Background: Serotonin (5-HT) and its neurotrophic support system, specifically brain-derived neurotrophic factor (BDNF), are thought to modulate energy homeostasis and susceptibility to obesity. Moreover, a polymorphism (5-HTTLPR) in the serotonin reuptake transporter (5-HTT) gene impairs its transcription, thereby altering serotonergic tone and potentially contributing to such susceptibility. This study aims to investigate the effect of BDNF, biallelic 5-HTTLPR, and central in-vivo 5-HTT availability in highly obese versus non-obese subjects using positron emission tomography (PET) and 5-HTT selective [11C]DASB. Methods: Thirty-eight subjects, 24 obese (body mass index, BMI, >35 kg/m2), otherwise mentally and physically healthy, and 14 non-obese (BMI ≤ 25 kg/m2), age- and sex-matched healthy controls were included in this study. Parametric images of binding potential were generated from PET data. Central 5-HTT availability, 5-HTTLPR genotype, and serum BDNF concentrations were analyzed, first in a volume of interest, then in a voxel-wise manner. Results: Overall, our results showed an absence of a linear correlation between BDNF, in-vivo central 5-HTT availability, and body mass index (BMI). 5-HTTLPR genotyping revealed BDNF and hippocampal 5-HTT availability to be negatively correlated (r = −0.57, p = 0.007) in long allelic homozygotes. However, obese subjects exhibited opposing effects of BDNF levels on 5-HTT availability in the nucleus accumbens (NAcc) relative to our non-obese controls. Conclusions: Our data did not confirm an overall correlation between serum BDNF, in-vivo central 5-HTT availability, 5-HTTLPR, and BMI. However, there is evidence that serotonergic tone linked to BDNF, specifically in the NAcc, is involved in the pathophysiology of obesity, although this needs further exploration over a wide range of reward-related eating behaviors.

Le cerveau immature est le siège de processus développementaux qui permettent de passer d'une structure primitive à un réseau mature et fonctionnel. L'activité synaptique spontanée générée dans le système nerveux en développement joue un rôle fondamental dans ces processus. Un des principaux moyens par lesquels cette activité peut être traduite en changement phénotypique au niveau neuronal est la sécrétion de neurotrophines. Les neurotrophines sont sécrétées par les neurones et contrôlent toutes les étapes du développement neuronal. Dans l'hippocampe en développement, la neurotrophine principale est le BDNF (brain derived neurotrophic factor). Cette protéine est synthétisée sous forme immature, le proBDNF, dont le rôle est encore méconnu. Durant ma thèse, j'ai montré que le BDNF exerce un contrôle bidirectionnel sur l'efficacité des synapses GABAergiques en développement. La polarité de la plasticité est déterminée par le type d'activité endurée par les neurones et la forme sous laquelle le BDNF est présenté à ces derniers. J'ai ainsi décrit une séquence développementale qui pourrait s'inscrire dans les processus développementaux permettant la maturation du réseau GABAergique dans l'hippocampe de rat. / The immature brain is the place of developmental processes that allow the switch from a primitive structure to a mature and functional network. Spontaneous synaptic activity generated in the developing nervous system plays a fundamental role in these processes. One of the principal ways this activity is translated into phenotypical changes at the neuronal level is the secretion of neurotrophins. Neurotrophins are secreted by neurons and control each step of neuronal development. In the developing hippocampus, the major neurotrophin is BDNF (brain derived neurotrophic factor). This protein is synthetized under an immature form, proBDNF, which role is still poorly known. During my thesis, I showed that BDNF exerts a bidirectional control on the efficacy of developing GABAergic synapses, which polarity is set by the type of activity endured by neurons and the form of BDNF that is presented to them. I described a developmental sequence which could be a part of the developmental processes allowing the maturation of the GABAergic network in the developing rat hippocampus.

A doença de Alzheimer é uma afecção crônica degenerativa que não possui tratamento até o momento. O uso de alimentos funcionais como a romã na prevenção e/ou tratamento de doenças neurodegenerativas têm sido amplamente pesquisados. Diante disto, o presente trabalho teve como objetivo avaliar a quantidade de compostos bioativos (antocianinas, compostos fenólicos e flavonoides), atividade anticolinesterásica e a capacidade antioxidante in vitro e on line dos extratos de polpa e casca de romã e posteriormente estudar o possível efeito neuroprotetor de micropartículas obtidas a partir do extrato da casca de romã em um animal submetido a infusão crônica de peptídeo β-amilóide. O extrato de casca de romã apresentou maior teor de antocianinas, compostos fenólicos, flavonoides e atividade antioxidante in vitro e on line do que o extrato da polpa. Na análise de compostos não voláteis pela técnica de GC-MS foram identificados 38 compostos no extrato da casca e 37 da polpa de romã, sendo o ácido gálico a principal substância detectada. Foram encontrados no total 13 compostos no extrato de casca e 8 no extrato de polpa de romã que apresentaram atividade antioxidante pelo método HPLC-ABTS on line. A punicalagina, epicatequina e ácido gálico foram os compostos determinantes para a atividade antioxidante em ambos os extratos. O extrato da casca de romã apresentou atividade anticolinesterásica superior ao da polpa. Estes resultados, em conjunto, indicaram um possível potencial da casca de romã como um agente neuroprotetor na doença de Alzheimer. Para estudar o possível efeito neuroprotetor do extrato da casca de romã foram utilizados camundongos C57BL/6 cronicamente infundidos com peptídeo βA1-42 e/ou veículo através de mini-bombas osmóticas durante 35 dias e foram avaliados biomarcadores e alterações comportamentais. Micropartículas de extrato de casca de romã, produzidas em spray dryer, foram diluídas em água e administradas na dose de 800 mg de casca de romã/kg de animal/dia. A memória espacial foi avaliada em labirinto de Barnes e uma redução no número de erros para encontrar a caixa de escape foi verificada nos animais tratados com micropartículas de casca de romã e nos animais do grupo controle, mas não nos animais do grupo βA. A atividade da acetilcolinesterase, neurotrofina BDNF, TNF-α e a enzima SOD foram avaliadas no hipocampo, córtex e soro dos animais. A peroxidação lipídica foi avaliada no fígado dos animais. Como a casca de romã não é comumente consumida foram dosados marcadores de dano isquêmico hepático. O consumo de micropartículas de casca de romã promoveu uma redução do acumulo de placas amiloides, aumento da expressão de neurotrofinas, redução da atividade da enzima acetilcolinesterase, redução da peroxidação lipídica e da citocina pró-inflamatória TNF-α em animais infundidos com peptídeo β-amilóide. O consumo das microcáspulas de casca de romã não acarretou nenhum tipo de lesão hepática. No geral, verificou-se que os compostos presentes na casca de romã podem apresentar um efeito neuroprotetor em animais submetidos a infusão crônica de peptídeo β-amilóide. / Alzheimer\'s disease is a chronic and degenerative condition that have no treatment until now. The research of functional foods such as pomegranate for the prevention and/or treatment of many conditions, including neurodegenerative diseases, is increasing year after year. The amount of bioactive compounds (anthocyanins, phenolic compounds and flavonoids), acetylcholinesterase activity and antioxidant capacity in vitro and on line of pomegranate peel and pulp extracts were evaluated. Pomegranate peel extract has higher content of anthocyanins, phenolic compounds, flavonoids and antioxidant activity in vitro and on line than pulp. The analyses of the profile of non-volatile compounds identified 38 compounds in the peel and 37 in the pulp. The gallic acid was main compound detected. Pomegranate peel showed 13 compounds with antioxidant activity by the HPLC-ABTS method online and pulp showed eight compounds. Punicalagin, Gallic acid and epicatechin were determinants for the antioxidant capacity of the aqueous-alcoholic extract of pomegranate. Pomegranate peel extract had greater anticholinesterase activity than pulp. These results together indicated a possible potential of pomegranate peel as a neuroprotective agent in Alzheimer\'s disease. This research had as objective to study the possible neuroprotective effect of pomegranate peel on an animal model of the Alzheimer\'s disease. For that purpose, mice model of Alzheimer\'s disease were used and biomarkers and behavioral changes were evaluated. C57BL/6 mice were chronically infused with βA1-42 peptide and/or vehicle by mini - osmotic pumps during 35 days. Microparticles of pomegranate peel extract, produced by spray drying, were diluted in water and administered at a dose of 800 mg of pomegranate peel/ kg animal/day. The spatial memory was evaluated in the Barnes maze and a reduction of the errors to find the scape box was verified in animals treated with the PPE, as observed in the Control group, but not in th Aβ group. The activity of acetylcholinesterase, neurotrophin BDNF, TNF-α and SOD were measured in the hippocampus, cortex and serum. Lipid peroxidation was evaluated in the liver. As the pomegranate peel is not commonly consumed, biomarkers of liver ischemic damage were measured. Pomegranate peel consumption promoted a reduction of amyloid plaques, increasing neurotrophin expression, reduction in a AChE activity, reduced lipid peroxidation and reduced TNF-α in animal models of Alzheimer\'s disease. The consumption of pomegranate peel did not cause liver injury. In general, pomegranate peel showed a neuroprotective effect on animal models of the Alzheimer\'s disease.

A doença de Alzheimer é uma afecção crônica degenerativa que não possui tratamento até o momento. O uso de alimentos funcionais como a romã na prevenção e/ou tratamento de doenças neurodegenerativas têm sido amplamente pesquisados. Diante disto, o presente trabalho teve como objetivo avaliar a quantidade de compostos bioativos (antocianinas, compostos fenólicos e flavonoides), atividade anticolinesterásica e a capacidade antioxidante in vitro e on line dos extratos de polpa e casca de romã e posteriormente estudar o possível efeito neuroprotetor de micropartículas obtidas a partir do extrato da casca de romã em um animal submetido a infusão crônica de peptídeo β-amilóide. O extrato de casca de romã apresentou maior teor de antocianinas, compostos fenólicos, flavonoides e atividade antioxidante in vitro e on line do que o extrato da polpa. Na análise de compostos não voláteis pela técnica de GC-MS foram identificados 38 compostos no extrato da casca e 37 da polpa de romã, sendo o ácido gálico a principal substância detectada. Foram encontrados no total 13 compostos no extrato de casca e 8 no extrato de polpa de romã que apresentaram atividade antioxidante pelo método HPLC-ABTS on line. A punicalagina, epicatequina e ácido gálico foram os compostos determinantes para a atividade antioxidante em ambos os extratos. O extrato da casca de romã apresentou atividade anticolinesterásica superior ao da polpa. Estes resultados, em conjunto, indicaram um possível potencial da casca de romã como um agente neuroprotetor na doença de Alzheimer. Para estudar o possível efeito neuroprotetor do extrato da casca de romã foram utilizados camundongos C57BL/6 cronicamente infundidos com peptídeo βA1-42 e/ou veículo através de mini-bombas osmóticas durante 35 dias e foram avaliados biomarcadores e alterações comportamentais. Micropartículas de extrato de casca de romã, produzidas em spray dryer, foram diluídas em água e administradas na dose de 800 mg de casca de romã/kg de animal/dia. A memória espacial foi avaliada em labirinto de Barnes e uma redução no número de erros para encontrar a caixa de escape foi verificada nos animais tratados com micropartículas de casca de romã e nos animais do grupo controle, mas não nos animais do grupo βA. A atividade da acetilcolinesterase, neurotrofina BDNF, TNF-α e a enzima SOD foram avaliadas no hipocampo, córtex e soro dos animais. A peroxidação lipídica foi avaliada no fígado dos animais. Como a casca de romã não é comumente consumida foram dosados marcadores de dano isquêmico hepático. O consumo de micropartículas de casca de romã promoveu uma redução do acumulo de placas amiloides, aumento da expressão de neurotrofinas, redução da atividade da enzima acetilcolinesterase, redução da peroxidação lipídica e da citocina pró-inflamatória TNF-α em animais infundidos com peptídeo β-amilóide. O consumo das microcáspulas de casca de romã não acarretou nenhum tipo de lesão hepática. No geral, verificou-se que os compostos presentes na casca de romã podem apresentar um efeito neuroprotetor em animais submetidos a infusão crônica de peptídeo β-amilóide. / Alzheimer\'s disease is a chronic and degenerative condition that have no treatment until now. The research of functional foods such as pomegranate for the prevention and/or treatment of many conditions, including neurodegenerative diseases, is increasing year after year. The amount of bioactive compounds (anthocyanins, phenolic compounds and flavonoids), acetylcholinesterase activity and antioxidant capacity in vitro and on line of pomegranate peel and pulp extracts were evaluated. Pomegranate peel extract has higher content of anthocyanins, phenolic compounds, flavonoids and antioxidant activity in vitro and on line than pulp. The analyses of the profile of non-volatile compounds identified 38 compounds in the peel and 37 in the pulp. The gallic acid was main compound detected. Pomegranate peel showed 13 compounds with antioxidant activity by the HPLC-ABTS method online and pulp showed eight compounds. Punicalagin, Gallic acid and epicatechin were determinants for the antioxidant capacity of the aqueous-alcoholic extract of pomegranate. Pomegranate peel extract had greater anticholinesterase activity than pulp. These results together indicated a possible potential of pomegranate peel as a neuroprotective agent in Alzheimer\'s disease. This research had as objective to study the possible neuroprotective effect of pomegranate peel on an animal model of the Alzheimer\'s disease. For that purpose, mice model of Alzheimer\'s disease were used and biomarkers and behavioral changes were evaluated. C57BL/6 mice were chronically infused with βA1-42 peptide and/or vehicle by mini - osmotic pumps during 35 days. Microparticles of pomegranate peel extract, produced by spray drying, were diluted in water and administered at a dose of 800 mg of pomegranate peel/ kg animal/day. The spatial memory was evaluated in the Barnes maze and a reduction of the errors to find the scape box was verified in animals treated with the PPE, as observed in the Control group, but not in th Aβ group. The activity of acetylcholinesterase, neurotrophin BDNF, TNF-α and SOD were measured in the hippocampus, cortex and serum. Lipid peroxidation was evaluated in the liver. As the pomegranate peel is not commonly consumed, biomarkers of liver ischemic damage were measured. Pomegranate peel consumption promoted a reduction of amyloid plaques, increasing neurotrophin expression, reduction in a AChE activity, reduced lipid peroxidation and reduced TNF-α in animal models of Alzheimer\'s disease. The consumption of pomegranate peel did not cause liver injury. In general, pomegranate peel showed a neuroprotective effect on animal models of the Alzheimer\'s disease.

No description available.

More than half of all spinal cord injuries are anatomically incomplete, yet many of these result in complete loss of motor function below the level of injury. One approach to enhance functional recovery is to exploit spared CNS axons (that extend past the point of injury) to sprout and connect to potential targets. We have previously found that application of the neurotrophin; BDNF, to the sensory-motor cortex stimulates expression of regeneration associated genes such as GAP-43, and Tαl tubulin, and results in enhanced sprouting of injured corticospinal fibers rostral to the site of injury. Here, we investigated whether infusion of BDNF into the intact sensorimotor cortex induces sprouting of undamaged corticospinal fibers into denervated cervical spinal cord. We also studied the effect of this treatment using several behavioral tasks: gait analysis, forelimb inhibition during swimming, and food pellet reaching task. The results show that BDNF infusion into the intact sensorimotor cortex subsequent to a unilateral pyramidal lesion increases (3.2 fold) the sprouting of intact corticospinal fibers into the denervated, contralateral grey matter at the lumbar level of the spinal cord when compared with vehicle treated rats. This effect was not seen at the cervical level of the spinal cord. Functionally, unilateral pyramidal injury of corticospinal axons significantly increased toe spread of the contralateral denervated forelimb and hindlimb when compared to the uninjured side. BDNF treatment showed a recovery to presurgical levels. Testing of fine motor control with a food pellet reaching task demonstrated deficits in the impaired forelimb but did not show any improvement due to BDNF treatment.

No description available.

More than half of all spinal cord injuries are anatomically incomplete, yet many of these result in complete loss of motor function below the level of injury. One approach to enhance functional recovery is to exploit spared CNS axons (that extend past the point of injury) to sprout and connect to potential targets. We have previously found that application of the neurotrophin; BDNF, to the sensory-motor cortex stimulates expression of regeneration associated genes such as GAP-43, and Tαl tubulin, and results in enhanced sprouting of injured corticospinal fibers rostral to the site of injury. Here, we investigated whether infusion of BDNF into the intact sensorimotor cortex induces sprouting of undamaged corticospinal fibers into denervated cervical spinal cord. We also studied the effect of this treatment using several behavioral tasks: gait analysis, forelimb inhibition during swimming, and food pellet reaching task. The results show that BDNF infusion into the intact sensorimotor cortex subsequent to a unilateral pyramidal lesion increases (3.2 fold) the sprouting of intact corticospinal fibers into the denervated, contralateral grey matter at the lumbar level of the spinal cord when compared with vehicle treated rats. This effect was not seen at the cervical level of the spinal cord. Functionally, unilateral pyramidal injury of corticospinal axons significantly increased toe spread of the contralateral denervated forelimb and hindlimb when compared to the uninjured side. BDNF treatment showed a recovery to presurgical levels. Testing of fine motor control with a food pellet reaching task demonstrated deficits in the impaired forelimb but did not show any improvement due to BDNF treatment.

More than half of all spinal cord injuries are anatomically incomplete, yet many of these result in complete loss of motor function below the level of injury. One approach to enhance functional recovery is to exploit spared CNS axons (that extend past the point of injury) to sprout and connect to potential targets. We have previously found that application of the neurotrophin; BDNF, to the sensory-motor cortex stimulates expression of regeneration associated genes such as GAP-43, and Tαl tubulin, and results in enhanced sprouting of injured corticospinal fibers rostral to the site of injury. Here, we investigated whether infusion of BDNF into the intact sensorimotor cortex induces sprouting of undamaged corticospinal fibers into denervated cervical spinal cord. We also studied the effect of this treatment using several behavioral tasks: gait analysis, forelimb inhibition during swimming, and food pellet reaching task. The results show that BDNF infusion into the intact sensorimotor cortex subsequent to a unilateral pyramidal lesion increases (3.2 fold) the sprouting of intact corticospinal fibers into the denervated, contralateral grey matter at the lumbar level of the spinal cord when compared with vehicle treated rats. This effect was not seen at the cervical level of the spinal cord. Functionally, unilateral pyramidal injury of corticospinal axons significantly increased toe spread of the contralateral denervated forelimb and hindlimb when compared to the uninjured side. BDNF treatment showed a recovery to presurgical levels. Testing of fine motor control with a food pellet reaching task demonstrated deficits in the impaired forelimb but did not show any improvement due to BDNF treatment. / Medicine, Faculty of / Graduate

ude.dravrah.egelloc@gnufynnej / This research was supported by awards from the National Institutes of Health (NIH), the Eunice Kennedy Shriver Institute of Child Health and Human Development (R01-HD-059835) and the National Institute for Minority Health and Health Disparities (T37-MD000149). The NIH had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The authors wish to thank the dedicated staff members of Asociacion Civil Proyectos en Salud (PROESA), Peru and Instituto Especializado Materno Perinatal, Peru for their expert technical assistance with this research. / Revisión por pares