Arethuza Dornelles

Universidade Federal do Rio Grande do Sul, Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil

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Publications (14)49.92 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Histone acetylation, a type of chromatin modification that allows increased gene transcription and can be pharmacologically promoted by histone deacetylase (HDAC) inhibitors (HDACis), has been consistently associated with promoting memory formation in the hippocampus. The basolateral nucleus of the amygdala (BLA) is a brain area crucially involved in enabling hormones and drugs to influence memory formation. Here, we show that BLA activity is required for memory enhancement by intrahippocampal administration of an HDACi. Two different HDACis, sodium butyrate (NaB) and trichostatin A (TSA), differentially enhanced the retention of memory for inhibitory avoidance (IA) when administered to the dorsal hippocampus after training. TSA showed a biphasic pattern of response during consolidation, in which infusions given immediately or 3 h after training produced memory enhancement, whereas no effect was observed when it was infused 1.5 or 6 h posttraining. Muscimol (MUS)-induced unilateral functional inactivation of the BLA prevented the enhancement of memory retention produced by posttraining infusion of TSA into the ipsilateral hippocampus. TSA did not affect IA extinction or reconsolidation. These results indicate that HDACis can increase IA memory retention when given into the hippocampus, and, most importantly, BLA activity is necessary for enabling HDACi-induced influences on memory formation.
    Neurobiology of Learning and Memory 01/2014; · 3.33 Impact Factor
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    ABSTRACT: We have recently shown that chronic treatment with cannabidiol (CBD) was able to recover memory deficits induced by brain iron loading in a dose-dependent manner in rats. Brain iron accumulation is implicated in the pathogenesis of neurodegenerative diseases, including Parkinson's and Alzheimer's, and has been related to cognitive deficits in animals and human subjects. Deficits in synaptic energy supply have been linked to neurodegenerative diseases, evidencing the key role played by mitochondria in maintaining viable neural cells and functional circuits. It has also been shown that brains of patients suffering from neurodegenerative diseases have increased expression of apoptosisrelated proteins and specific DNA fragmentation. Here, we have analyzed the expression level of brain proteins involved with mitochondrial fusion and fission mechanisms (DNM1L and OPA1), the main integral transmembrane protein of synaptic vesicles (synaptophysin), and caspase 3, an apoptosis-related protein, to gain a better understanding of the potential of CBD in restoring the damage caused by iron loading in rats. We found that CBD rescued iron-induced effects, bringing hippocampal DNM1L, caspase 3, and synaptophysin levels back to values comparable to the control group. Our results suggest that iron affects mitochondrial dynamics, possibly trigging synaptic loss and apoptotic cell death and indicate that CBD should be considered as a potential molecule with memory-rescuing and neuroprotective properties to be used in the treatment of cognitive deficits observed in neurodegenerative disorders.
    Molecular Neurobiology 07/2013; · 5.47 Impact Factor
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    ABSTRACT: In the present study, we investigated whether sepsis induced by cecal ligation and puncture (CLP) modifies Na(+), K(+)-ATPase activity, mRNA expression, and cerebral edema in hippocampus and cerebral cortex of rats and if antioxidant (ATX) treatment prevented the alterations induced by sepsis. Rats were subjected to CLP and were divided into three groups: sham; CLP-rats were subjected to CLP without any further treatment; and ATX-CLP plus administration of N-acetylcysteine plus deferoxamine. Several times (6, 12, and 24) after CLP or sham operation, the rats were killed and hippocampus and cerebral cortex were isolated. Na(+), K(+)-ATPase activity was inhibited in the hippocampus 24 h after sepsis, and ATX treatment was not able to prevent this inhibition. The Na(+), K(+)-ATPase activity also was inhibited in cerebral cortex 6, 12, and 24 h after sepsis. No differences on Na(+), K(+)-ATPase catalytic subunit mRNA levels were found in the hippocampus and cerebral cortex after sepsis. ATX treatment prevents Na(+), K(+)-ATPase inhibition only in the cerebral cortex. Na(+), K(+)-ATPase inhibition was not associated to increase brain water content. In conclusion, the present study demonstrated that sepsis induced by CLP inhibits Na(+), K(+)-ATPase activity in a mechanism dependent on oxidative stress, but this is not associated to increase brain water content.
    Molecular Neurobiology 07/2012; 46(2):467-74. · 5.47 Impact Factor
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    ABSTRACT: Iron accumulation in the brain has been associated to the pathogenesis of neurodegenerative disorders. We have previously demonstrated that iron overload in the neonatal period results in severe and persistent memory deficits in adult rats. Alterations in histone acetylation have been associated with memory deficits in models of neurological disorders. Here we examine histone acetylation in the brain and the effects of the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) on memory in the neonatal iron overload model in rats. Rats received vehicle or 30.0-mg/kg Fe⁺² orally at postnatal days 12-14. When animals reached adulthood, they were given training in either novel object recognition or inhibitory avoidance. Histone acetylation in the dorsal hippocampus and the effects of NaB were examined in separate sets of rats. Iron overload led to a reduction in H3 lysine 9 acetylation in the hippocampus, without affecting the acetylation of other H3 and H4 lysine residues. A single systemic injection of NaB (1.2 g/kg) immediately after training ameliorated iron-induced memory impairments. The results suggest that a reduction in H3K9 acetylation might play a role in iron-induced memory impairment and support the view that HDACis can rescue memory dysfunction in models of brain disorders.
    Neuroscience 10/2011; 200:42-9. · 3.12 Impact Factor
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    ABSTRACT: We have previously shown that pharmacological blockade of the gastrin-releasing peptide receptor (GRPR) during the neonatal period in rats produces behavioral features of developmental neuropsychiatric disorders. Here, we show that social interaction deficits in this model are reversed by the atypical antipsychotic clozapine given in the adulthood. In addition, we analyzed the mRNA expression of three neuronal receptors potentially involved in the etiology of disorders of the autism spectrum. Rats were injected with the GRPR antagonist RC-3095 or saline (SAL) from postnatal days 1-10, and tested for social behavior and recognition memory in the adulthood. One hour prior to the behavioral testing, rats were given a systemic injection of clozapine or saline. The mRNA expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor, the epidermal growth factor receptor (EGFR), and GRPR was measured in the hippocampus and cortex of a separate set of rats given RC-3095 or SAL neonatally. Rats given neonatal RC-3095 showed decreased social interaction and impaired object recognition memory. Clozapine rescued the social interaction impairment. Neonatal treatment with RC-3095 also resulted in dose-dependent decreases in the expression of GRPR, NR1, and EGFR in the cortex, whereas all three receptor mRNAs were increased in the hippocampus in rats treated with the lower dose of RC-3095. The results contribute to further validate the novel rat model of neurodevelopmental disorders induced by GRPR blockade, and shows alterations in the expression of neuronal receptors in this model.
    Journal of Neural Transmission 08/2011; 119(3):319-27. · 3.05 Impact Factor
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    ABSTRACT: Alterations in attachment behavior might play a role in the dysfunction in social behavior displayed by autistic infants. Here we show that neonatal gastrin-releasing peptide receptor (GRPR) blockade induces a reduction in maternal odor preference, a task involving attachment behavior, in infant rats. These findings provide the first evidence that the GRPR regulates odor preference, supporting the view that the GRPR is involved in attachment and social behaviors.
    Behavioural brain research 12/2010; 214(2):456-9. · 3.22 Impact Factor
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    ABSTRACT: The role of dopamine receptors in regulating the formation of recognition memory remains poorly understood. Here we show the effects of systemic administration of dopamine receptor agonists and antagonists on the formation of memory for novel object recognition in rats. In Experiment I, rats received an intraperitoneal (i.p.) injection of vehicle, the selective D1 receptor agonist SKF38393 (1.0 and 5.0mg/kg), or the D2 receptor agonist quinpirole (1.0 and 5.0mg/kg) immediately after training. In Experiment II, rats received an injection of vehicle, the dopamine receptor antagonist SCH23390 (0.1 and 0.05 mg/kg), or the D2 receptor antagonist raclopride (0.5 and 0.1mg/kg) before training, followed by an injection of vehicle or the nonselective dopamine receptor agonist apomorphine (0.05 mg/kg) immediately after training. SKF38393 at 5mg/kg produced an enhancement of novel object recognition memory measured at both 24 and 72 h after training, whereas the dose of 10mg/kg impaired 24-h retention. Posttraining administration of quinpirole did not affect 24-h retention. Apomorphine enhanced memory in rats given pretraining raclopride, suggesting that the effect was mediated by selective activation of D1 receptors. The results indicate that activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhanced novel object recognition memory even under conditions in which control rats showed significant retention.
    Neurobiology of Learning and Memory 12/2010; 95(3):305-10. · 3.33 Impact Factor
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    ABSTRACT: Increasing evidence indicates that excessive iron in selective regions of the brain may be involved in the etiology of neurodegenerative disorders. Accordingly, increased levels of iron have been described in brain regions of patients in Parkinson's and Alzheimer's diseases. We have characterized neonatal iron loading in rodents as a novel experimental model that mimics the brain iron accumulation observed in patients with neurodegenerative diseases and produces severe cognitive impairment in the adulthood. In the present study we have investigated the involvement of the cholinergic system on iron-induced memory impairment. The effects of a single administration of the acetylcholinesterase (AChE) inhibitor galantamine or the muscarinic receptor agonist oxotremorine on iron-induced memory deficits in rats were examined. Male Wistar rats received vehicle or iron (10.0 mg/kg) orally at postnatal days 12 to 14. At the age of 2-3 months, animals were trained in a novel object recognition task. Iron-treated rats showed long-term impairments in recognition memory. The impairing effect was reversed by systemic administration of galantamine (1 mg/kg) immediately after training. In addition, iron-treated rats that received oxotremorine (0.5 mg/kg) showed enhanced memory retention. Rats given iron showed a decreased AChE activity in the striatum when compared to controls. The results suggest that, at least in part, iron-induced cognitive deficits are related to a dysfunction of cholinergic neural transmission in the brain. These findings might have implications for the development of novel therapeutic strategies aimed at ameliorating cognitive decline associated with neurodegenerative disorders.
    Current neurovascular research 02/2010; 7(1):15-22. · 3.23 Impact Factor
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    ABSTRACT: Increased levels of iron in brain regions have been reported in neurodegenerative disorders as well as in normal brain aging. We have previously demonstrated that neonatal iron loading induces cognitive impairment in adult rats. Here, we evaluate the effects of neonatal iron treatment on cognition in aged rats. We also investigated the effects of a late subchronic rosuvastatin treatment on iron- and age-induced cognitive deficits. Rats received vehicle or 10.0mg/kg Fe(2+) orally at postnatal days 12-14. When animals reached the age of 23 months, they received daily intraperitoneal injections of saline or rosuvastatin (0.2 or 2.0mg/kg) for 21 days. Twenty-four hours after the last injection, they were submitted to novel object recognition training. Retention test sessions were performed 1.5 and 24h after training, in order to assess short-term and long-term memory, respectively. Results indicated that aged animals that received iron in the neonatal period showed more severe memory deficits than vehicle-treated ones, suggesting that iron potentiates age-associated memory impairments. Rosuvastatin improved recognition memory deficits associated with iron loading and aging, providing evidence that statins may be considered for the treatment of age-associated cognitive decline.
    Experimental gerontology 02/2010; 45(5):351-6. · 3.34 Impact Factor
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    ABSTRACT: Abnormally high levels of iron are observed in the brain of patients suffering from neurodegenerative disorders. The mechanisms involved in iron accumulation in neurodegenerative disorders remain poorly understood. In the present study we investigated the effects of aging and neonatal iron overload on the mRNA expression of proteins critically involved in controlling iron homeostasis. Wistar rat pups received a single daily dose of vehicle or iron (10 mg/kg of b.w. of Fe(2+)), at postnatal days 12-14. The expression of Transferrin Receptor (TfR), H-Ferritin, and IRP2 were analyzed by a semi-quantitative reverse transcriptase polymerase chain reaction assay in cortex, hippocampus and striatum of rats sacrificed at three different ages (15-day-old; 90-day-old and 2-year old rats). Results indicate that TfR, H-ferritin, and IRP2 mRNA expression was differentially affected by aging and by neonatal iron treatment in all three brain regions. These findings might have implications for the understanding of iron homeostasis misregulation associated with neurodegenerative disorders.
    Neurochemical Research 11/2009; 35(4):564-71. · 2.13 Impact Factor
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    ABSTRACT: It is now generally accepted that iron accumulates in the brain during the ageing process. Increasing evidence demonstrate that iron accumulation in selective regions of the brain may generate free radicals, thereby possessing implications for the etiology of neurodegenerative disorders. In a previous study we have reported that aged rats present recognition memory deficits. The aim of the present study was to evaluate the effect of desferoxamine (DFO), an iron chelator agent, on age-induced memory impairment. Aged Wistar rats received intraperitoneal injections of saline or DFO (300mg/kg) for 2 weeks. The animals were submitted to a novel object recognition task 24h after the last injection. DFO-treated rats showed normal recognition memory while the saline group showed long-term recognition memory deficits. The results show that DFO is able to reverse age-induced recognition memory deficits. We also demonstrated that DFO reduced the oxidative damage to proteins in cortex and hippocampus. Thus, the present findings provide the first evidence that iron chelators might prevent age-related memory dysfunction.
    Neurobiology of aging 08/2008; 29(7):1052-9. · 5.94 Impact Factor
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    ABSTRACT: Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects. However, previous studies have not examined the effects of EPI on consolidation of recognition memory. Here we report that systemic administration of EPI enhances consolidation of memory for a novel object recognition (NOR) task under different training conditions. Control male rats given a systemic injection of saline (0.9% NaCl) immediately after NOR training showed significant memory retention when tested at 1.5 or 24, but not 96h after training. In contrast, rats given a post-training injection of EPI showed significant retention of NOR at all delays. In a second experiment using a different training condition, rats treated with EPI, but not SAL-treated animals, showed significant NOR retention at both 1.5 and 24-h delays. We next showed that the EPI-induced enhancement of retention tested at 96h after training was prevented by pretraining systemic administration of the beta-adrenoceptor antagonist propranolol. The findings suggest that, as previously observed in experiments using aversively motivated tasks, epinephrine modulates consolidation of recognition memory and that the effects require activation of beta-adrenoceptors.
    Neurobiology of Learning and Memory 08/2007; 88(1):137-42. · 3.33 Impact Factor
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    ABSTRACT: Many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD), are caused by different mechanisms but may share a common pathway to neuronal injury as a result of the overstimulation of glutamate receptors. It has been suggested that this pathway can be involved in generation of cognitive deficits associated with normal aging. Previous studies performed in our laboratory have demonstrated that aged rats presented recognition memory deficits. The aim of the present study was to evaluate the effect of memantine, a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, on age-induced recognition memory deficits. Additionally, parameters of oxidative damage in cerebral regions related to memory formation were evaluated. In order to do that, male Wistar rats (24 months old) received daily injections of saline solution or memantine (20 mg/kg i.p.) during 21 days. The animals were submitted to a novel object recognition task 1 week after the last injection. Memantine-treated rats showed normal recognition memory while the saline group showed long-term recognition memory deficits. The results show that memantine is able to reverse age-induced recognition memory deficits. We also demonstrated that memantine reduced the oxidative damage to proteins in cortex and hippocampus, two important brain regions involved in memory formation. Thus, the present findings suggest that, at least in part, age-induced cognitive deficits are related to oxidative damage promoted by NMDA receptor overactivation.
    Neuroscience 07/2007; 146(4):1719-25. · 3.12 Impact Factor
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    ABSTRACT: Topiramate is a new antiepileptic drug proposed to facilitate synaptic inhibition and block excitatory receptors. However, little is known about the effects of topiramate on memory. In the first experiment, intraperitoneal injection of topiramate at doses of 10.0 and 100.0 mg/kg, immediately after training, induced a deficit in short-term memory (STM) of a novel object recognition (NOR) task tested 1.5 hours after training in rats. In a long-term memory (LTM) test given to the same rats 24 hours after training, topiramate 0.1mg/kg enhanced, whereas 10.0 and 100.0 mg/kg impaired, NOR retention. In the second experiment, administration of topiramate 0.01 and 0.10 mg/kg 1 hour prior to the LTM retention test improved NOR retention, whereas 10.0 and 100.0 mg/kg produced retrieval deficits. The results indicate that low doses of topiramate improve, whereas high doses impair, consolidation and retrieval of recognition memory in rats.
    Epilepsy & Behavior 03/2007; 10(1):32-7. · 1.84 Impact Factor

Publication Stats

157 Citations
49.92 Total Impact Points

Institutions

  • 2014
    • Universidade Federal do Rio Grande do Sul
      • Institute of Basic Sciences and Health
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil
  • 2008–2013
    • Pontifícia Universidade Católica de Goiás (PUC Goiás)
      Goyaz, Goiás, Brazil
  • 2012
    • Pontifícia Universidade Católica do Rio Grande do Sul
      • Departamento de Biologia Celular e Molecular
      Pôrto de São Francisco dos Casaes, Rio Grande do Sul, Brazil