An?lise do envolvimento do Fator Neutr?fico Derivado do C?rebro (BDNF) e do metabolismo glicol?tico cerebral atrav?s do escaneamento com microPET na disfun??o cognitiva induzida pelo ac?mulo de ferro cerebral

Submitted by PPG Biologia Celular e Molecular ([email protected]) on 2017-10-05T12:11:04Z No. of bitstreams: 1 LUISA_AZAMBUJA_ALCALDE_DIS.pdf: 1021854 bytes, checksum: 5eb77630a0526fda862d94ab0a753c16 (MD5)Approved for entry into archive by Caroline Xavier ([email protected]) on 2017-10-05T14:47:01Z (GMT) No. of bitstreams: 1 LUISA_AZAMBUJA_ALCALDE_DIS.pdf: 1021854 bytes, checksum: 5eb77630a0526fda862d94ab0a753c16 (MD5)Made available in DSpace on 2017-10-05T14:58:04Z (GMT). No. of bitstreams: 1 LUISA_AZAMBUJA_ALCALDE_DIS.pdf: 1021854 bytes, checksum: 5eb77630a0526fda862d94ab0a753c16 (MD5) Previous issue date: 2017-02-23Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPESBrain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the mammalian Central Nervous System, and plays a key role in development and physiology, as well as in pathological states. Post-mortem studies demonstrated that BDNF levels are reduced in the brains of patients affected by neurodegenerative diseases, such as Alzheimer?s disease (AD). Iron accumulation has consistently been associated to the pathogenesis of neurodegenerative diseases. In rats, neonatal iron overload induces memory deficits, and increases oxidative stress and apoptotic markers, and decreases the expression of the synaptic marker, synaptophysin. Deferiprone (DFP) is an oral iron chelator used for the treatment of systemic iron overload disorders, and has recently been tested in Parkinson?s disease patients. Here, we aimed to determine the effects of iron overload on BDNF levels and glucose metabolism, measured by 18FDG uptake using positron emission tomography. Moreover, we intended to characterize the effects of DFP on iron-induced memory deficits and BDNF levels, as well as on glucose metabolism. Rats received iron or vehicle at postnatal days 12-14 and when adults, received chronic DFP or water. Recognition memory was tested 19 days after the beginning of chelation therapy. 18FDG uptake was performed 24 h after the last day of treatment. Another subset of animals was sacrificed 24 h after the last day of treatment for BDNF measurements, and TrkB and p75 expression analysis. DFP was able to restore memory impairment and increase hippocampal BDNF levels, ameliorating iron-induced effects. The present findings support the use of DFP in clinical trials including AD patients.O ferro ? essencial no c?rebro neonatal para o desenvolvimento neurol?gico normal e para o estabelecimento da concentra??o de ferro no c?rebro adulto, j? que a absor??o de ferro ? m?xima durante o per?odo neonatal. Acredita-se que a sobrecarga de ferro contribui para o desenvolvimento da neurodegenera??o, na exacerba??o das taxas normais de apoptose, em grande parte devido ? sua participa??o na rea??o de Fenton e ? produ??o de esp?cies reativas de oxig?nio. Estudos pr?vios em nosso laborat?rio demonstraram que o tratamento com ferro no per?odo neonatal induz altera??es significativas de mem?ria, bem como aumento em par?metros de estresse oxidativo e em n?veis de prote?nas apopt?ticas. Recentemente, tamb?m demonstramos que esse tratamento reduz os n?veis de sinaptofisina (um marcador sin?ptico) no hipocampo. O BDNF ? a neutrofina mais abundante no SNC dos mam?feros, tendo sua a??o mediada pelo receptor tirosina cinase de alta afinidade (TrKB). Atualmente, estudos tem demonstrado que o BDNF apresenta um papel cr?tico na forma??o da mem?ria de longa dura??o. Assim, o presente estudo teve dois objetivos principais. O primeiro objetivo foi verificar o envolvimento do BDNF nos d?ficits de mem?ria induzidos pelo ac?mulo de ferro, al?m de verificar se o tratamento com ferro alteraria os n?veis de BDNF e a express?o de seus receptores, TrKB e p75. Os ratos Wistar machos receberam ve?culo ou ferro carbonila (30 mg/kg) do 12? ao 14? dia p?s-natal. Na idade adulta, os animais foram tratados por 21 dias com o quelante de ferro, deferiprona (125 mg/kg/dia), e submetidos ? tarefa de reconhecimento do objeto. A an?lise da mem?ria foi realizada atrav?s do ?ndice de reconhecimento, expresso pela raz?o entre a quantidade de tempo gasto na explora??o do objeto novo sobre o tempo total gasto explorando ambos os objetos. Os n?veis prot?icos de BDNF e a express?o g?nica de seus receptores no hipocampo foram quantificados atrav?s de ELISA e PCR real time, respectivamente. O segundo objetivo foi avaliar o metabolismo glicol?tico cerebral realizado atrav?s do escaneamento no TriumphTM microPET e a capta??o de 18F-FDG utilizando o software PMOD v3.5 e Fusion Toolbox. Para este experimento, foram inclu?dos 4 grupos experimentais: os grupos que receberam ve?culo ou ferro no per?odo neonatal que foram divididos em subgrupos que receberam ve?culo ou deferiprona durante 21 dias consecutivos na idade adulta. Os ratos tratados com ferro no per?odo neonatal apresentaram uma diminui??o significativa nos n?veis de BDNF no hipocampo, sem altera??o da express?o g?nica dos receptrores TrkB e p75. A deferiprona foi capaz de reverter os d?ficits de mem?ria de reconhecimento, bem como aumentar os n?veis prot?icos de BDNF no hipocampo, melhorando os efeitos induzidos pelo tratamento com ferro no per?odo neonatal. N?o foram observadas altera??es no metabolismo da glicose cerebral nos animais tratados com ferro e/ou deferiprona. Os presentes achados fornecem embasamento para uso da deferiprona em ensaios cl?nicos, incluindo pacientes com doen?a de Alzheimer

Neonatal gastrin-releasing peptide receptor blockade reduces maternal odor preference in rats

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

Early life stress decreases hippocampal BDNF content and exacerbates recognition memory deficits induced by repeated D-amphetamine exposure

Adverse experiences early in life may have profound influences on brain development, for example, determining alterations in response to psychostimulant drugs, an increased risk of developing a substance abuse disorder, and individual differences in the vulnerability to neuropsychiatric disorders later in life. Here, we investigated the effects of exposure to an early adverse life event, maternal deprivation, combined with repeated D-amphetamine (AMPH) administration in adulthood, on recognition memory and brain-derived neurotrophic factor (BDNF) levels in rats' brain and serum. Rats were exposed to one of the following maternal rearing conditions from postnatal days 1 to 14: non-deprived (ND) or deprived (D). in adulthood, both groups received injections of saline (SAL) or AMPH (2.0 mg/kg, i.p.) for 7 days. in Experiment I (performed 24 h after the last AMPH injection), AMPH induced long-term memory (LTM) impairments in ND and D groups. the D + AMPH group also presented short-term memory (STM) impairments, indicating that the effects of AMPH on memory were more pronounced when the animals where maternally deprived. the group exposed to D + SAL (SAL) showed only LTM impairments. in Experiment II (performed 8 days after the last injection), AMPH detrimental effects on memory persisted in ND and D groups. BDNF levels were decreased in the hippocampus of D + SAL rats. in conclusion, AMPH produces severe and persistent recognition memory impairments that were more pronounced when the animals were maternally deprived, suggesting that an early adverse life event may increase the vulnerability of cognitive function to exposure to a psychostimulant later in life. (C) 2011 Elsevier B.V. All rights reserved.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Pontifical Catholic Univ, Dept Physiol Sci, Fac Biosci, Neurobiol & Dev Biol Lab, BR-90619900 Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Bipolar Disorders Program, BR-90035003 Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Lab Mol Psychiat, BR-90035003 Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Inst Basic Hlth Sci, Dept Pharmacol, Lab Neuropharmacol & Neural Tumor Biol, BR-90050170 Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Univ Hosp Res Ctr CPE HCPA, Canc Res Lab, BR-90035003 Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Psychobiol, BR-04024002 São Paulo, BrazilUniv So Santa Catarina, Hlth Sci Unit, Postgrad Program Hlth Sci, Neurosci Lab, BR-88806000 Criciuma, SC, BrazilNatl Inst Translat Med INCT TM, BR-90035003 Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Psychobiol, BR-04024002 São Paulo, BrazilCAPES: 657/2008Web of Scienc