species (ROS) production in those cells. Disruption of the mitochondrial redox biology has been seen in the onset and progression of neurodegenerative diseases. In this regard, we have tested here whether kahweol (KW; C20H26O3), a diterpene present in coffee, would be able to promote mitochondrial protection in the human neuroblastoma SH-SY5Y cells exposed to hydrogen peroxide (H2O2). A pretreatment (for 12 h) with KW (at 10 µM) decreased the impact of H2O2 (at 300 µM) on the levels of oxidative stress markers in the mitochondrial membranes, as well as reduced the production of ROS by the organelles. KW pretreatment also suppressed the effects of H2O2 on the activity of components of the OXPHOS. The KW-induced mitochondria-related effects were blocked by inhibition of the phosphoinositide 3-kinase/Akt (PI3K/Akt) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, silencing of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibition of the heme oxygenase-1 (HO-1) enzyme abrogated the KW-induced protective effects on the mitochondria. Therefore, KW promoted mitochondrial protection by the PI3K/Akt and p38 MAPK/Nrf2/HO-1 axis in H2O2-challenged SH-SY5Y cells.

Targeting STATs in neuroinflammation: The road less traveled!

JAK/STAT transduction pathway is a highly conserved pathway implicated in regulating cellular proliferation, differentiation, survival and apoptosis. Dysregulation of this pathway is involved in the onset of autoimmune, haematological, oncological, metabolic and neurological diseases. Over the last few years, the research of anti-neuroinflammatory agents has gained considerable attention. The ability to diminish the STAT-induced transcription of inflammatory genes is documented for both natural compounds (such as polyphenols) and chemical drugs. Among polyphenols, quercetin and curcumin directly inhibit STAT, while Berberis vulgaris L. and Sophora alopecuroides L extracts act indirectly. Also, the Food and Drug Administration has approved several JAK/STAT inhibitors (direct or indirect) for treating inflammatory diseases, indicating STAT can be considered as a therapeutic target for neuroinflammatory pathologies. Considering the encouraging data obtained so far, clinical trials are warranted to demonstrate the effectiveness and potential use in the clinical practice of STAT inhibitors to treat inflammation-associated neurodegenerative pathologies.

Evaluation of the Mitochondria-Related Redox and Bioenergetics Effects of Gastrodin in SH-SY5Y Cells Exposed to Hydrogen Peroxide.

Mitochondrion is the main site of ATP production in animal cells and also orchestrates signaling pathways associated with cell survival and death. Mitochondrial dysfunction has been linked to bioenergetics and redox impairment in human diseases, such as neurodegeneration and cardiovascular disease. Protective agents able to attenuate mitochondrial impairment are of pharmacological interest. Gastrodin (GAS; 4-hydroxybenzyl alcohol 4-O-beta-D-glucoside) is a phenolic glucoside obtained from the Chinese herbal medicine Gastrodia elata Blume and exhibits antioxidant, anti-inflammatory, and antiapoptotic effects in several cell types. GAS is able to cross the blood-brain barrier, reducing the impact of different stressors on the cognition of experimental animals. In the present work, we investigated whether GAS would protect mitochondria of human SH-SY5Y neuroblastoma cells against an exposure to a pro-oxidant agent. The cells were treated with GAS at 25 µM for 30 min before the administration of hydrogen peroxide (H2O2) at 300 µM for an additional 3 or 24 h, depending on the assay. We evaluated both mitochondrial redox state and function parameters and analyzed the mechanism by which GAS protected mitochondria in this experimental model. Silencing of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor suppressed the GAS-induced mitochondrial protection seen here. Moreover, Nrf2 knockdown abrogated the effects of GAS on cell viability, indicating a potential role for Nrf2 in both mitochondrial and cellular protection promoted by GAS. Further research would be necessary to investigate whether GAS would be able to induce similar effects in in vivo experimental models.

Carnosic Acid Suppresses the H2O2-Induced Mitochondria-Related Bioenergetics Disturbances and Redox Impairment in SH-SY5Y Cells: Role for Nrf2.

The phenolic diterpene carnosic acid (CA, C20H28O4) exerts antioxidant, anti-inflammatory, anti-apoptotic, and anti-cancer effects in mammalian cells. CA activates the nuclear factor erythroid 2-related factor 2 (Nrf2), among other signaling pathways, and restores cell viability in several in vitro and in vivo experimental models. We have previously reported that CA affords mitochondrial protection against various chemical challenges. However, it was not clear yet whether CA would prevent chemically induced impairment of the tricarboxylic acid cycle (TCA) function in mammalian cells. In the present work, we found that a pretreatment of human neuroblastoma SH-SY5Y cells with CA at 1 µM for 12 h prevented the hydrogen peroxide (H2O2)-induced impairment of the TCA enzymes (aconitase, α-ketoglutarate dehydrogenase (α-KGDH), succinate dehydrogenase (SDH)) and abolished the inhibition of the complexes I and V and restored the levels of ATP by a mechanism associated with Nrf2. CA also exhibited antioxidant abilities by enhancing the levels of reduced glutathione (GSH) and decreasing the content oxidative stress markers (cellular 8-oxo-2'-deoxyguanosine (8-oxo-dG), and mitochondrial malondialdehyde (MDA), protein carbonyl, and 3-nitrotyrosine). Silencing of Nrf2 by small interfering RNA (siRNA) abrogated the protective effects elicited by CA in mitochondria of SH-SY5Y cells. Therefore, CA prevented the H2O2-triggered mitochondrial impairment by an Nrf2-dependent mechanism. The specific role of Nrf2 in ameliorating the function of TCA enzymes function needs further research.

Ginsenoside Rb1 as a neuroprotective agent: A review.

Ginsenosides represent the major bioactive components of ginseng. These triterpenoid saponins have been shown to exert numerous beneficial effects on the human body. Recent evidences suggest that ginsenosides may be useful for the management and treatment of several diseases of the central nervous system (CNS). In particular, numerous in vitro and in vivo models have shown that ginsenosides can modulate numerous pharmacological effects on the brain, including attenuation of excitotoxicity, oxidative stress and neuroinflammation, maintenance of neurotransmitter balance, anti-apoptotic effects, and mitochondrial stabilization effects. Regulations of these pathophysiological mechanisms have been shown to improve cognitive function and protect the brain against several neurodegenerative diseases. This review will critically address the pharmacological effects and mechanisms of action of ginsenosides in the CNS, and particularly those associated with therapeutic efficacies in Parkinson's disease, Alzheimer's disease, Huntington's disease, and traumatic brain injury, and ischemia.

Carnosic Acid Affords Mitochondrial Protection in Chlorpyrifos-Treated Sh-Sy5y Cells.

Carnosic acid (CA; C20H28O4) is a phenolic diterpene found in rosemary (Rosmarinus officinalis L.) and exhibits protective properties, e.g., antioxidant, anti-inflammatory, antitumor, and antimicrobial activities. In this context, CA has been viewed as a neuroprotective agent due to its ability in rescuing neuronal cells from pro-oxidant and pro-apoptotic challenges. In the present work, we found that CA pretreatment at 1 µM for 12 h suppressed the mitochondria-related pro-oxidant and mitochondria-dependent pro-apoptotic effects of chlorpyrifos (CPF) in human neuroblastoma SH-SY5Y cells. CA prevented mitochondrial membrane potential disruption and decreased the levels of oxidative stress markers in mitochondrial membranes obtained from cells exposed to CPF. CA also inhibited cytochrome c release and activation of the caspases-9 and -3, as well as decreased DNA fragmentation, in CPF-treated cells. CA upregulated the content of glutathione (GSH) in mitochondria by a mechanism involving the activation of the phosphoinositide-3-kinase (PI3K)/Akt/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, since inhibition of PI3K/Akt or silencing of Nrf2 using siRNA strategy abolished the protection exerted by CA in SH-SY5Y cells. Therefore, CA protected mitochondria of SH-SY5Y cells through the activation of the PI3K/Akt/Nrf2 axis, causing upregulation of the mitochondrial GSH content and consequent antioxidant and anti-apoptotic effects.

Vitamin A and Retinoids as Mitochondrial Toxicants.

Vitamin A and its derivatives, the retinoids, are micronutrient necessary for the human diet in order to maintain several cellular functions from human development to adulthood and also through aging. Furthermore, vitamin A and retinoids are utilized pharmacologically in the treatment of some diseases, as, for instance, dermatological disturbances and some types of cancer. In spite of being an essential micronutrient with clinical application, vitamin A exerts several toxic effects regarding redox environment and mitochondrial function. Moreover, decreased life quality and increased mortality rates among vitamin A supplements users have been reported. However, the exact mechanism by which vitamin A elicits its deleterious effects is not clear yet. In this review, the role of mitochondrial dysfunction in the mechanism of vitamin A-induced toxicity is discussed.

The effects of vitamin A supplementation for 3 months on adult rat nigrostriatal axis: increased monoamine oxidase enzyme activity, mitochondrial redox dysfunction, increased ß-amyloid(1-40) peptide and TNF-α contents, and susceptibility of mitochondria to an in vitro H2O2 challenge.

Even though vitamin A has been viewed as an antioxidant molecule, recent findings demonstrate that such vitamin elicits pro-oxidant effects in vivo. Moreover, vitamin A supplements utilization may increase mortality rates among healthy subjects. However, the mechanism by which vitamin A elicits such effects remains to be better analyzed. In this regard, we investigated here the consequences of vitamin A supplementation at 500, 1000, or 2500 IU/kg day(-1) for 3 months on adult rat substantia nigra and striatum total and mitochondrial redox state (both oxidative and nitrosative stress markers), electron transfer chain activity, monoamine oxidase (MAO) enzyme activity, endoplasmic reticulum stress marker (BiP), α- and ß-synucleins, ß-amyloid peptide (1-40), dopamine D2 receptor (D2R), receptor for advanced glycation end products (RAGE), caspase-3 and caspase-8 enzyme activity and tumor necrosis factor-α (TNF-α) levels. Also, nigrostriatal mitochondria were isolated and challenged with 50 µM H2O2 in vitro after vitamin A supplementation and complexes I-III, II-III, and IV enzyme activity was recorded. We observed both total and mitochondrial oxidative and nitrosative stress, increased MAO enzyme activity, and increased levels of α-synuclein, ß-amyloid peptide, RAGE, and TNF-α, but decreased D2R in both rat brain areas. Furthermore, vitamin A supplementation induced a decrease in nigral, but not striatal, ß-synuclein levels in this work. Moreover, mitochondria isolated from both substantia nigra and striatum of vitamin A-treated rats were more sensitive to H2O2 than control mitochondria as assessed through the in vitro assay. Overall, these data may be useful to explain how vitamin A elicits neurotoxic effects chronically.

L-NAME cotreatment did prevent neither mitochondrial impairment nor behavioral abnormalities in adult Wistar rats treated with vitamin A supplementation.

Vitamin A has been characterized as a potential neurotoxin, because ingestion of such vitamin - or its derivatives, the retinoids - at moderate to high doses elicits a myriad of deleterious effects, from acute intoxication involving head-ache, confusion, and 'pseudo tumor cerebri' to chronic, and perhaps irreversible, abnormalities, including irritability, anxiety, depression, and suicide ideation. Nevertheless, it still remains to be found the mechanism by which vitamin A induces cognitive decline. Based on the fact that vitamin A at clinical doses is a potent pro-oxidant agent to the central nervous system, we performed the present work to analyze whether a cotreatment with L-NAME at 30 mg/kg (four times a week) was able to prevent (or minimize) the biochemical and/or behavioral disturbances resulting from a 28-day daily supplementation with retinol palmitate at doses from 1000 to 9000 IU/kg/day. Then, we investigated mitochondrial function, redox parameters, and the levels of proteins potentially involved in neurodegenerative events, as for instance α-synuclein and receptor for advanced glycation endproducts. Besides, monoamine oxidase enzyme activity was quantified in this work. We observed that L-NAME cotreatment was not completely effective in preventing the redox disturbances induced by vitamin A supplementation. Moreover, L-NAME cotreatment did not affect the behavioral deficits elicited by vitamin A supplementation. We conclude that other parameters rather than NO levels or its derivatives, as for example ONOO(-), take a more important role in mediating the negative effects triggered by vitamin A supplementation.

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.

Vitamin A supplementation among women is a common habit worldwide in an attempt to slow aging progression due to the antioxidant potential attributed to retinoids. Nonetheless, vitamin A elicits a myriad of side effects that result from either therapeutic or inadvertent intake at varying doses for different periods. The mechanism behind such effects remains to be elucidated. In this regard, we performed the present work aiming to investigate the effects of vitamin A supplementation at 100, 200, or 500IU/kgday(-1) for 2 months on female rat brain, analyzing tissue lipid peroxidation levels, antioxidant enzyme activities (both Cu/Zn-superoxide dismutase - SOD - and Mn-SOD); glutathione S-transferase (GST) and monoamine oxidase (MAO) enzyme activity; mitochondrial respiratory chain activity and redox parameters in mitochondrial membranes, as well as quantifying α- and ß-synucleins, ß-amyloid peptide(1-40), immunoglobulin heavy-chain binding protein/78kDa glucose-regulated protein (BiP/GRP78), receptor for advanced glycation end products (RAGE), D2 receptor, and tumor necrosis factor-α (TNF-α) contents in rat frontal cortex, hippocampus, striatum, and cerebellum. We observed increased lipid peroxidation marker levels, altered Cu/Zn-SOD and Mn-SOD enzyme activities, mitochondrial nitrosative stress, and impaired respiratory chain activity in such brain regions. On the other hand, we did not find any change in MAO and GST enzyme activities, and on α- and ß-synucleins, ß-amyloid peptide(1-40), GRP78/BiP, RAGE, D2 receptor, and TNF-α contents. Importantly, we did not observed any evidence regarding an antioxidant effect of such vitamin at low doses in this experimental model. The use of vitamin A as an antioxidant therapy among women needs to be reexamined.

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.

Vitamin A supplementation has caused concern among public health researchers due to its ability in decreasing life quality from acute toxicological effects to increasing mortality rates among vitamin supplement users. For example, it was described cognitive decline (i.e. irritability, anxiety, and depression) in patients subjected to long-term vitamin A therapy, as occurs in cancer treatment. However, the mechanism by which vitamin A affects mammalian cognition is not completely understood. Then, we performed the present work to investigate the effects of vitamin A supplementation at clinical doses (1,000-9,000 IU/kg day(-1)) for 28 days on rat hippocampal nitrosative stress levels (both total and mitochondrial), bioenergetics states, brain-derived neurotrophic factor (BDNF), alpha- and beta-synucleins, BiP and dopamine receptor 2 (D2 receptor) contents, and glutamate uptake. We observed mitochondrial impairment regarding respiratory chain function: increased complex I-III, but decreased complex IV enzyme activity. Also, decreased BDNF levels were observed in vitamin A-treated rats. The present data demonstrates, at least in part, that mitochondrial dysfunction and decreased BDNF and D2 receptors levels, as well as decreased glutamate uptake may take an important role in the mechanism behind the previously reported cognitive disturbances associated to vitamin A supplementation.

Vitamin A supplementation for different periods alters rat vascular redox parameters.

Vitamin A plays physiological and antioxidants properties and is associated with protective effects on arterial level. However, deleterious effects have been reported, including those observed by our group, which has demonstrated pro-oxidant properties in other systems. Therefore, it is needed to better understand the redox effects of retinoids on arterial system. Thus, our aim was to compare vascular redox parameters among animals supplemented or not with vitamin A. Eighty-five adult male rats were treated with different retinyl palmitate doses (1,000-9,000 IU kg(-1) day(-1)) or saline for 3 (25 rats, n=5 for each group), 7 (25 rats, n=5 for each group), and 28 (35 rats, n=7 for each group) days periods. Aorta artery was surgically removed, cleaned to remove the blood, and homogenized. It was evaluated thiobarbituric reactive species (TBARS), total reduced sulfhydryl (SH), and activities of superoxide dismutase (SOD) and catalase (CAT). Statistics were conducted by one-way ANOVA with Dunnet's post hoc and significance value of p≤0.05. About TBARS, we observed no modifications after 3 days, but a decrease after 7 days in all doses and after 28 days in three higher doses. The two higher doses yielded an increase on SH only after 3 days. SOD activity decreased in three higher doses after 3 days and in all doses after 28 days, but no modifications after 7 days, while CAT activity increased in all doses after 3 days, decreased in all doses after 7 days, and did not change after 28 days. In conclusion, vitamin A induces antioxidant status on vascular level.

Long-term vitamin A supplementation at therapeutic doses induces mitochondrial electrons transfer chain (METC) impairment and increased mitochondrial membrane-enriched fraction (MMEF) 3-nitrotyrosine on rat heart.

The aim of the present study was to compare electrons flux and oxidative/nitrosative stress parameters on the heart among rats supplemented with vitamin A and one not supplemented long-term. Vitamin A has important roles for the cardiovascular system as well as antioxidant properties. However, pro-oxidant properties have been reported. Male adult rats were treated with four different doses of retinyl palmitate (1000-9000 IU/Kg/day) or saline (control) for 28 days and the heart was removed for analysis. Electrons flux and oxidative/nitrosative stress parameters were evaluated and statistics were conducted with Anova one-way followed by Dunnet's post hoc and significance level of p<0.05. The supplementation induced increase on lipids/proteins oxidation and mitochondrial 3-nitrotyrosine content, an imbalance on enzymatic activity and a decrease on respiratory chain complexes activities. The results suggest that vitamin A induces oxidative/nitrosative stress and mitochondrial impairment on a cardiac level.

Pharmacological doses of vitamin A increase caspase-3 activity selectively in cerebral cortex.

Vitamin A exerts a wide range of physiological roles from embryonic to adulthood stages of the mammalian life. However, there is a great concern regarding the deleterious effects of vitamin A use even therapeutically. It was shown that vitamin A induces behavioral impairments, for instance, anxiety-like behavior and depression, in experimental animals and humans. Caspases are enzymes associated with cell death; however, there is a role for such enzymes also in synaptic plasticity. Then, based on previously published data, we have investigated the effects of vitamin A supplementation at clinical doses (1000-9000 IU/kg/day) for 28 days on caspase-3 and caspase-8 activities in adult rat cerebral cortex, cerebellum, striatum, and hippocampus. Furthermore, we have quantified TNF-alpha levels, a pro-inflammatory cytokine that, besides other biological roles, trigger the extrinsic apoptotic pathway in several cellular types, in those rat brain regions. Interestingly, we found increased caspase-3 activity only in rat cerebral cortex. In all the other regions caspase-3 and caspase-8 activities did not change, as well as the levels of TNF-alpha. The presented results, herein, indicate that more caution is needed regarding vitamin A clinical use and, also importantly, the consumption of vitamin A-fortified foods, which are not exclusively distributed among vitamin A-deficient subjects.

Vitamin A supplementation at pharmacological doses induces nitrosative stress on the hypothalamus of adult Wistar rats.

Vitamin A is a micronutrient involved in the regulation of a normal mammalian brain function. In spite of this, it has been demonstrated that vitamin A exerts a wide range of deleterious effects regarding neuronal homeostasis, for instance impairing brain metabolism and suppressing neurogenesis, to cite a few. In addition, vitamin A is a redox active molecule, i.e. it is both anti- and pro-oxidant, depending on its concentration. In the herein presented work, we performed some experiments aiming to investigate the effects of clinically applied doses of vitamin A (1000-9000 IU/kg/day during 28 days) on rat hypothalamic redox state and mitochondrial electron transfer chain (METC) activity, as well as on hypothalamic alpha-synuclein and D2 receptor (dopamine receptor) contents. Additionally, we quantified caspase-3 activity and tumor necrosis factor-alpha (TNF-alpha) levels to assess either neuronal death or an inflammatory state in such brain area. We found that vitamin A supplementation increased free radical production, as well as oxidative and nitrosative stress, in rat hypothalamus. Also, we observed increased complex I-III activity, but decreased complex IV activity in the hypothalamus of vitamin A-treated rats, which may give rise to the increased superoxide anion (O(2)(-)) production found here. Other parameters investigated here, i.e. alpha-synuclein and D2 receptor contents did not change. Even though we did not observe signs of increased cell death or inflammation in the rat hypothalamus, more attention is needed when vitamin A is the choice of treatment in certain pathologies.

Increased receptor for advanced glycation endproducts immunocontent in the cerebral cortex of vitamin A-treated rats.

Vitamin A, beyond its biological role, is an alternative choice in treating some life threatening pathologies, for instance leukemia and immunodeficiency. On the other hand, vitamin A therapy at moderate to high doses has caused concern among public health researchers due to the toxicological aspect resulting from such habit. It has been described hepatotoxicity, cognitive disturbances and increased mortality rates among subjects ingesting increased levels of vitamin A daily. Then, based on the previously reported data, we investigated here receptor for advanced glycation endproducts (RAGE) immunocontent and oxidative damage levels in cerebral cortex of vitamin A-treated rats at clinical doses (1,000-9,000 IU/kg day(-1)). RAGE immunocontent, as well as oxidative damage levels, were observed increased in cerebral cortex of vitamin A-treated rats. Whether increased RAGE levels exert negative effects during vitamin A supplementation it remains to be investigated, but it is very likely that deleterious consequences may arise from such alteration.

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.

Vitamin A at moderate to high doses is applied in the treatment of some life threatening pathological conditions, for instance cancers. Additionally, vitamin A at low concentrations is a known antioxidant molecule. However, by increasing vitamin A (or its derivatives) concentrations, there is an increase in the levels of oxidative stress markers in several experimental models. Furthermore, it was reported that vitamin A therapy at high doses might induce cognitive decline among the patients, which may become anxious or depressive, for example, depending on vitamin A levels intake. We have previously reported increased levels of oxidative stress markers in rat substantia nigra and striatum. However, the mechanism by which this vitamin altered the redox environment in such rat brain regions remains to be elucidated. In the herein presented work, we have investigated the effects of vitamin A supplementation at clinical doses (1000-9000 IU/kg day(-1)) for 28 days on rat substantia nigra and striatum mitochondrial electron transfer chain (METC) activity, which may produce superoxide anion radical (O(2)(-*)) when impaired. Additionally, the levels of non-enzymatic antioxidant defenses were evaluated, as well as 3-nitrotyrosine, alpha- and beta-synucleins and TNF-alpha levels through ELISA assay. We observed impaired METC in both rat brain regions. Moreover, we found increased O(2)(-*) production and nitrotyrosine content in the nigrostriatal axis of vitamin A-treated rats, suggesting that the use of vitamin A at therapeutic doses may be rethought due to this toxic effects found here.

Vitamin A supplementation for different periods alters oxidative parameters in lungs of rats.

Lungs require an adequate supply of vitamin A (retinol) for normal embryonic development, postnatal maturation, and maintenance and repair during adult life. However, recent intervention studies revealed that supplementation with retinoids resulted in higher incidence of lung cancer, although the mechanisms underlying this effect are still unknown. Here, we studied the effect of vitamin A supplementation on oxidative stress parameters in lungs of Wistar rats. Vitamin A supplementation at either therapeutic (1,000 and 2,500 IU/kg) or excessive (4,500 and 9,000 IU/kg) doses for 3, 7, or 28 days induced lipid peroxidation, protein carbonylation, and oxidation of protein thiol groups, as well as change in catalase and superoxide dismutase activity. Together, these results suggest that vitamin A supplementation causes significant changes in redox balance, which are frequently associated with severe lung dysfunction.

Decreased anxiety-like behavior and locomotor/exploratory activity, and modulation in hypothalamus, hippocampus, and frontal cortex redox profile in sexually receptive female rats after short-term exposure to male chemical cues.

Chemical cues are widely used for intraspecific social communication in a vast majority of living organisms ranging from bacteria to mammals. As an example, mammals release olfactory cues with urine that promote neuroendocrine modulations with changes in behavior and physiology in the receiver. In this work, four-month-old Wistar (regular 4-day cyclic) virgin female rats were utilized in the proestrus-to-estrus phase of the reproductive cycle for experimental exposure. In an isolated room, female rats were exposed for 90 min to male-soiled bedding (MSB). Elevated plus-maze assay, open field test, and light/dark box task were performed to analyze behavioral alterations on females after exposure. For biochemical assays, female rats were killed and the hypothalamus, hippocampus, and frontal cortex were isolated for further analysis. Antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase), non-enzymatic antioxidant defense measurements (TRAP and TAR), and the oxidative damage parameters (TBARS, Carbonyl and SH content) were analyzed. In behavioral analyses we observe that female rats show decreased anxiety and locomotory/exploratory activities after MSB exposure. In biochemical assays we observed an increase in both enzymatic and non-enzymatic antioxidant defenses in different central nervous system (CNS) structures analyzed 30 and 90 min after MSB exposure. Furthermore, hippocampus and frontal cortex showed diminished free radical oxidative damage at 180 and 240 min after exposure. These results provide the first evidence that oxidative profile of female CNS structures are altered by chemical cues present in the MSB, thus suggesting that pheromonal communication is able to modulate radical oxygen species production and/or clearance in the female brain.