Ana Flávia Furian

Universidade Federal de Santa Maria, Santa Maria da Boca do Monte, Rio Grande do Sul, Brazil

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Publications (46)137.18 Total impact

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    ABSTRACT: Together with pharmacoresistant seizures, the quality of life of temporal lobe epilepsy (TLE) patients is negatively impacted by behavioral comorbidities including but not limited to depression, anxiety and cognitive deficits. The pilocarpine model of TLE has been widely used to study characteristics of human TLE, including behavioral comorbidities. Since the outcomes of pilocarpine-induced TLE might vary depending on several experimental factors, we sought to investigate potential gender-related differences regarding selected behavioral alterations in C57BL6 mice. We found that epileptic mice, independently of gender, displayed increased anxiety-like behavior in the open-field test. In the object recognition test, epileptic mice, regardless of gender, showed decreased recognition index at 24 (but not at 4) hours after training. On the other hand, no significant differences were found regarding mice learning and memory performance in the Barnes maze paradigm. Motor coordination and balance as assessed by the beam walk test was impaired in epileptic mice of both gender. However, female mice, independently of epilepsy, performed the task with fewer footslips than their male counterparts. Lastly, we found that only male epileptic mice displayed disturbed behavior in the forced swim test, but mice of both gender displayed anhedonia-like behavior in the taste preference test. In summary, taking the potential differences in account may help to choose the more appropriated gender for a given task, which also may be of value for minimize the number of animals used during the experiments.
    Physiology & Behavior 03/2014; · 3.16 Impact Factor
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    ABSTRACT: Zearalenone (ZEA) is a mycotoxin commonly found as a contaminant in cereals. ZEA toxicity targets mainly the reproductive system, and oxidative stress plays an etiological role in its toxic effects. Therefore, the present study aimed to investigate the effect of lycopene, a potent carotenoid antioxidant, on markers of oxidative stress in liver, kidney and testes, and on reproductive, hematological and histopathological parameters after ZEA administration. Adult Swiss albino male mice received lycopene (20 mg/kg, p.o.) for ten days before a single oral administration of ZEA (40 mg/kg, p.o.), and 48 h thereafter tissues (liver, kidney, testes and blood) were collected for biochemical, hematological and histological analyses. Lycopene prevented ZEA-induced changes in hematological parameters (increased number of leukocytes, segmented neutrophils, sticks, eosinophils and monocytes and decreased number of red blood cells (RBC), number of lymphocytes and platelets). Moreover, lycopene prevented the reduction in the number and motility of spermatozoa and the testicular tissue damage induced by ZEA. In addition, lycopene prevented the decrease in glutathione-S-transferase activity in kidney and testes and increased glutathione-S-transferase activity per se in the liver, kidneys and testes as well as superoxide dismutase activity in the liver. In summary, lycopene was able to prevent ZEA-induced acute toxic effects in male mice, suggesting that this antioxidant carotenoid may represent a promising prophylactic strategy against ZEA toxicity.
    Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 01/2014; · 1.43 Impact Factor
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    ABSTRACT: There are evidences indicating the role of kinins in pathophysiology of traumatic brain injury, but little is known about their action on memory deficits. Our aim was to establish the role of bradykinin receptors B1 (B1R) and B2 (B2R) on the behavioral, biochemical, and histologic features elicited by moderate lateral fluid percussion injury (mLFPI) in mice. The role of kinin B1 and B2 receptors in brain damage, neuromotor, and cognitive deficits induced by mLFPI, was evaluated by means of subcutaneous injection of B2R antagonist (HOE-140; 1 or 10 nmol/kg) or B1R antagonist (des-Arg9-[Leu8]-bradykinin (DAL-Bk; 1 or 10 nmol/kg) 30 min and 24 h after brain injury. Brain damage was evaluated in the cortex, being considered as lesion volume, inflammatory, and oxidative damage. The open field and elevated plus maze tests were performed to exclude the nonspecific effects on object recognition memory test. Our data revealed that HOE-140 (10 nmol/kg) protected against memory impairment. This treatment attenuated the brain edema, interleukin-1β, tumor necrosis factor-α, and nitric oxide metabolites content elicited by mLFPI. Accordingly, HOE-140 administration protected against the increase of nicotinamide adenine dinucleotide phosphate oxidase activity, thiobarbituric-acid-reactive species, protein carbonylation generation, and Na(+) K(+) ATPase inhibition induced by trauma. Histologic analysis showed that HOE-140 reduced lesion volume when analyzed 7 days after brain injury. This study suggests the involvement of the B2 receptor in memory deficits and brain damage caused by mLFPI in mice.
    Psychopharmacology 11/2013; · 4.06 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) is a devastating disease that commonly causes persistent mental disturbances and cognitive deficits. Although studies have indicated that overproduction of free radicals, especially superoxide (O2(-)) derived from Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a common underlying mechanism of pathophysiology of TBI, little information is available regarding the role of apocynin, an NADPH oxidase inhibitor, in neurological consequences of TBI. Therefore, the present study evaluated the therapeutic potential of apocynin for treatment of inflammatory and oxidative damage, in addition to determining its action on neuromotor and memory impairments caused by moderate fluid percussion injury in mice (mLFPI). Statistical analysis revealed that apocynin (5 mg/kg), when injected subcutaneously (s.c.) 30 min and 24 h after injury, had no effect on neuromotor deficit and brain edema, however it provided protection against mLFPI-induced object recognition memory impairment 7 days after neuronal injury. The same treatment protected against mLFPI-induced IL-1β, TNF-α, nitric oxide metabolite content (NOx) 3 and 24 hours after neuronal injury. Moreover, apocynin treatment reduced oxidative damage (protein carbonyl, lipoperoxidation) and was effective against mLFPI-induced Na(+)K(+)-ATPase activity inhibition. The present results were accompanied by effective reduction in lesion volume when analyzed 7 days after neuronal injury. These data suggest that superoxide (O2(-)) derived from NADPH oxidase can contribute significantly to cognitive impairment, and that the post injury treatment with specific NADPH oxidase inhibitors, such as apocynin, may provide a new therapeutic approach to the control of neurological disabilities induced by TBI.
    Neurochemistry International 09/2013; · 2.66 Impact Factor
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    ABSTRACT: The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67μmol/g as a function of animal age). In the following days (29th-31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) levels in the blood, as well as levels of IL-1β, TNF-α, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1β and TNF-α levels. Concomitantly, MMA increased levels of IL-1β, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia.
    Immunobiology 04/2013; · 2.81 Impact Factor
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    ABSTRACT: The present study aimed to investigate whether Na(+),K(+)-ATPase activity and phosphorylation state of the catalytic α subunit are altered by pentylenetetrazol (PTZ)-induced seizures. PTZ (30, 45 or 60g/kg, i.p.) was administered to adult male Swiss mice, and Na(+),K(+)-ATPase activity and phosphorylation state were measured in the cerebral cortex 15min after PTZ administration. Na(+),K(+)-ATPase activity significantly decreased after PTZ-induced seizures (60mg/kg). Immunoreactivity of phosphorylated Ser943 at α subunit was increased after PTZ-induced seizures. A significant positive correlation between Na(+),K(+)-ATPase activity and latency to myoclonic jerks and generalized seizures was found. Conversely, a strong negative correlation between Ser943 phosphorylation and latency to generalized seizures was detected. Given the role of Na(+),K(+)-ATPase as a major regulator of brain excitability, Ser943 at Na(+),K(+)-ATPase α subunit may represent a potentially valuable new target for drug development for seizure disorders.
    Epilepsy research 04/2013; · 2.48 Impact Factor
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    ABSTRACT: Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with atorvastatin for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last atorvastatin administration. We found that atorvastatin withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex. Catalase, glutathione-S-transferase and xanthine oxidase activities were not altered by atorvastatin treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the atorvastatin withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects.
    Pharmacological Research 02/2013; · 4.35 Impact Factor
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    ABSTRACT: Methylmalonic acidemias are inherited metabolic disorders characterized by methylmalonate (MMA) accumulation and neurological dysfunction, including seizures. Dietary fatty acids are known as an important energy source and reduce seizure activity in selected acute animal models. This study investigated whether chronic treatment with fish oil or with oleic acid attenuates MMA-induced seizures and whether maintenance of Na(+),K(+)-ATPase activity was involved in such an effect. Adult male Wistar rats were given fish oil (85mg/kg), oleic acid (85mg/kg) or vehicle (0.42% aqueous Cremophor EL™, 4mL/kg/body weight/day), p.o., for 75 days. On the 73th day a cannula was implanted in the right lateral ventricle with electrodes over the parietal cortex for EEG recording. On the 76th day the animals were injected with NaCl (2.5μmol/2.5μL, i.c.v.), or with MMA (2.5μmol/2.5μL, i.c.v.), and seizure activity was measured by electroencephagraphic (EEG) recording with concomitant behavior monitoring. The effect of prostaglandin E(2) (PGE(2)) on Na(+),K(+)-ATPase activity of slices of cerebral cortex from NaCl-injected animals was determined. Fish oil increased the latency to MMA-induced tonic-clonic seizures, reduced the mean amplitude of ictal EEG recordings, and prevented PGE(2)-induced decrease of Na(+),K(+)-ATPase activity in cortical slices in vitro. Oleic acid decreased mean amplitude of ictal EEG recordings. The results support that fish oil decreases MMA-induced seizures. The decreased sensitivity of Na(+),K(+)-ATPase to the inhibitory effect of PGE(2)in fish oil-treated animals may be related to the currently reported anticonvulsant activity.
    Epilepsy research 01/2013; · 2.48 Impact Factor
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    ABSTRACT: Administration of the compound triterpene 3β, 6β, 16β-trihidroxilup-20(29)-ene (TTHL) resulted in antinociceptive activity in several pain models in mice. Because pain and epilepsy have common mechanisms, and several anticonvulsants are clinically used to treat painful disorders, we investigated the anticonvulsant potential of TTHL. Behavioral and electrographic recordings revealed that pretreatment with TTHL (30 mg/kg; i.g.) increased the latencies to the first clonic seizure to the tonic-clonic and reduced the duration of the generalized seizures induced by the GABA(A) receptor antagonist PTZ (80 mg/Kg; i.p.). The TTHL pretreatment also protected against PTZ-induced deleterious effects, as characterized by protein carbonylation, lipid peroxidation, [(3)H] glutamate uptake and the inhibition of Na(+),K(+)-ATPase (subunits α(1)and α(2)/α(3)). Although TTHL did not exhibit DPPH, ABTS radical scavenging activity per se and does not alter the binding of [(3)H]flunitrazepam to the benzodiazepinic site of the GABA(A) receptor, this compound was effective in preventing behavioral and EEG seizures, as well as the inhibition of Na(+),K(+)-ATPase induced by ouabain. These results suggest that the protection against PTZ-induced seizures elicited by TTHL is due to Na(+),K(+)-ATPase activity maintenance. In fact, experiments in homogenates of the cerebral cortex revealed that PTZ (10 mM) reduced Na(+),K(+)-ATPase activity and that previous incubation with TTHL (10 μM) protected against this inhibition. Collectively, these data indicate that the protection exerted by TTHL in this model of convulsion is not related to antioxidant activity or GABAergic activity. However, these results demonstrated that the effective protection of Na(+),K(+)-ATPase elicited by this compound protects against the damage due to neuronal excitability and oxidation that is induced by PTZ.
    Neuropharmacology 12/2012; · 4.11 Impact Factor
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    ABSTRACT: A growing body of evidence indicates that creatine (Cr) exerts beneficial effects on a variety of pathologies where energy metabolism and oxidative stress play an etiological role. However, the benefits of Cr treatment for epileptics are still shrouded in controversy. In the present study, we found that acute Cr treatment (300 mg/kg, p.o.) prevented the increase in electroencephalographic wave amplitude typically elicited by PTZ (30, 45 or 60 mg/kg, i.p.). Cr treatment also increased the latency periods of first myoclonic jerks, lengthened the latency periods of the generalized tonic-clonic seizures and reduced the time spent in the generalized tonic-clonic seizures induced by PTZ (60 mg/kg). Administration of PTZ (all doses) decreased Na(+), K(+)-ATPase activity as well as adenosine triphosphate (ATP) and adenosine diphosphate levels in the cerebral cortex, but Cr treatment prevented these effects. Cr administration also prevented increases in xanthine oxidase activity, adenosine monophosphate levels, adenosine levels, inosine levels and uric acid levels that normally occur after PTZ treatment (60 mg/kg, i.p.). We also showed that Cr treatment increased the total Cr (Cr + PCr) content, creatine kinase activity and the mitochondrial membrane potential (ΔΨ) in the cerebral cortex. In addition, Cr prevented PTZ-induced mitochondrial dysfunction characterized by decreasing ΔΨ, increasing thiobarbituric acid-reactive substance levels and increasing protein carbonylation. These experimental findings reinforce the idea that mitochondrial dysfunction plays a critical role in models of epileptic seizures and suggest that buffering brain energy levels through Cr treatment may be a promising therapeutic approach for the treatment of this neurological disease.
    Amino Acids 10/2012; · 3.91 Impact Factor
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    ABSTRACT: From a pharmacological point of view, organoseleniums are compounds with important and interesting antioxidant and biological activities. The aim of this study was to evaluate the hepatoprotective effect of bis(4-methylbenzoyl) diselenide (BMD) against carbon tetrachloride (CCl(4) )-induced oxidative damage in mice. The animals received BMD (25 mg/kg p.o., for 3 days), and after 1 day, CCl(4) (1 mg/kg body weight) was administered by intraperitoneal route. One day after the CCl(4) exposure, the animals were euthanized for biochemical and histological analysis. Treatment with BMD (25 mg/kg p.o.) protected against aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase and lactate dehydrogenase activity increases induced by CCl(4) plasma exposure. Treatment with BMD (25 mg/kg) protected against increases in thiobarbituric reactive species and decreasing non-protein thiols and ascorbic acid levels in liver of mice. Catalase and superoxide dismutase activity inhibition in the liver caused by CCl(4) were protected by treatment with BMD (25 mg/kg). Glutathione S-transferase activity was inhibited by CCl(4) and remained unaltered even after treatment with BMD. Sections of liver from CCl(4) -exposed mice presented an intense infiltration of inflammatory cells and loss of the cellular architecture. BMD (25 mg/kg) attenuated CCl(4) -induced hepatic histological alterations. The results demonstrated the hepatoprotective effects of BMD in the mouse liver, possibly by modulating the antioxidant status. Copyright © 2012 John Wiley & Sons, Ltd.
    Cell Biochemistry and Function 09/2012; · 1.85 Impact Factor
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    ABSTRACT: Achievements made over the past few years have demonstrated the important role of the creatine and phosphocreatine system in the buffering and transport of high-energy phosphates into the brain; however, the non-energetic processes elicited by this guanidine compound in the hippocampus are still poorly understood. In the present study we disclosed that the incubation of rat hippocampal slices with creatine (10mM) for 30 min increased Na(+),K(+)-ATPase activity. In addition, intrahippocampal injection of creatine (5 nmol/site) also increased the above-mentioned activity. The incubation of hippocampal slices with N-methyl-d-aspartate (NMDA; MK-801, 10 μM) and NMDA Receptor 2B (NR2B; ifenprodil, 3 μM) antagonists but not with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA)/kainate antagonist (DNQX, 10 μM) and nitric oxide synthase inhibitor (NOS; l-NAME, 100 μM), blunted the effect of creatine on Na(+),K(+)-ATPase activity. Furthermore, the calcineurin inhibitor (cyclosporine A, 200 nM) as well as the Protein Kinase C (PMA, 100 nM) and Protein Kinase A (8-Br-cAMP, 30 μM) activators attenuated the creatine-induced increase of Na(+),K(+)-ATPase activity. In addition, the incubation of hippocampal slices with creatine (10mM) for 30 min increased calcineurin activity. The results presented here suggest that creatine increases Na(+),K(+)-ATPase activity via NMDA-calcineurin pathway, proposing an putative underlying non-energetic role of this guanidine compound. However, more studies are needed to assess the contribution of this putative alternative role in neurological diseases that present decreased Na(+),K(+)-ATPase activity.
    Brain research bulletin 06/2012; 88(6):553-9. · 2.18 Impact Factor
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    ABSTRACT: Although Creatine (Cr) and Phosphocreatine (PCr) systems play a key role in cellular energy and energy transport in neuronal cells, its implications for learning and memory are still controversial. Thus, we decided to investigate the involvement of cAMP-dependent protein kinase A (PKA), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and cAMP responsive element binding protein (CREB) in the spatial consolidation after an intrahippocampal injection of Cr. Statistical analysis revealed that Cr (2.5 nmol/hippocampus) (post-training) decreased the latency for escape and the mean number of errors on Barnes maze test. Post-training co-administration of the PKA inhibitor (H-89 25 ρmol/hippocampus) did not alter the facilitatory effect of Cr in this memory test. On the other hand, Cr-induced spatial retention was reverted by co-administration of the CaMKII inhibitor (STO-609 5 nmol/hippocampus). Neurochemical analysis revealed that intrahippocampal injection of Cr, when analyzed after 30 min rather than after 3 h, increased the levels of pCREB and pCaMKII but not pPKA levels. Statistical analysis also revealed that the post-training co-administration of STO-609 but not H-89 reversed the increase of pCREB levels induced by Cr. The results presented in this report suggest that intracellular CaMKII/CREB pathway plays a key role in the Cr-induced spatial retention. Thus, it is plausible to propose that Cr plays a putative role as a neuromodulator in the brain, and that at least some of its effects may be mediated by intracellular CaMKII/CREB pathway.
    Amino Acids 06/2012; · 3.91 Impact Factor
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    ABSTRACT: Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin produced by several species of Fusarium, commonly found in the soil in temperate and warm countries and is a frequent contaminant of cereal crops worldwide. Accordingly, it has been implicated in several mycotoxicosis in farm animals and in humans, but the underlying mechanisms remain largely unknown. Therefore, the current study was aimed to investigate the effect of an acute dose of ZEA (40 mg/kg, p.o.) on reproductive and hematological parameters, as well as on markers of oxidative stress in liver, kidney and testes in mice. Adult Swiss albino male mice were exposed to a single oral administration of ZEA, and 48 h thereafter behavioral and biochemical tests were performed. No differences in locomotor or exploratory activity were observed in the open-field test. On the other hand, ZEA increased the number of leukocytes, segmented neutrophils, sticks, eosinophils, monocytes and decreased platelets and lymphocytes number. Moreover, ZEA drastically reduced the number and motility of live spermatozoa. Additionally, while levels of thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH) and ascorbic acid in liver, kidney and testes were not altered by ZEA administration, superoxide dismutase activity increased in all tissues evaluated, catalase activity increased in the kidney, and glutathione-S-transferase activity decreased in kidney and testes. In summary, we showed that ZEA have acute toxic effects mainly in reproductive system of adult male Swiss albino mice and its effect probably is related to a reduced activity of GST and increased in SOD activity in testes.
    Toxicon 05/2012; 60(3):358-66. · 2.92 Impact Factor
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    ABSTRACT: Polyamines, including spermidine, facilitate seizures by positively modulating N-methyl-d-aspartate receptors (NMDAr). Although NMDAr antagonists decrease seizures, it remains to be determined whether traxoprodil, a selective antagonist at the NR2B subunit of the NMDAr, decreases seizures and whether spermidine facilitates pentylenetetrazol (PTZ)-induced seizures. Adult male Wistar rats were injected in the lateral ventricle with 0.9% NaCl (1μl, i.c.v.), spermidine (0.02, 0.2 or 2nmol/site, i.c.v.) or traxoprodil (0.2, 2 or 20nmol, i.c.v.) and with PTZ (35 or 70mg/kg, i.p.). The effect of orally administered traxoprodil (60mg/kg, p.o.) on seizures was also investigated. Latencies to clonic and generalized seizures, as well the total time spent in seizures were recorded by behavioral and electrographic methods (EEG). Spermidine (2nmol/site; i.c.v.) facilitated the seizures induced by a sub-threshold dose of PTZ (35mg/kg; i.p.), but did not alter seizure activity induced by a convulsant dose of PTZ (70mg/kg; i.p.). Traxoprodil (20nmol i.c.v.) increased the latency to generalized tonic-clonic seizures induced by PTZ (70mg/kg; i.p.). Traxoprodil (60mg/kg, p.o.) increased the latency to clonic and generalized seizures, and decreased the total time spent in seizures. These results support the role for the NR2B subunit in PTZ-induced seizures.
    Epilepsy research 01/2012; 100(1-2):12-9. · 2.48 Impact Factor
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    ABSTRACT: Achievements made over the last years have highlighted the important role of creatine in health and disease. However, its effects on hyperexcitable circuit and oxidative damage induced by traumatic brain injury (TBI) are not well understood. In the present study we revealed that severe TBI elicited by fluid percussion brain injury induced oxidative damage characterized by protein carbonylation, thiobarbituric acid reactive species (TBARS) increase and Na(+),K(+)-ATPase activity inhibition 4 and 8 days after neuronal injury. Statistical analysis showed that after TBI creatine supplementation (300 mg/kg, p.o.) decreased the levels of protein carbonyl and TBARS but did not protect against TBI-induced Na(+),K(+)-ATPase activity inhibition. Electroencephalography (EEG) analysis revealed that the injection of a subconvulsant dose of PTZ (35 mg/kg, i.p.), 4 but not 8 days after neuronal injury, decreased latency for the first clonic seizures and increased the time of spent generalized tonic-clonic seizures compared with the sham group. In addition, creatine supplementation had no effect on convulsive parameters induced by a subconvulsant dose of PTZ. Current experiments provide evidence that lipid and protein oxidation represents a separate pathway in the early post-traumatic seizures susceptibility. Furthermore, the lack of consistent anticonvulsant effect exerted by creatine in this early phase suggests that its apparent antioxidant effect does not protect against excitatory input generation induced by TBI.
    Brain research bulletin 10/2011; 87(2-3):180-6. · 2.18 Impact Factor
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    ABSTRACT: Although the importance of brain trauma as risk factor for the development of epilepsy is well established, the mechanisms of epileptogenesis are not well understood. In the present study, we revealed that the injection of a subthreshold dose of PTZ (30 mg/Kg, i.p.) after 5 weeks of injury induced by Fluid Percussion Brain Injury (FPI) decreased latency for first clonic seizures, increased the time of spent generalized tonic-clonic seizures and electrocorticographic (EEG) wave amplitude. In addition, statistical analysis revealed that N-acetylcysteine (NAC) (100mg/kg) supplementation during 5 weeks after neuronal injury protected against behavioral and electrographical seizure activity elicited by subthreshold dose of PTZ. The supplementation of this antioxidant compound also protected against the Na(+),K(+)-ATPase activity inhibition and concomitant increase in the levels of oxidative stress markers (protein carbonylation and thiobarbituric acid-reactive substances-TBARS) in site and peri-contusional cortical tissue. In summary, the current experiments clearly showed that FPI model induces early posttraumatic seizures and suggest that an alteration in the lipid/protein oxidation, membrane fluidity, and Na(+),K(+)-ATPase activity may be correlated with neuronal excitability, a significant component of the secondary injury cascade that accompanies TBI.
    Journal of the neurological sciences 09/2011; 308(1-2):35-40. · 2.32 Impact Factor
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    ABSTRACT: Statins are selective inhibitors of 3-hydroxyl-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway for cholesterol biosynthesis. Increasing evidence indicates that statins, particularly atorvastatin, are neuroprotective in several conditions, including stroke, cerebral ischemia, traumatic brain injury, and excitotoxic amino acid exposure. However, only a few studies have investigated whether statins modulate seizure activity. In the current study we investigated whether atorvastatin or simvastatin alters the seizures induced by pentylenetetrazol (PTZ), a classical convulsant. Adult male Wistar rats were treated with atorvastatin or simvastatin for 7 days (10 mg/kg/day). Seizure activity was induced by PTZ (60 mg/kg, i.p.), and evaluated by behavioral and electrographic methods. Cholesterol levels were determined by a standard spectrophotometric method. Blood-brain barrier (BBB) permeability was assessed by the fluorescein method. Atorvastatin levels in the plasma and cerebral cortex were determined by high-performance liquid chromatography tandem mass spectrometry. We found that oral atorvastatin treatment increased the latency to PTZ-induced generalized seizures. In contrast, when the 7-day atorvastatin treatment was withheld for 1 day (i.e., atorvastatin withdrawal), PTZ-induced seizures were facilitated, as evidenced by a decrease in the latency to clonic and generalized tonic-clonic seizures induced by PTZ. In contrast, simvastatin treatment for 7 days (10 mg/kg/day, p.o.), with or without withdrawal, did not alter PTZ-induced seizures. Interestingly, the effects of atorvastatin treatment and withdrawal were not accompanied by changes in plasma or cerebral cortex cholesterol levels or in the BBB permeability. Atorvastatin levels in the plasma and cerebral cortex after 7 days of treatment were above the half maximal inhibitory concentration for inhibition of HMG-CoA reductase, whereas atorvastatin was not detectable in the plasma or cerebral cortex following a 24 h washout period (atorvastatin withdrawal). We conclude that atorvastatin treatment and withdrawal have differential effects on pentylenetetrazol-induced seizures, which are not related to changes in plasma or cerebral cortex cholesterol levels or in BBB permeability. Additional studies are necessary to evaluate the molecular mechanisms underlying our findings as well as its clinical implications.
    Epilepsia 09/2011; 52(11):2094-104. · 3.96 Impact Factor
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    ABSTRACT: Although the favorable effects of physical exercise in neurorehabilitation after traumatic brain injury (TBI) are well known, detailed pathologic and functional alterations exerted by previous physical exercise on post-traumatic cerebral inflammation have been limited. In the present study, it is showed that fluid percussion brain injury (FPI) induced motor function impairment, followed by increased plasma fluorescein extravasation and cerebral inflammation characterized by interleukin-1β, tumor necrosis factor-α (TNF-α) increase, and decreased IL-10. In addition, myeloperoxidase (MPO) increase and Na⁺,K⁺-ATPase activity inhibition after FPI suggest that the opening of blood-brain barrier (BBB) followed by neurtrophils infiltration and cerebral inflammation may contribute to the failure of selected targets leading to secondary damage. In fact, Pearson's correlation analysis revealed strong correlation of MPO activity increase with Na⁺,K⁺-ATPase activity inhibition in sedentary rats. Statistical analysis also revealed that previous running exercise (4 weeks) protected against FPI-induced motor function impairment and fluorescein extravasation. Previous physical training also induced IL-10 increase per se and protected against cerebral IL-1β, and TNF-α increase and IL-10 decrease induced by FPI. This protocol of physical training was effective against MPO activity increase and Na⁺,K⁺-ATPase activity inhibition after FPI. The present protection correlated with MPO activity decrease suggests that the alteration of cerebral inflammatory status profile elicited by previous physical training reduces initial damage and limits long-term secondary degeneration after TBI. This prophylactic effect may facilitate functional recovery in patients suffering from brain injury induced by TBI.
    Neurotoxicity Research 07/2011; 21(2):175-84. · 2.87 Impact Factor
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    ABSTRACT: Aging and a variety of pathologies, including cancer, diabetes, cardiovascular and inflammatory diseases have been associated with reactive oxygen species (ROS), such as superoxide anion (O₂·⁻), hydroxyl radical (·OH) and hydrogen peroxide (H₂O₂) generation. Plant polyphenols bear radical scavenging/antioxidant activity. A phytomedicinal preparation obtained from aerial parts of Dicksonia sellowiana (Dicksoniaceae), a native plant from Central and South America, has been widely used in Brazil against asthma and presents beneficial effects in several other diseases, including cardiovascular disturbance. In this work, we investigated whether Dicksonia sellowiana, which is also known to contain high levels of polyphenols, presents antioxidant activity. The antioxidant activity of the hydroalcoholic extract obtained from Dicksonia sellowiana leaves (HEDS) was investigated by in vitro and in vivo tests. HEDS (0.1-100 μg/mL) exhibited a strong scavenging activity against all reactive species tested (DPPH, O₂·⁻,·OH and H₂O₂; IC₅₀=6.83±2.05, 11.6±5.4, 2.03±0.4, and 4.8±0.4 μg/mL, respectively). HEDS strongly protected endothelial cells against H₂O₂-induced oxidative stress by mechanisms other than increasing catalase activity. In addition, HEDS protected cell membrane from oxidative damage. HEDS, (20 and 40 mg/kg) inhibited lipid peroxidation in vivo (29.8% and 24.5%, respectively). According to our results, we can speculate that the traditional uses of Dicksonia sellowiana for cardiovascular diseases, asthma and skin diseases could be, at least in part, related to the potent antioxidant and endothelial protective activities of the plant.
    Journal of ethnopharmacology 02/2011; 133(3):999-1007. · 2.32 Impact Factor

Publication Stats

439 Citations
137.18 Total Impact Points

Institutions

  • 2003–2014
    • Universidade Federal de Santa Maria
      • • Centre of Natural and Exact Sciences (CCNE)
      • • Department of Physiology and Pharmacology
      • • Department of Health Sciences
      • • Department of Chemistry
      Santa Maria da Boca do Monte, Rio Grande do Sul, Brazil
  • 2011–2012
    • Universidade Federal do Pampa (Unipampa)
      Caçapava, Rio Grande do Sul, Brazil
  • 2008
    • Universidade Federal do Rio Grande do Sul
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil