Abel Santamaría

Instituto Nacional de Neurología y Neurocirugía, Tlalpam, The Federal District, Mexico

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Publications (103)257.39 Total impact

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    ABSTRACT: 3-Hydroxykynurenine (3-HK), an intermediate metabolite of the kynurenine pathway, has been largely hypothesized as a neurotoxic molecule contributing to neurodegeneration in several experimental and clinical conditions. Interestingly, the balance in literature points to a dual role of this molecule in the CNS: in vitro studies describe neurotoxic and/or antioxidant properties, whereas in vivo studies suggest a role of this metabolite as a weak neurotoxin. This work was designed to investigate, under different experimental conditions, whether or not 3-HK is toxic to cells, and if the redox activity exerted by this molecule modulates its actions in the rat striatum. In order to evaluate these effects, 3-HK was administered in vitro to isolated striatal slices, and in vivo to the striatum of rats. In striatal slices, 3-HK exerted a concentration- and time-dependent effect on lipid peroxidation, inducing both pro-oxidant actions at low (5-20) micromolar concentrations, and antioxidant activity at a higher concentration (100µM). Interestingly, while 3-HK was unable to induce mitochondrial dysfunction in slices, at the same range of concentrations it prevented the deleterious effects exerted by the neurotoxin and related metabolite quinolinic acid (QUIN), the mitochondrial toxin 3-nitropropionic acid, and the pro-oxidant compound iron sulfate. These protective actions were related to the stimulation of glutathione S-transferase (GST) and superoxide dismutase (SOD) activities. In addition, 3-HK stimulated the protein content of the transcription factor and antioxidant regulator Nrf2, and some of its related proteins. Accordingly, 3-HK, but not QUIN, exhibited reducing properties at high concentrations. The striatal tissue of animals infused with 3-HK exhibited moderate levels of lipid and protein oxidation at short times post-lesion (hours), but these endpoints were substantially decreased at longer times (days). These effects were correlated with an early increase in glutathione reductase (GR) and GST activities. However, these changes were likely to be merely compensatory as 3-HK-infused animals did not display behavioral (rotation) alterations or morphological changes in their injected striata. Altogether, these findings suggest that, despite 3-HK might exert pro-oxidant actions under certain conditions, these changes serve to evoke a redox modulatory activity that, in turn, could decrease the risk of cell damage. In light of this evidence, 3-HK seems to be more a redox modulatory molecule than a neurotoxic metabolite.
    Brain research. 09/2014;
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    ABSTRACT: Recently, it has been proposed that the receptor for advanced glycation end-products (RAGE) plays a crucial role in damaging cellular processes, such as neuroinflammation, neurodegeneration, excitotoxicity and oxidative stress. RAGE is a multiligand receptor belonging to the immunoglobulin superfamily of cell surface molecules acting as a counter-receptor for diverse molecules. Engagement of RAGE converts a brief pulse of cellular activation into sustained cellular dysfunction and tissue damage. Indeed, the involvement of RAGE in physiopathological processes has been demonstrated for several neurodegenerative diseases. It is the full-length form of RAGE the one constituting the cellular receptor which is able to activate intracellular signals. After the binding of ligands to RAGE, oxidative stress is increased; then, over-expression of RAGE produces vicious cycles that perpetuate oxidative stress and contribute to neuroinflammation by nuclear factor-kB (NF-kB) up-regulation. The NF-kB activation promotes the expression of pro-inflammatory cytokines, including RAGE expression, to induce a prolonged activation and promotion of signaling mechanisms for cell damage. Because inflammatory and oxidative events have been demonstrated to concertedly interact during neurodegenerative events, this review is aimed to discuss the role of RAGE as mediator of an interaction between inflammation and oxidative stress through NF-kB signaling pathway.
    CNS & neurological disorders drug targets. 08/2014;
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    ABSTRACT: Melatonin is produced and released by the pineal gland in a circadian rhythm. This neurohormone has proven to be an antioxidant and anti-inflammatory molecule able to reduce or mitigate cell damage associated with oxidative stress and inflammation, and this phenomenon underlies neurodegenerative disorders. These facts have drawn attention to this indole,triggering interest in evaluating its changes and in its relationship to the processes indicated, and analyzing its role in the mechanisms involved at the onset and development of neurodegenerative diseases, as well as its therapeutic potential. Multiple sclerosis, the most common cause of non-traumatic disability in young adults, is a chronic neuroinflammatory disease, characterized by demyelination, inflammation, and neuronal and oxidative damage. In its early diagnosis, it often requires a differential screening with other neurodegenerative diseases with similar symptoms, such as Huntington's disease, an autosomal dominant disorder. The onset of both diseases occurs in the second or third decade of life. On the other hand, cerebral ischemia is a major cause of human disability all over the world. Although a cerebral stroke can occur as the result of different damaging insults, severe ischemia produces the death of neuronal cells within minutes. Changes in melatonin levels have been observed in these processes (Huntington's disease, multiple sclerosis and cerebral ischemia) as part of their pathogenic features. This review aims to update and discuss the role played by melatonin during neurodegenerative processes, specifically in multiple sclerosis, Huntington's disease, and cerebral ischemia, and its possible therapeutic use. We also provide readers with an update on the many neuroprotective mechanisms exerted by this neurohormone in the Central Nervous System.
    CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) 08/2014; · 3.77 Impact Factor
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    ABSTRACT: Astrocytes are key players for brain physiology, protecting neurons by releasing antioxidant enzymes; however, they are also susceptible to damage by neurotoxins. Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a central regulator of the antioxidant response, and therefore, pharmacologic inducers are often used to activate this transcription factor to induce cellular protection. To date, it still remains unknown if cells from aged animals are capable of developing this response. Therefore, the purpose of this work was to determine if cortical astrocytes derived from old rats are able to respond to tertbuthyl-hydroquinene (tBHQ) pretreatment and stimulate the Nrf2-antioxidant response pathway to induce an antioxidant strategy against MPP+ toxicity, one of the most used molecules to model Parkinson's disease. Our results show that, although astrocytes from adult and old rats were more susceptible to MPP+ toxicity than astrocytes from newborn rats, when pretreated with tertbuthyl-hydroquinene, they were able to transactivate Nrf2, increasing antioxidant enzymes and developing cellular protection. These results are discussed in terms of the doses used to create protective responses.
    Neurobiology of aging 02/2014; · 5.94 Impact Factor
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    ABSTRACT: Glutamate-induced excitotoxicity involves a state of acute oxidative stress, which is a crucial event during neuronal degeneration and is part of the physiopathology of neurodegenerative diseases. In this work, we evaluated the ability of sulforaphane (SULF), a natural dietary isothiocyanate, to induce the activation of transcription factor Nrf2 (a master regulator of redox state in the cell) in a model of striatal degeneration in rats infused with quinolinic acid (QUIN). Male Wistar rats received SULF (5 mg/kg, i.p.) 24 h and 5 min before the intrastriatal infusion of QUIN. SULF increased the reduced glutathione (GSH) levels 4 h after QUIN infusion, which was associated with its ability to increase the activity of glutathione reductase (GR), an antioxidant enzyme capable to regenerate GSH levels at 24 h. Moreover, SULF treatment increased glutathione peroxidase (GPx) activity, while no changes were observed in γ-glutamyl cysteine ligase (GCL) activity. SULF treatment also prevented QUIN-induced oxidative stress (measured by oxidized proteins levels), the histological damage and the circling behavior. These results suggest that the protective effect of SULF could be related to its ability to preserve GSH levels and increase GPx and GR activities.
    Neuroscience 01/2014; 272:188–198. · 3.12 Impact Factor
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    ABSTRACT: Nrf2 is a transcription factor involved in the orchestration of antioxidant responses. Although its pharmacological activation has been largely hypothesized as a promising tool to ameliorate the progression of neurodegenerative events, the actual knowledge about its modulation in neurotoxic paradigms remains scarce. In this study, we investigated the early profile of Nrf2 modulation in striatal slices of rodents incubated in the presence of the toxic kynurenine pathway metabolite, quinolinic acid (QUIN). Tissue slices from rats and mice were obtained and used throughout the experiments in order to compare inter-species responses. Nuclear Nrf2 protein levels and oxidative damage to lipids were compared. Time and concentration response curves of all markers were explored. Nrf2 nuclear activation was corroborated through phase 2 antioxidant proteins expression. The effects of QUIN on Nrf2 modulation and oxidative stress were also compared between slices of wild-type (Nrf2(+/+)) and Nrf2 knock-out (Nrf2(-/-)) mice. The possible involvement of the N-methyl-D-aspartate receptor (NMDAr) in the Nrf2 modulation and lipid peroxidation was further explored in mice striatal slices. In rat striatal slices, QUIN stimulated the Nrf2 nuclear translocation. This effect was accompanied by augmented lipid peroxidation. In the mouse striatum, QUIN per se exerted an induction of Nrf2 factor only at 1 h of incubation, and a concentration-response effect on lipid peroxidation after 3 h of incubation. QUIN stimulated the striatal content of phase 2 enzymes. Nrf2(-/-) mice were slightly more responsive than Nrf2(+/+) mice to the QUIN-induced oxidative damage, and completely unresponsive to the NMDAr antagonist MK-801 when tested against QUIN. Findings of this study indicate that: 1) Nrf2 is modulated in rodent striatal tissue in response to QUIN; 2) Nrf2(-/-) striatal tissue was moderately more vulnerable to oxidative damage than the Wt condition; and 3) early Nrf2 up-regulation reflects a compensatory response to the QUIN-induced oxidative stress in course as part of a general defense system, whereas Nrf2 down-regulation might contribute to more intense oxidative cell damage.
    Neuroscience 12/2013; · 3.12 Impact Factor
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    ABSTRACT: Craniopharyngiomas (CPs) are benign epithelial cystic tumors of the sellar and suprasellar region with a high survival rate and high recurrence in children. CPs contain dense oily fluid, but little is known yet about this content and its contribution to tissue damage and tumoral growth. In this study, we developed a simple experimental model produced by intracortical injection to rats of the cyst fluid content collected from human CPs to explore its possible contribution to brain tissue damage. The cyst fluid of the CPs ("oil machinery fluid") was collected during surgical removal, briefly preserved and further tested in rats through intracortical infusion. The group receiving "oil machinery fluid" presented increased reactive oxygen species formation, oxidative damage to lipids and reactive gliosis accompanied by augmented immunoreactivity to peroxiredoxin and thioredoxin reductase 1 at 15, 30 and 45 days post-injection. Other markers of inflammation and cell damage were stimulated at all post-lesion days tested. There was also a body weight gain. The persistence of tissue damage and oxidative stress suggests that "oil machinery fluid" exerts progressive alterations similar to those observed in patients with CPs, supporting the concept that some components of cyst fluid may contribute to brain tissue damage in these patients.
    Acta histochemica 11/2013; · 1.61 Impact Factor
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    ABSTRACT: Abstract The neuroprotective properties of S-allyl cysteine (SAC) have been demonstrated in different neurotoxic paradigms, and it may be partially attributable to its antioxidant and anti-inflammatory profile. Recently, SAC has also been shown to induce neuroprotection in the rat striatum in a toxic model induced by 6-hydroxydopamine in rats through a concerted antioxidant response involving Nrf2 transcription factor nuclear transactivation and phase 2 enzymes upregulation. In this work, we investigated whether the SAC-induced in vivo striatal and nigral neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridinium (MPTP) toxicity recruits Nrf2 transactivation in C57BL/6J mice. SAC (120 mg/kg, i.p. × 5 days) partially ameliorated the MPTP (30 mg/kg, i.p. ×5 days)-induced striatal and nigral dopamine and tyrosine hydroxylase depletion, attenuated the loss of Mn-SOD and HO-1 activities, and preserved the protein content of these enzymes. While no significant changes were detected for the striatal Nrf2 nuclear protein levels, the nigral Nrf2 nuclear content was decreased by MPTP and stimulated by SAC. Our findings suggest that SAC can exert neuroprotection since the origin of the dopaminergic lesion -at the substantia nigra (SN)- not only by means of direct antioxidant actions, but also through Nrf2 nuclear transactivation and phase 2 enzymes upregulation.
    Free Radical Research 10/2013; · 3.28 Impact Factor
  • A L Colin-Gonzalez, A Santamaria
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    ABSTRACT: Probenecid (PROB) has been widely used for long time for different clinical purposes, from gout treatment to designs as a coadjutant for antibiotic agents. Among its many properties, the ability of PROB to preserve high concentrations of several metabolites and other agents in the CNS, together with its relative lack of side-effects, have made this drug a valuable pharmacological tool for clinical and basic research. Nowadays, biomedical research offers evidence about new targets for PROB that may help to explain its many beneficial actions. In this regard, despite most of its protective actions in the brain have been largely related to its capacity to accumulate the inhibitory metabolite kynurenic acid to further inhibit the glutamate-related excitotoxicity in different animal models of neurological disorders, in this review we describe the basic aspects of PROB's pharmacokinetics and mechanisms of action and discuss other alternative targets recently described for this drug that may complement its pattern of activity in the CNS, including its role as anti-inflammatory and anti-nociceptive agent when targeting different key proteins.
    CNS & neurological disorders drug targets 07/2013; · 3.57 Impact Factor
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    ABSTRACT: There is evidence to support that an impaired energy metabolism and the excessive generation of reactive oxygen species (ROS) contribute to brain injury in neurodegenerative disorders such as Parkinson's disease (PD), whereas diets enriched in foods with an antioxidant action may modulate its progression. Several studies have proved that the antioxidant components produced by Spirulina, a microscopic blue-green alga, might prevent cell death by decreasing free radicals, inhibiting lipoperoxidation and upregulating the antioxidant enzyme systems. In our study, we investigated the protective effect of the Spirulina maxima (S. maxima) against the 6-OHDA-caused toxicity in the rat striatum. The S. maxima (700 mg/kg/day, vo) was administered for 40 days before and 20 days after a single injection of 6-OHDA (16 μg/2 μL) into the dorsal striatum. At 20-day postsurgery, the brain was removed and the striatum was obtained to evaluate the indicators of toxicity, such as nitric oxide levels, ROS formation, lipoperoxidation, and mitochondrial activity. These variables were found significantly stimulated in 6-OHDA-treated rats and were accompanied by declines in dopamine levels and motor activity. In contrast, the animals that received the chronic treatment with S. maxima had a restored locomotor activity, which is associated with the decreased levels of nitric oxide, ROS, and lipoperoxidation in the striatum, although mitochondrial functions and dopamine levels remained preserved. These findings suggest that supplementation with antioxidant phytochemicals (such as contained in S. maxima) represents an effective neuroprotective strategy against 6-OHDA-caused neurotoxicity vía free radical production to preserve striatal dopaminergic neurotransmission in vivo.
    Journal of Neural Transmission 02/2013; · 3.05 Impact Factor
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    ABSTRACT: Recent evidence suggests that the malfunctioning disposal system of cell protein called ubiquitin-proteasome system (UPS) plays an important role in the development of disorders, including cancer and neurodegenerative diseases. Accumulating evidence suggests that the abnormal regulation of the E3 ubiquitin ligases, essential components of the UPS, contributes to uncontrolled proliferation, genomic instability and cancer, since these ligases and their substrates are involved in the regulation of cell cycle progression, gene transcription, signal transduction, DNA replication and others. Through selective degradation of specific substrates, E3 ligases regulate different biological processes. Cullins are a family of proteins that confer substrate specificity to multimeric complex of E3 ligases acting as scaffold proteins. So far, seven members of the cullin family of proteins have been identified. Interestingly, the data generated by several groups indicate that cullin 3 (Cul3) has begun to emerge as a protein involved in the etiopathology of multiple diseases. In this paper we examine the latest advances in basic research on the biology of Cul3 and how it could help to direct drug discovery efforts on this target.
    Redox biology. 01/2013; 1(1):366-372.
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    ABSTRACT: 6-Hydroxydopamine (6-OHDA) is a neurotoxin that generates an experimental model of Parkinson's disease in rodents and is commonly employed to induce a lesion in dopaminergic pathways. The characterization of those molecular mechanisms linked to 6-OHDA-induced early toxicity is needed to better understand the cellular events further leading to neurodegeneration. The present work explored how 6-OHDA triggers early downstream signaling pathways that activate neurotoxicity in the rat striatum. Mitochondrial function, caspases-dependent apoptosis, kinases signaling (Akt, ERK 1/2, SAP/JNK and p38) and crosstalk between nuclear factor kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) were evaluated at early times post-lesion. We found that 6-OHDA initiates cell damage via mitochondrial complex I inhibition, cytochrome c and apoptosis-inducing factor (AIF) release, as well as activation of caspases 9 and 3 to induce apoptosis, kinase signaling modulation and NF-κB-mediated inflammatory responses, accompanied by inhibition of antioxidant systems regulated by the Nrf2 pathway. Our results suggest that kinases SAP/JNK and p38 up-regulation may play a role in the early stages of 6-OHDA toxicity to trigger intrinsic pathways for apoptosis and enhanced NF-κB activation. In turn, these cellular events inhibit the activation of cytoprotective mechanisms, thereby leading to a condition of general damage.
    Toxicology 12/2012; · 4.02 Impact Factor
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    ABSTRACT: Oxidative stress has been recognized as a potential mediator of cell death. Astrocytes play an active role in brain physiology responding to harmful stimuli by activating astrogliosis, which in turn has been associated either with survival or degenerative events. The characterization of the mechanistic actions exerted by different toxins in astrocytes is essential to understand the brain function and pathology. As age plays a critical role in degenerative processes, the aim of this study was to determine whether the administration of equimolar concentrations of two neurotoxins evoking different toxic patterns can induce differential effects on primary astrocytes obtained either from newborn or adult rats, with particular emphasis on those events linked to oxidative stress as a potential source of damage. Primary cortical astrocyte cultures derived from rat brains were exposed to 1-methyl-4-phenylpyridinium (MPP+) or beta-amyloid peptide (β-amyloid). Mitochondrial functionality and cell viability were determined as physiological parameters, whereas lipid and protein oxidation were used as markers of oxidative damage. The results of these experiments pointed towards a higher vulnerability to MPP + over β-amyloid, on most of the tested markers. Hence, in order to allow a comprehensive evaluation of astrocytic responses against MPP + intoxication, a third astrocyte group was included for dose-response experiments: astrocytes derived from aged rats. The present data indicate that the differences associated with age were mainly found in astrocytes exposed to MPP + (25 and 50 μM) at 1-h treatment. Results are discussed in terms of the differential mechanisms involved in each model. Copyright © 2012 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 12/2012; · 2.60 Impact Factor
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    ABSTRACT: Kynurenine pathway is gaining attention because of the many metabolic processes in which it has been involved. The tryptophan conversion into several other metabolites through this pathway provides neuronal and redox modulators useful for maintenance of major functions in the brain. However, when physiopathological conditions prevail -i.e. oxidative stress, excitotoxicity and inflammation-, preferential formation and accumulation of toxic metabolites could trigger factors for degeneration in neurological disorders. 3-Hydroxykynurenine has been largely described as one of these toxic metabolites capable of inducing oxidative damage and cell death; consequently, this metabolite has been hypothesized to play a pivotal role in different neurological and psychiatric disorders. Supporting evidence has shown altered 3-hydroxykynurenine levels in samples of patients from several disorders. In contrast, some experimental studies have provided evidence on antioxidant and scavenging properties inherent to this molecule. In this review, we explored most of literature favoring one or the other concept, in order to provide an accurate vision on the real participation of this tryptophan metabolite in both experimental paradigms and human brain pathologies. Through this collected evidence, we provide an integrative hypothesis on how 3-hydroxykynurenine is exerting its dual actions in the Central Nervous System and what will be the course of investigations in this field for the next years.
    NeuroToxicology 12/2012; · 2.65 Impact Factor
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    ABSTRACT: Quinolinic acid (QA)-induced overactivation of N-methyl-D-aspartate receptors yields excitotoxicity, oxidative stress and mitochondrial dysfunction, which altogether contribute to trigger a wide variety of toxic pathways with biochemical, behavioral and neuropathological alterations similar to those observed in Huntington's disease. Noteworthy, in the brains of these patients, increased expression of heme oxygenase-1 (HO-1) levels can be found. It has been proposed that this enzyme can exert a dual role, as it can be either protective or deleterious to the CNS. While some evidence indicates that its overexpression affords cellular antioxidant protection due to decreased concentrations of its pro-oxidative substrate heme group, and increased bilirubin levels, other reports established that high HO-1 expression and activity may result in a pro-oxidizing atmosphere due to a release of Fe(2+). In this work, we examined the temporal evolution of oxidative damage to proteins, HO-1 expression, immunoreactivity, total activity, and cell death after 1, 3, 5 and 7 days of an intrastriatal QA infusion (240 nmol/μl). QA was found to induce cellular degeneration, increasing carbonylated proteins and generating a transitory response in HO-1 mRNA, protein content, immunoreactivity in neuronal cells, and activity. In order to study the role of HO-1 in the QA-induced cellular death, the tin protoporphyrin IX (SnPP), a well-known HO inhibitor, was administered to rats (30 μmol/kg, i.p.). The administration of SnPP to animals treated with QA inhibited the HO activation, and exacerbated the striatal cell damage induced by QA. Our findings reveal a potential modulatory role of HO-1 in the toxic paradigm evoked by QA in rats. This evidence provides a valuable tool for further approaches on HO-1 regulation in neurotoxic paradigms.
    Neuroscience 11/2012; · 3.12 Impact Factor
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    ABSTRACT: In a previous report, we have characterized the antiperoxidative properties of alpha-mangostin in different toxic models tested in nerve tissue preparations. Here, the modulatory effects of this xanthone on the glutathione system (reduced glutathione (GSH) levels, glutathione peroxidase (GPx), and glutathione S-transferase (GST) activities) were tested in synaptosomal P2 fractions isolated from rat brains in order to provide further information on key mechanisms exerted by this antioxidant in the nervous system. Synaptosomes were exposed to increasing concentrations of the xanthone, and also challenged to the toxic actions of a free radical generator, ferrous sulfate (FeSO(4)). For comparative purposes, the mitochondrial toxin 3-nitropropionic acid (3-NP) was also explored. Alpha-mangostin significantly decreased the levels of GSH, and increased GPx activity. This finding was interpreted as a modulatory action of the GSH system in preparation to exert antioxidant responses. Although FeSO(4) exhibited similar effects, these were interpreted as a compensatory response to the toxic actions of the pro-oxidant. We came to this conclusion based on our previous report where alpha-mangostin produced antiperoxidative effects and FeSO(4) produced oxidative damage to lipids. GST activity remained unaffected by both the antioxidant and the pro-oxidant. Our results suggest that alpha-mangostin is able to modulate GPx activity as a potential antioxidant strategy, thereby transiently consuming GSH levels.
    Nutritional Neuroscience 09/2012; 15(5):13-9. · 1.65 Impact Factor
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    07/2012: pages 271-286; , ISBN: 978 1 62100 766 1
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    ABSTRACT: Pharmacological activation at the basal ganglia of the transcription factor Nrf2, guardian of redox homeostasis, holds a strong promise for the slow progression of Parkinson's disease (PD). However, a potent Nrf2 activator in the brain still must be found. In this study, we have investigated the potential use of the antioxidant compound S-allyl cysteine (SAC) in the activation of Nrf2 in 6-hydoxydopamine (6-OHDA)-intoxicated rats. In the rat striatum, SAC by itself promoted the Nrf2 dissociation of Keap-1, its nuclear translocation, the subsequent association with small MafK protein, and further binding of the Nrf2/MafK complex to ARE sequence, as well as the up-regulation of Nrf2-dependent genes encoding the antioxidant enzymes HO-1, NQO-1, GR, and SOD-1. In vivo and in vitro experiments to identify signaling pathways activated by SAC pointed to Akt as the most likely kinase participating in Nrf2 activation by SAC. In PC12 cells, SAC stimulated the activation of Akt and ERK1/2 and inhibited JNK1/2/3 activation. In the rat striatum, the SAC-induced activation of Nrf2 is likely to contribute to inhibit the toxic effects of 6-OHDA evidenced by phase 2 antioxidant enzymes up-regulation, glutathione recovery, and attenuation of reactive oxygen species (ROS), nitric oxide (NO), and lipid peroxides formation. These early protective effects correlated with the long-term preservation of the cellular redox status, the striatal dopamine (DA) and tyrosine hydroxylase (TH) levels, and the improvement of motor skills. Therefore, this study indicates that, in addition to direct scavenging actions, the activation of Nrf2 by SAC might confer neuroprotective responses through the modulation of kinase signaling pathways in rodent models of PD, and suggests that this antioxidant molecule may have a therapeutic value in this human pathology.
    Free Radical Biology & Medicine 07/2012; 53(5):1024-40. · 5.27 Impact Factor
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    ABSTRACT: Neurological diseases comprise a group of heterogeneous disorders characterized by progressive brain dysfunction and cell death. In the next years, these diseases are expected to constitute a world-wide health problem. Because excitotoxicity and oxidative stress are involved in neurodegenerative diseases, it becomes relevant to describe pharmacological therapies designed to activate endogenous cytoprotective systems. Activation of transcription factor Nrf2 stimulates cytoprotective vitagenes involved in antioxidant defense. In this work, we investigated the ability of the antioxidant curcumin to induce transcription factor Nrf2 in a neurodegenerative model induced by quinolinic acid in rats. Animals were administered with curcumin (400 mg/kg, p.o.) for 10 days, and then intrastriatally infused with quinolinic acid (240 nmol) on day 10 of treatment. Curcumin prevented rotation behavior (6 days post-lesion), striatal morphological alterations (7 days post-lesion) and neurodegeneration (1 and 3 days post-lesion) induced by quinolinic acid. Curcumin also reduced quinolinic acid-induced oxidative stress (measured as protein carbonyl content) at 6 h post-lesion. The protective effects of curcumin were associated to its ability to prevent the quinolinic acid-induced decrease of striatal intra-nuclear Nrf2 levels (30 and 120 min post-lesion), and total superoxide dismutase and glutathione peroxidase activities (1 day post-lesion). Therefore, results of this study support the concept that neuroprotection induced by curcumin is associated with its ability to activate the Nrf2 cytoprotective pathway and to increase the total superoxide dismutase and glutathione peroxidase activities.
    The Journal of nutritional biochemistry 06/2012; · 4.29 Impact Factor
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    ABSTRACT: Selenium (Se) is a crucial element exerting antioxidant and neuroprotective effects in different toxic models. It has been suggested that Se acts through selenoproteins, of which thioredoxin reductase (TrxR) is relevant for reduction of harmful hydroperoxides and maintenance of thioredoxin (Trx) redox activity. Of note, the Trx/TrxR system remains poorly studied in toxic models of degenerative disorders. Despite previous reports of our group have demonstrated a protective role of Se in the excitotoxic/pro-oxidant model induced by quinolinic acid (QUIN) in the rat striatum (Santamaría et al., 2003, 2005), the precise mechanism(s) by which Se is inducing protection remains unclear. In this work, we characterized the time course of protective events elicited by Se as pretreatment (Na(2)SO(3), 0.625 mg/kg/day, i.p., administered for 5 consecutive days) in the toxic pattern produced by a single infusion of QUIN (240 nmol/μl) in the rat striatum, to further explore whether TrxR is involved in the Se-induced protection and how is regulated. Se attenuated the QUIN-induced early reactive oxygen species formation, lipid peroxidation, oxidative damage to DNA, loss of mitochondrial reductive capacity and morphological alterations in the striatum. Our results also revealed a novel pattern in which QUIN transiently stimulated an early TrxR cellular localization/distribution (at 30 min and 2 h post-lesion, evidenced by immunohistochemistry), to further stimulate a delayed protein activation (at 24 h) in a manner likely representing a compensatory response to the oxidative damage in course. In turn, Se induced an early stimulation of TrxR activity and expression in a time course that "matches" with the reduction of the QUIN-induced oxidative damage, suggesting that the Trx/TrxR system contributes to the resistance of nerve tissue to QUIN toxicity.
    Neurochemistry International 05/2012; 61(2):195-206. · 2.66 Impact Factor

Publication Stats

1k Citations
257.39 Total Impact Points

Institutions

  • 1991–2014
    • Instituto Nacional de Neurología y Neurocirugía
      • Clinical Laboratory of Neurodegenerative Diseases
      Tlalpam, The Federal District, Mexico
  • 2013
    • National Polytechnic Institute
      Villa Gustavo A. Madero, The Federal District, Mexico
  • 2009–2010
    • University of Cordoba (Spain)
      • Facultad de Medicina
      Córdoba, Andalusia, Spain
    • Midwestern University
      • Department of Pharmaceutical Sciences in Glendale
      Glendale, AZ, United States
  • 1998–2007
    • The National Institute of Neurology and Neurosurgery
      Tlalpam, The Federal District, Mexico
  • 2001
    • Universidad Nacional Autónoma de México
      • Department of Biology
      Ciudad de México, The Federal District, Mexico
  • 1999
    • Instituto Nacional de Pediatría
      Ciudad de México, The Federal District, Mexico
  • 1994
    • Metropolitan Autonomous University
      • Departamento de Química
      Mexico City, The Federal District, Mexico