Antioxidant activity of glucosamine and its effects on ROS production, Nrf2, and O-GlcNAc expression in HMEC-1 cells.

Glucosamine (GlcN) is the most used supplement for osteoarthritis treatment. In vitro studies have related GlcN to beneficial and detrimental effects on health. The aim of this study was to evaluate the effects of O-linked-N-acetylglucosaminylation (O-GlcNAc) on GlcN-induced ROS production and Nrf2 expression in human dermal microvascular endothelial cells-1 (HMEC-1) and to evaluate the antioxidant capacity of GlcN compared to well-known antioxidants. For this, we evaluate the antioxidant capacity by in vitro assays. Besides, the GlcN (5-20 mM) effects on cell viability, reactive oxygen species (ROS) production, O-GlcNAc, and nuclear factor erythroid-2-related factor 2 (Nrf2) expression with and without the O-GlcNAc inhibitor OSMI-1 (10 µM) in HMEC-1 were evaluated. GlcN showed high inhibitory concentration (low scavenging activity) against superoxide (O2•─, IC20 = 47.67 mM), 2,2-diphenyl-1-picrylhydrazyl (DPPH•, IC50 = 21.32 mM), and hydroxyl (HO•, IC50 = 14.04 mM) radicals without scavenging activity against hydrogen peroxide (H2O2) and low antioxidant capacity determined by oxygen radical absorbance capacity (ORAC, 0.001 mM Trolox equivalent) and ferric reducing antioxidant power (FRAP, 0.046 mM Trolox equivalent). In cell culture, GlcN (20 mM) reduced cell viability up to 26 % and induced an increase in ROS production (up to 70 %), O-GlcNAc (4-fold-higher vs. control), and Nrf2 expression (56 %), which were prevented by OSMI-1. These data suggest an association between O-GlcNAc, ROS production, and Nrf2 expression in HMEC-1 cells stimulated with GlcN.

Stenocereus huastecorum-fruit juice concentrate protects against cisplatin-induced nephrotoxicity by nitric oxide pathway activity and antioxidant and antiapoptotic effects.

Cisplatin (CP) is an antineoplastic agent used to treat solid tumors, that has high nephrotoxicity caused by physiologic, hemodynamic, and biochemical alterations. Some studies have shown that naturally derived bioactive compounds in CP-induced nephrotoxicity reduce the side effects of this antineoplastic drug. Pitaya is an endemic fruit from Mexico with a high bioactive compound content, including betalains and phenolic compounds, with reports of antioxidant and anti-inflammatory properties. In this study, the aim was to establish the effect of a pitaya juice concentrate (PJC) on CP-induced nephrotoxicity in Wistar male rats through the identification of metabolites, determination of its chemical composition and antioxidant activity, and evaluation of the protective effect of a PJC on CP-induced nephrotoxicity in rats. The PJC showed a high content of betanins with antioxidant activity by an oxygen radical absorbance capacity assay (1299.6 ± 2.80 Trolox equivalents/g). PJC was administered daily (400 mg day-1, p. o.) for 3 days before CP administration until the end of the experiment. On day four, rats were administered a single injection of CP (6 mg kg, i.p.-1) and sacrificed 72 h later. We observed that CP provoked renal dysfunction (1.0 ± 0.1 vs. 0.4 ± 0.07 serum creatinine levels), oxidative stress, a decrease in nitrate and nitrite (NO2¯/NO3¯) levels (0.1 ± 0.08 vs. 0.4 ± 0.3) and activation of apoptosis and immune responses in kidney tissue. In addition, CP treatment induced tubular damage threefold. PJC administration prevented renal dysfunction (0.5 ± 0.06 vs. 1.0 ± 0.1), normalized degenerative structural damage prevented the increase in lipoperoxidation levels (0.04 ± 0.01 vs. 0.2 ± 0.1) and reduced the apoptosis index by 2.5 in kidney tissue. However, it did not modify the immune response caused by CP. Furthermore, PJC treatment increased nuclear factor erythroid two related factors two protein levels two times and NO2¯/NO3¯ levels 22 times in kidney tissue, which may play a role in the renoprotective effect. In conclusion, the renoprotective effect of PJC on CP-induced nephrotoxicity was associated with the attenuation of dysfunction, structural damage, apoptosis activation, and oxidative stress and was related to changes in the tumor necrosis factor-alpha and renal nitric oxide (NO) pathways. The changes in the NO pathway may be involved in renal hemodynamics. Pitaya could be used as a functional food and therapeutic coadjuvant during CP treatments due to its high bioactive levels and renoprotective compounds.

Alteration of mitochondrial supercomplexes assembly in metabolic diseases.

Deregulation of nutrient, hormonal, or neuronal signaling produces metabolic alterations that result in increased mitochondrial reactive oxygen species (ROS) production. The associations of the mitochondrial respiratory chain components into supercomplexes could have pathophysiological relevance in metabolic diseases, as supramolecular arrangements, by sustaining a high electron transport rate, might prevent ROS generation. In this review, the relationship between mitochondrial dysfunction and supercomplex arrangement of the mitochondrial respiratory chain components in obesity, insulin resistance, hepatic steatosis and diabetes mellitus is summarized and discussed.

Sulforaphane protects from myocardial ischemia-reperfusion damage through the balanced activation of Nrf2/AhR.

The activation of the transcription factor Nrf2 and the consequent increment in the antioxidant response might be a powerful strategy to contend against reperfusion damage. In this study we compared the effectiveness between sulforaphane (SFN), a well known activator of Nrf2 and the mechanical maneuver of post-conditioning (PostC) to confer cardioprotection in an in vivo cardiac ischemia-reperfusion model. We also evaluated if additional mechanisms, besides Nrf2 activation contribute to cardioprotection. Our results showed that SFN exerts an enhanced protective response as compared to PostC. Bot, strategies preserved cardiac function, decreased infarct size, oxidative stress and inflammation, through common protective pathways; however, the aryl hydrocarbon receptor (AhR) also participated in the protection conferred by SFN. Our data suggest that SFN-mediated cardioprotection involves transient Nrf2 activation, followed by phase I enzymes upregulation at the end of reperfusion, as a long-term protection mechanism.

Jacareubin inhibits FcεRI-induced extracellular calcium entry and production of reactive oxygen species required for anaphylactic degranulation of mast cells.

Mast cells (MCs) are important effectors in allergic reactions since they produce a number of pre-formed and de novo synthesized pro-inflammatory compounds in response to the high affinity IgE receptor (FcεRI) crosslinking. IgE/Antigen-dependent degranulation and cytokine synthesis in MCs have been recognized as relevant pharmacological targets for the control of deleterious inflammatory reactions. Despite the relevance of allergic diseases worldwide, efficient pharmacological control of mast cell degranulation has been elusive. In this work, the xanthone jacareubin was isolated from the heartwood of the tropical tree Callophyllum brasilense, and its tridimensional structure was determined for the first time by X-ray diffraction. Also, its effects on the main activation parameters of bone marrow-derived mast cells (BMMCs) were evaluated. Jacareubin inhibited IgE/Ag-induced degranulation in a dose-response manner with an IC50 = 46 nM. It also blocked extracellular calcium influx triggered by IgE/Ag complexes and by the SERCA ATPase inhibitor thapsigargin (Thap). Inhibition of calcium entry correlated with a blockage on the reactive oxygen species (ROS) accumulation. Antioxidant capacity of jacareubin was higher than the showed by α-tocopherol and caffeic acid, but similar to trolox. Jacareubin shown inhibitory actions on xanthine oxidase, but not on NADPH oxidase (NOX) activities. In vivo, jacareubin inhibited passive anaphylactic reactions and TPA-induced edema in mice. Our data demonstrate that jacareubin is a potent natural compound able to inhibit anaphylactic degranualtion in mast cells by blunting FcεRI-induced calcium flux needed for secretion of granule content, and suggest that xanthones could be efficient anti-oxidant, antiallergic, and antiinflammatory molecules.

Role of sphingomyelinase in mitochondrial ceramide accumulation during reperfusion.

Ceramide accumulation in mitochondria has been associated with reperfusion damage, but the underlying mechanisms are not clearly elucidated. In this work we investigate the role of sphingomyelinases in mitochondrial ceramide accumulation, its effect on reactive oxygen species production, as well as on mitochondrial function by using the sphingomyelinase inhibitor, tricyclodecan-9-yl-xanthogenate (D609). Correlation between neutral sphingomyelinase (nSMase) activity and changes in ceramide content were performed in whole tissue and in isolated mitochondria from reperfused hearts. Overall results demonstrated that D609 treatment attenuates cardiac dysfuncion, mitochondrial injury and oxidative stress. Ceramide was accumulated in mitochondria, but not in the microsomal fraction of the ischemic-reperfused (I/R) group. In close association, the activity of nSMase increased, whereas glutathione (GSH) levels diminished in mitochondria after reperfusion. On the other hand, reduction of ceramide levels in mitochondria from I/R+D609 hearts correlated with diminished nSMase activity, coupling of oxidative phosphorylation and with mitochondrial integrity maintenance. These results suggest that mitochondrial nSMase activity contributes to compartmentation and further accumulation of ceramide in mitochondria, deregulating their function during reperfusion.

Curcumin prevents maleate-induced nephrotoxicity: relation to hemodynamic alterations, oxidative stress, mitochondrial oxygen consumption and activity of respiratory complex I.

The potential protective effect of the dietary antioxidant curcumin (120 mg/Kg/day for 6 days) against the renal injury induced by maleate was evaluated. Tubular proteinuria and oxidative stress were induced by a single injection of maleate (400 mg/kg) in rats. Maleate-induced renal injury included increase in renal vascular resistance and in the urinary excretion of total protein, glucose, sodium, neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl ß-D-glucosaminidase (NAG), upregulation of kidney injury molecule (KIM)-1, decrease in renal blood flow and claudin-2 expression besides of necrosis and apoptosis of tubular cells on 24 h. Oxidative stress was determined by measuring the oxidation of lipids and proteins and diminution in renal Nrf2 levels. Studies were also conducted in renal epithelial LLC-PK1 cells and in mitochondria isolated from kidneys of all the experimental groups. Maleate induced cell damage and reactive oxygen species (ROS) production in LLC-PK1 cells in culture. In addition, maleate treatment reduced oxygen consumption in ADP-stimulated mitochondria and diminished respiratory control index when using malate/glutamate as substrate. The activities of both complex I and aconitase were also diminished. All the above-described alterations were prevented by curcumin. It is concluded that curcumin is able to attenuate in vivo maleate-induced nephropathy and in vitro cell damage. The in vivo protection was associated to the prevention of oxidative stress and preservation of mitochondrial oxygen consumption and activity of respiratory complex I, and the in vitro protection was associated to the prevention of ROS production.

Sulforaphane reduces the alterations induced by quinolinic acid: modulation of glutathione levels.

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 (5mg/kg, i.p.) 24h and 5min before the intrastriatal infusion of QUIN. SULF increased the reduced glutathione (GSH) levels 4h 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 24h. 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.

New insights into antioxidant strategies against paraquat toxicity.

Paraquat (PQ, 1,1'-dimethyl-4-4'-bipyridinium dichloride) is a highly toxic quaternary ammonium herbicide widely used in agriculture, it exerts its toxic effects mainly because of its redox cycle through the production of superoxide anions in organisms, leading to an imbalance in the redox state of the cell causing oxidative damage and finally cell death. The contribution of mitochondrial dysfunction including increased production of reactive oxygen species besides the reduction in oxygen consumption as well as in the activity of some respiratory complexes has emerged as a key component in the mechanisms through which PQ induces cell death. Although several aspects of PQ-mitochondria interaction remain to be clarified, recent advances have been conducted with reproducible results. Currently, there is no treatment for PQ poisoning; however, several studies taking into account oxidative stress as the main mechanism of PQ-induced toxicity suggest an antioxidant therapy as a viable alternative. In fact, it has been shown that the antioxidants naringin, sylimarin, edaravone, Bathysa cuspidata extracts, alpha-lipoic acid, pirfenidone, lysine acetylsalicylate, selenium, quercetin, C-phycocyanin, bacosides, and vitamin C may be useful in the treatment against PQ toxicity. The main mechanisms involved in the protective effect of these antioxidants include the reduction of oxidative stress and inflammation and the induction of antioxidant defenses. Interestingly, recent findings suggest that the induction of nuclear factor erythroid like-2 (Nrf2), a major regulator of the antioxidant response, by some of the above-mentioned antioxidants, has been involved in the protective effect against PQ-induced toxicity.

Early modulation of the transcription factor Nrf2 in rodent striatal slices by quinolinic acid, a toxic metabolite of the kynurenine pathway.

Nuclear factor (erythroid-derived 2)-like 2 (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 protein 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 1h of incubation, and a concentration-response effect on lipid peroxidation after 3h 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.

Antioxidant activity of topiramate: an antiepileptic agent.

A number of experimental and clinical reports suggest the involvement of oxidative stress in pathophysiology of epilepsy. Topiramate, a new antiepileptic drug, induces antioxidant effect in epileptic animals. However, to date, no further studies appear to be carried out in order to demonstrate the ability of topiramate to act as antioxidant. Therefore, the objective of this work was to evaluate the in vitro superoxide (O2(·-)), hydroxyl radical (OH·), hypochlorous acid (HOCl), hydrogen peroxide (H2O2), singlet oxygen ((1)O2) and peroxynitrite (ONOO(-)) scavenging capacity of topiramate in comparison with reference compounds. In addition, we investigated the possible antitumour activity of this compound in some cancer cell lines. Topiramate displays a scavenging capacity compared to the reference compound, with the exception of ONOO(-), although it was less efficient than nordihydroguaiaretic acid, dimethylthiourea, ascorbic acid, sodium pyruvate and glutathione for O2(·-), OH·, HOCl, H2O2 and (1)O2(P < 0.0001), respectively, and not induced significant growth inhibition in cancer cell lines. The direct antioxidant properties of topiramate could explain the neuroprotective effects attributed to this compound and suggest its use as chemopreventive agent in a future.

Heme oxygenase-1 (HO-1) upregulation delays morphological and oxidative damage induced in an excitotoxic/pro-oxidant model in the rat striatum.

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 anti-oxidant 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, and immunoreactivity and activity in nerve cells. 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.

Effect of glycolysis inhibition on mitochondrial function in rat brain.

Inhibition of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase enhances the neural vulnerability to excitotoxicity both in vivo and in vitro through an unknown mechanism possibly related to mitochondrial failure. However, as the effect of glycolysis inhibition on mitochondrial function in brain has not been studied, the aim of the present work was to evaluate the effect of glycolysis inhibition induced by iodoacetate on mitochondrial function and oxidative stress in brain. Mitochondria were isolated from brain cortex, striatum and cerebellum of rats treated systemically with iodoacetate (25 mg/kg/day for 3 days). Oxygen consumption, ATP synthesis, transmembrane potential, reactive oxygen species production, lipoperoxidation, glutathione levels, and aconitase activity were assessed. Oxygen consumption and aconitase activity decreased in the brain cortex and striatum, showing that glycolysis inhibition did not trigger severe mitochondrial impairment, but a slight mitochondrial malfunction and oxidative stress were present.

On the antioxidant properties of kynurenic acid: free radical scavenging activity and inhibition of oxidative stress.

Kynurenic acid (KYNA) is an endogenous metabolite of the kynurenine pathway for tryptophan degradation and an antagonist of both N-methyl-D-aspartate (NMDA) and alpha-7 nicotinic acetylcholine (α7nACh) receptors. KYNA has also been shown to scavenge hydroxyl radicals (OH) under controlled conditions of free radical production. In this work we evaluated the ability of KYNA to scavenge superoxide anion (O(2)(-)) and peroxynitrite (ONOO(-)). The scavenging ability of KYNA (expressed as IC(50) values) was as follows: OH=O(2)(-)>ONOO(-). In parallel, the antiperoxidative and scavenging capacities of KYNA (0-150 µM) were tested in cerebellum and forebrain homogenates exposed to 5 µM FeSO(4) and 2.5 mM 3-nitropropionic acid (3-NPA). Both FeSO(4) and 3-NPA increased lipid peroxidation (LP) and ROS formation in a significant manner in these preparations, whereas KYNA significantly reduced these markers. Reactive oxygen species (ROS) formation were determined in the presence of FeSO(4) and/or KYNA (0-100 µM), both at intra and extracellular levels. An increase in ROS formation was induced by FeSO(4) in forebrain and cerebellum in a time-dependent manner, and KYNA reduced this effect in a concentration-dependent manner. To further know whether the effect of KYNA on oxidative stress is independent of NMDA and nicotinic receptors, we also tested KYNA (0-100 µM) in a biological preparation free of these receptors - defolliculated Xenopus laevis oocytes - incubated with FeSO(4) for 1 h. A 3-fold increase in LP and a 2-fold increase in ROS formation were seen after exposure to FeSO(4), whereas KYNA attenuated these effects in a concentration-dependent manner. In addition, the in vivo formation of OH evoked by an acute infusion of FeSO(4) (100 µM) in the rat striatum was estimated by microdialysis and challenged by a topic infusion of KYNA (1 µM). FeSO(4) increased the striatal OH production, while KYNA mitigated this effect. Altogether, these data strongly suggest that KYNA, in addition to be a well-known antagonist acting on nicotinic and NMDA receptors, can be considered as a potential endogenous antioxidant.

NAD(P)H oxidase contributes to neurotoxicity in an excitotoxic/prooxidant model of Huntington's disease in rats: protective role of apocynin.

Intrastriatal injection of quinolinic acid (QUIN) to rodents reproduces some biochemical, morphological, and behavioral characteristics of Huntington's disease. NAD(P)H oxidase is an enzymatic complex that catalyzes superoxide anion (O(2).(-)) production from O(2) and NADPH. The present study evaluated the role of NAD(P)H oxidase in the striatal damage induced by QUIN (240 nmol/microl) in adult male Wistar rats by means of apocynin (APO; 5 mg/kg i.p.), a specific NAD(P)H oxidase inhibitor. Rats were given APO 30 min before and 1 hr after QUIN injection or only 30 min after QUIN injection. NAD(P)H oxidase activity was measured in striatal homogenates by O2(*)(-) production. QUIN infusion to rats significantly increased striatal NAD(P)H oxidase activity (2 hr postlesion), whereas APO treatments decreased the QUIN-induced enzyme activity (2 hr postlesion), lipid peroxidation (3 hr postlesion), circling behavior (6 days postlesion), and histological damage (7 days postlesion). The addition of NADH to striatal homogenates increased NAD(P)H oxidase activity in striata from QUIN-treated animals but not from sham rats. Interestingly, O2(*)(-) production in QUIN-lesioned striata was unaffected by the addition of substrates for intramitochondrial O2(*)(-) production, xanthine oxidase and nitric oxide synthase, suggesting that NAD(P)H oxidase may be the main source of O2(*)(-) in QUIN-treated rats. Moreover, the administration of MK-801 to rats as a pretreatment resulted in a complete prevention of the QUIN-induced NAD(P)H activation, suggesting that this toxic event is completely dependent on N-methyl-D-aspartate receptor overactivation. Our results also suggest that NAD(P)H oxidase is involved in the pathogenic events linked to excitotoxic/prooxidant conditions.

Effects of alpha-mangostin on mitochondrial energetic metabolism.

Although alpha-mangostin prevents from toxicity associated to oxidative stress, it also promotes apoptotic cell death in cancer cells. Such effects have been associated with mitochondrial membrane depolarization and cytochrome c release. Therefore, the aim of this work was to analyze the potentially harmful effect of this natural compound on relevant parameters of mitochondrial function from normal tissue. Our results showed that alpha-mangostin protected mitochondria from peroxidative damage, but at high concentration, it acted as an uncoupler, reduced dramatically ADP-stimulated respiration and inhibited the activity of respiratory complex IV, making mitochondria prone to permeability transition, which is a mitochondrial player on cell fate.

Papel de la hemooxigenasa-1 en las enfermedades neurodegenerativas / Role of hemeoxygenase-1 in the neurodegenerative disorders

Objetivo. Revisar evidencias de la participación de la hemooxigenasa-1 (HO-1) en enfermedades neurodegenerativas. Desarrollo. La HO cataliza la degradación del grupo hemo a monóxido de carbono, hierro y biliverdina. Se han caracterizado ampliamente dos isoformas de la HO: una inducible (HO-1) y una constitutiva (HO-2). Como la expresión de HO-1 confiere citoprotección en varias líneas celulares y en modelos animales bajo estrés oxidativo, se considera que la activación del gen de HO-1 es un mecanismo de defensa celular. En estudios post mortem en cerebro se ha encontrado un incremento en la expresión de la HO-1 en pacientes con enfermedades de Alzheimer, Parkinson y Huntington. Aunque no se han determinado la causa y el significado de este aumento, existen evidencias de que la sobreexpresión de la HO-1 contribuye a la acumulación de hierro en la mitocondria, lo que sugeriría que la expresión de la HO-1 tiene un efecto citotóxico. En contraste, hay evidencias de que la sobreexpresión de la HO-1 disminuye la muerte celular en ratones transgénicos y cultivos neuronales expuestos a compuestos neurotóxicos, lo que sugeriría que esta enzima tiene un papel citoprotector. Conclusión. Existe controversia sobre si la expresión de la HO-1 durante enfermedades neurodegenerativas confiere citoprotección o, por el contrario, promueve la neurodegeneración. Por tanto, es necesario continuar el estudio del papel de la HO-1 en modelos de daño neuronal

Aim. To review some evidences about the role of hemeoxygenase-1 (HO-1) in neurodegenerative disorders. Development. HO is the rate-limiting enzyme that catalyzes the conversion of heme into biliverdin, carbon monoxide, and free iron. They are the inducible HO-1 and the constitutive HO-2. A large body of evidence suggests that HO-1 confers cytoprotection against oxidative stress. Postmortem studies conducted in humans have revealed increase in HO-1 protein in association with Alzheimer disease, Parkinson disease and Huntington disease. It is unknown the meaning of that increase. Nevertheless, there are evidences indicating that the overexpression of HO-1 contributes to the pathological iron deposition suggesting a detrimental role of HO-1. In contrast, there are evidences indicating that the overexpression of HO-1 decreases the neurotoxin-induced cell death in transgenic mice and neuronal cultures suggesting a cytoprotective role of HO-1. Conclusion. It is controversial if the overexpression of HO-1 has a detrimental or cytoprotective role. Therefore, it is necessary to continue the study about the role of the HO-1 in neurodegenerative diseases

[Role of hemeoxygenase-1 in the neurodegenerative disorders]. / Papel de la hemooxigenasa-1 en las enfermedades neurodegenerativas.

AIM: To review some evidences about the role of hemeoxygenase-1 (HO-1) in neurodegenerative disorders. DEVELOPMENT: HO is the rate-limiting enzyme that catalyzes the conversion of heme into biliverdin, carbon monoxide, and free iron. They are the inducible HO-1 and the constitutive HO-2. A large body of evidence suggests that HO-1 confers cytoprotection against oxidative stress. Postmortem studies conducted in humans have revealed increase in HO-1 protein in association with Alzheimer disease, Parkinson disease and Huntington disease. It is unknown the meaning of that increase. Nevertheless, there are evidences indicating that the overexpression of HO-1 contributes to the pathological iron deposition suggesting a detrimental role of HO-1. In contrast, there are evidences indicating that the overexpression of HO-1 decreases the neurotoxin-induced cell death in transgenic mice and neuronal cultures suggesting a cytoprotective role of HO-1. CONCLUSION: It is controversial if the overexpression of HO-1 has a detrimental or cytoprotective role. Therefore, it is necessary to continue the study about the role of the HO-1 in neurodegenerative diseases.

Excitotoxic brain damage involves early peroxynitrite formation in a model of Huntington's disease in rats: protective role of iron porphyrinate 5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III).

Oxidative/nitrosative stress is involved in NMDA receptor-mediated excitotoxic brain damage produced by the glutamate analog quinolinic acid. The purpose of this work was to study a possible role of peroxynitrite, a reactive oxygen/nitrogen species, in the course of excitotoxic events evoked by quinolinic acid in the brain. The effects of Fe(TPPS) (5,10,15,20-tetrakis (4-sulfonatophenyl)porphyrinate iron (III)), an iron porphyrinate and putative peroxynitrite decomposition catalyst, were tested on lipid peroxidation and mitochondrial function in brain synaptic vesicles exposed to quinolinic acid, as well as on peroxynitrite formation, nitric oxide synthase and superoxide dismutase activities, lipid peroxidation, caspase-3-like activation, DNA fragmentation, and GABA levels in striatal tissue from rats lesioned by quinolinic acid. Circling behavior was also evaluated. Increasing concentrations of Fe(TPPS) reduced lipid peroxidation and mitochondrial dysfunction induced by quinolinic acid (100 microM) in synaptic vesicles in a concentration-dependent manner (10-800 microM). In addition, Fe(TPPS) (10 mg/kg, i.p.) administered 2 h before the striatal lesions, prevented the formation of peroxynitrite, the increased nitric oxide synthase activity, the decreased superoxide dismutase activity and the increased lipid peroxidation induced by quinolinic acid (240 nmol/microl) 120 min after the toxin infusion. Enhanced caspase-3-like activity and DNA fragmentation were also reduced by the porphyrinate 24 h after the injection of the excitotoxin. Circling behavior from quinolinic acid-treated rats was abolished by Fe(TPPS) six days after quinolinic acid injection, while the striatal levels of GABA, measured one day later, were partially recovered. The protective effects that Fe(TPPS) exerted on quinolinic acid-induced lipid peroxidation and mitochondrial dysfunction in synaptic vesicles suggest a primary action of the porphyrinate as an antioxidant molecule. In vivo findings suggest that the early production of peroxynitrite, altogether with the enhanced risk of superoxide anion (O2*-) and nitric oxide formation (its precursors) induced by quinolinic acid in the striatum, are attenuated by Fe(TPPS) through a recovery in the basal activities of nitric oxide synthase and superoxide dismutase. The porphyrinate-mediated reduction in DNA fragmentation simultaneous to the decrease in caspase-3-like activation from quinolinic acid-lesioned rats suggests a prevention in the risk of peroxynitrite-mediated apoptotic events during the course of excitotoxic damage in the striatum. In summary, the protective effects that Fe(TPPS) exhibited both under in vitro and in vivo conditions support an active role of peroxynitrite and its precursors in the pattern of brain damage elicited by excitotoxic events in the experimental model of Huntington's disease. The neuroprotective mechanisms of Fe(TPPS) are discussed.