RESUMO
ß-Amyloid (Aß) peptides are derived from the sequential cleavage of the amyloid precursor protein (APP). They are enriched in plaques present in Alzheimer's brains and thus play important roles in the pathogenesis of this disease. APP is also known to be expressed in the neurons of dorsal root ganglion (DRG) and contributes to neuronal survival and axonal growth during development. However, whether APP and Aß peptides are involved in nociception and pathological pain states is mostly unknown. In the present study, we have used behavioral, biochemical and morphological approaches to address this issue in both adult rats and APP over-expressing CRND8 transgenic mice. We observed that the Aß peptide (17-24) was predominantly expressed in small-sized DRG neurons of rats. Following intraplantar (i.pl.) injection of complete Freud's adjuvant (CFA), the levels of APP and Aß peptides were significantly reduced in the ipsilateral lumbar 4-6 rat DRG. In 3-, 12- and 24-month-old CRND8 mice, pain sensitivity in response to heat and mechanical stimulation was significantly dampened compared to their age-matched wild-type littermates. In parallel with reduced pain sensitivity, the expression of pain mediators such as substance P, calcitonin gene-related peptide and transient receptor potential vanilloid-1 was significantly reduced in L4-6 DRG of CRND8 mice. Although i.pl. injection of CFA induced a rather similar pattern of inflammatory pain in 3-month-old CRND8 mice and their wild-type littermates, recovery from inflammatory pain seemed faster in 12-month-old CRND8 mice than wild-type mice. These findings suggest that APP and Aß peptides suppress both nociception and inflammatory pain and are likely involved in blunt pain perception of Alzheimer's patients in clinical settings.
Assuntos
Precursor de Proteína beta-Amiloide/biossíntese , Dor/metabolismo , Dor/psicologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Comportamento Animal/fisiologia , Western Blotting , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Adjuvante de Freund , Temperatura Alta , Humanos , Imuno-Histoquímica , Inflamação/psicologia , Masculino , Camundongos , Camundongos Transgênicos , Estimulação Física , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Substância P/metabolismo , Canais de Cátion TRPV/metabolismoRESUMO
Disturbances in olfactory circuitry have been associated with depression in humans. The olfactory bulbectomized (OBX lesion) has been largely used as a model of depression-like behavior in the rat. However, quantitative neuronal rearrangements in key brain regions in this animal model have not been evaluated yet. Accordingly, we investigated changes in hippocampal plasticity as well as behavioral deficits in this animal model. OBX-induced behavioral deficits were studied in a battery of tests, namely the open field test (OFT), forced swim test (FST), and spatial memory disturbances in the Morris water maze (MWM). To characterize the neuronal remodeling, neuroanatomical rearrangements were investigated in the CA1 hippocampus and piriform cortex (PirC), brain regions receiving inputs from the olfactory bulbs and associated with emotional or olfactory processes. Additionally, cell proliferation and survival of newborn cells in the adult dentate gyrus (DG) of the hippocampus were also determined. OBX induced hyperlocomotion and enhanced rearing and grooming in the OFT, increased immobility in the FST as well as required a longer time to find the hidden platform in the MWM. OBX also induced dendritic atrophy in the hippocampus and PirC. In addition, cell proliferation was decreased while the survival remained unchanged in the DG of these animals. These various features are also observed in depressed subjects, adding further support to the validity and usefulness of this model to evaluate potential novel antidepressants.
Assuntos
Sintomas Afetivos/patologia , Hipocampo/patologia , Transtornos da Memória/patologia , Plasticidade Neuronal/fisiologia , Bulbo Olfatório/cirurgia , Sintomas Afetivos/fisiopatologia , Animais , Depressão/patologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Imuno-Histoquímica , Masculino , Transtornos da Memória/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
Recent studies from our groups have shown that BIIE0246, a Y2 receptor antagonist, has antidepressant effect in olfactory bulbectomized (OBX) rat. However, its complex structure and high molecular weight limit its usefulness as an in vivo pharmacological tool. Alternatively, the novel and brain penetrant Y2 receptor antagonist, JNJ-31020028 is a useful tool to investigate the in vivo function of the Y2 receptor. In the present study, we evaluated the effect of chronic intracerebroventricular (icv) administration of JNJ-31020028 in a battery of behavioral tests in an animal model that mimics several deficits observed in the human depression, the OBX rat. Chronic administration of JNJ-31020028 induced a decrease in immobility time in the forced swim test in OBX while had no effect in control animals. Additionally, it decreased number of grooming events in OBX animals, but had no effects on some other behavioral deficits observed such as rearing and hyperlocomotion. Furthermore, JNJ-31020028 had no effect on behavior tests that are commonly used to evaluate anxiety, namely the social interaction test in both OBX and control animals. These data indicate that similar to BIIE0246, JNJ-31020028 also has antidepressant like effects in the OBX model.
Assuntos
Antidepressivos , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Bulbo Olfatório/fisiologia , Piperazinas/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Benzamidas/administração & dosagem , Asseio Animal/efeitos dos fármacos , Bombas de Infusão Implantáveis , Injeções Intraventriculares , Relações Interpessoais , Masculino , Atividade Motora/efeitos dos fármacos , Piperazinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Natação/psicologiaRESUMO
The neuropeptide Y (NPY) has been suggested to act as a major regulator of emotional processes and body weight. The full spectrum of biological effects of this peptide is mediated by at least four classes of receptors known as the Y(1), Y(2), Y(4), and Y(5) subtypes. However, the respective contribution of each of these receptor subtypes, especially the Y(5) subtype, in emotional processes is still mostly unknown. In the present study, we investigated the effect of long term administration of a selective Y(5) agonist [cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]hPP on emotional processes and body weight using two rat models of emotional dysfunctions, the corticosterone (CORT)-induced anxiety model as well as the olfactory bulbectomized (OBX) model of depression and anxiety in Wistar and Sprague-Dawley rats, respectively. The sub-chronic administration of the Y(5) agonist reversed the high levels of locomotion, rearing and grooming in the open field test and the impaired social activity induced by OBX, while increased the percentage of entries and time in the open arm of the elevated plus maze in CORT-treated rats. Furthermore, this Y(5) agonist increased body weight in both strains of control rats. These data further demonstrate that Y(5) receptors are not only involved in the control of body weight but also mediate emotional processing under challenged conditions. Thus, the pharmacotherapeutic administration of a Y(5) agonist could be considered as a potentially novel strategy to alleviate some forms of anxiety and depression in humans.
Assuntos
Peso Corporal/efeitos dos fármacos , Emoções/efeitos dos fármacos , Neuropeptídeo Y/análogos & derivados , Receptores de Neuropeptídeo Y/agonistas , Técnicas de Ablação/métodos , Análise de Variância , Animais , Anti-Inflamatórios/administração & dosagem , Corticosterona/administração & dosagem , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Comportamento Exploratório/efeitos dos fármacos , Resposta de Imobilidade Tônica/efeitos dos fármacos , Relações Interpessoais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neuropeptídeo Y/agonistas , Bulbo Olfatório/cirurgia , Fragmentos de Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Natação/psicologiaRESUMO
The N-methyl-D-aspartate subtype of ionotropic glutamate receptors (NMDARs) signals both prosurvival and death-inducing (excitotoxic) neuronal responses via synaptically (synaptic NMDAR) and extrasynaptically (extrasynaptic NMDAR) located receptor pools, respectively. Both receptor pools share similar, though not identical, postreceptor signaling molecules. The activation of the extrasynaptic NMDAR pathway is predominant. Therefore, in order to inhibit the extrasynaptic death pathway while sparing synaptic responses, it is critical to identify selective postreceptor effectors of extrasynaptic NMDARs. The present study addressed these issues by using primary cultures of rat hippocampal neurons and a pharmacological protocol of selective NMDAR stimulation for Western blot and immunocytochemistry analyses. We found that the activation of extrasynaptic NMDARs, either alone or together with synaptic NMDARs, triggers cyclin-D1-associated re-entry into the cell cycle, which does not proceed beyond the S-phase. This aberrant cell cycle re-entry is particularly associated with neuronal death triggered specifically via extrasynaptic NMDAR-induced c-Jun N-terminal protein kinase (JNK). In addition, NMDA-elicited neuronal death was significantly inhibited by pharmacological blockade of JNK-mediated cyclin D1 expression or by silencing cyclin D1 RNA. Taken together, these data suggest a causal relationship between cyclin D1 induction and extrasynaptic NMDAR-triggered neuronal death along the excitotoxic NMDA pathway. Therefore, cyclin D1 may be a putative target for the development of neuroprotective strategies sparing physiological synaptic NMDAR signaling.
Assuntos
Ciclina D1/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , N-Metilaspartato/farmacologia , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Animais Recém-Nascidos , Antracenos/farmacologia , Contagem de Células , Células Cultivadas , Ciclina D1/genética , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/citologia , Antígeno Ki-67/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , RNA Interferente Pequeno/fisiologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Fatores de Tempo , TransfecçãoRESUMO
Activation of microglia is regulated by controlling both its population size (through modulation of proliferation/death) and the production of inflammatory mediators. Retinoids control cellular proliferation, differentiation, and death. Natural retinoids have been shown to exhibit anti-inflammatory actions against activated microglia. However, the synthetic forms, which are regarded to be more stable in their actions, have not been explored for their capacity to modulate microglial activation, proliferation, and/or trigger cell death. The aim of the current study was to address these issues by using a model, lipopolysaccharide (LPS)-activated primary cultures of rat microglia, and the stable synthetic retinoid, 6-[3-adamantyl-4-hydroxyphenyl]-2-napthalene carboxylic acid (AHPN). Morphological observations of cluster of differentiation (CD) 11b (CD11b)-positive cells suggested that low concentration of AHPN (i.e. 5 µM) reduced LPS (1 µg/ml, 24 h)-activated morphology of microglia possibly toward a lower activated state, while attenuating nitrite production and the level of its synthesizing enzyme, inducible nitric oxide synthase (iNOS), as well as the chemokine, monocyte chemotactic protein-1 (MCP-1). The mechanisms behind these anti-inflammatory actions likely involved decreased activation of nuclear factor kappa B (NF-κB) as shown by the attenuated phosphorylation of its p65 subunit. In addition, fluorescence-activated cell sorting revealed that AHPN reduced the immunophenotypic marker of activation, CD68. LPS-mediated increase in cell number was reduced by low concentration AHPN, which resulted from inhibition of proliferation, based on decreased labeling for Ki-67 and reduced protein expression of cyclin D1, and not cell death. Higher concentrations of AHPN (50-100 µM) attenuated activation and cell number; however, the release of lactate dehydrogenase and appearance of annexin V and propidium iodide-positive cells suggested that cell death was its primary cause for reduced microglial activity. Overall, the current study shows that synthetic retinoids, such as AHPN, at low concentration attenuate microglial activation-associated responses, possibly via the inhibition of their cell proliferation without triggering cell death.
Assuntos
Microglia/efeitos dos fármacos , Retinoides/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Separação Celular , Citometria de Fluxo , Imuno-Histoquímica , Inflamação/metabolismo , Mediadores da Inflamação/farmacologia , Microglia/imunologia , Microglia/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologiaRESUMO
One of the hallmarks of Alzheimer's disease is the accumulation of senile plaques composed of extra-cellular aggregates of beta-amyloid (Aß) peptides. It is well established that at least in vitro, Aß triggers apoptotic cell death via the activation of caspase-dependent and -independent cell death effectors, namely caspase-3 and apoptosis inducing factor (AIF), respectively. Epidemiological studies have reported that elderly people have a lower risk (up to 50%) of developing dementia if they regularly eat fruits and vegetables and drink tea and red wine (in moderation). Numerous studies indicate that polyphenols derived from these foods and beverages account for the observed neuroprotective effects. In particular, we have reported that polyphenols extracted from green tea (i.e. epigallocatechin gallate or EGCG) and red wine (i.e. resveratrol) block Aß-induced hippocampal cell death, by at least partially inhibiting Aß fibrillisation. It has been shown that polyphenols may also modulate caspase-dependent and -independent programmed cell death (PCD) pathways. Indeed, polyphenols including resveratrol, EGCG and luteolin significantly inhibit the activation of the key apoptotic executioner, caspase-3 and are able to modulate mitogen-activated protein kinases known to play an important role in neuronal apoptosis. Moreover, it has been reported that polyphenols may exert their anti-apoptotic action by inhibiting AIF release from mitochondria, thus providing new mechanism of action for polyphenols. This review aims to update the current knowledge regarding the differential effects of polyphenols on PCD pathways and discuss their putative neuroprotective action resulting from their capacity to modulate these pathways.
Assuntos
Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Polifenóis/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Transdução de Sinais/efeitos dos fármacosRESUMO
The Douglas Mental Health University Institute, in collaboration with the McGill Centre for Studies in Aging, organized a 2-day symposium entitled "Biological Changes Associated with Healthy Versus Pathological Aging" that was held in 13 and 14 December 2007 on the Douglas campus. The symposium involved presentations on current trends in aging and dementia research across several sub-disciplines: genetics, neurochemistry, structural and functional neuroimaging and clinical treatment and rehabilitation. The goal of this symposium was to provide a forum for knowledge-transfer between scientists and clinicians with different specializations in order to promote cross-fertilization of research ideas that would lead to future collaborative neuroscience research in aging and dementia. In this review article, we summarize the presentations made by the 13 international scientists at the symposium and highlight: (i) past research, and future research trends in neuroscience of aging and dementia and (ii) links across levels of analysis that can lead to fruitful transdisciplinary research programs that will advance knowledge about the neurobiological changes associated with healthy aging and dementia.
Assuntos
Envelhecimento/fisiologia , Demência/fisiopatologia , Neurociências/tendências , Envelhecimento/genética , Envelhecimento/patologia , Encéfalo/patologia , Demência/patologia , Dopamina/metabolismo , Humanos , Comunicação Interdisciplinar , Imageamento por Ressonância Magnética , Tamanho do Órgão , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/metabolismoRESUMO
Beta-amyloid (Abeta)likely plays a pivotal role in the etiology of Alzheimer's disease (AD). Consequently, Abeta associated pathways are targets for the development of possible effective AD therapies. This review first updates strategies aimed at the inhibition of Abeta formation and then discusses the role of food-derived polyphenols as putative anti-amyloid drugs.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Flavonoides/farmacologia , Fenóis/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Flavonoides/química , Humanos , Estrutura Molecular , Fenóis/química , PolifenóisRESUMO
We investigated the cellular and subcellular distributions of neuregulin tyrosine kinase receptor ErbB4 in the postnatal rat frontal cortex and hippocampus by light-, confocal- and electron-microscopic immunocytochemistry. At birth, ErbB4-immunoreactivity (ErbB4-IR) was prominent in the apical cytoplasm and dendrites of cortical plate neurons and hippocampal pyramidal cells. Throughout postnatal development and in adulthood, ErbB4-IR in both regions remained confined to the somatodendritic compartment of neurons, which increased in number to reach the adult pattern by the end of the first postnatal month (P30). At all ages examined, double-labeling experiments revealed that ErbB4-IR always co-localized with the neuronal marker neuronal nuclei (NeuN) and never with glial markers Nestin or glial fibrillary acidic protein (GFAP). Immunoperoxidase labeling at the ultrastructural level confirmed the exclusive localization of ErbB4-IR in somatodendrites, and notably in dendritic spines. Immunogold labeling showed preponderant ErbB4-IR in the cytoplasm, where it was associated with microtubules. Furthermore, ErbB4-IR was abundant in the nucleus of adult cortical and hippocampal neurons, suggesting a role for ErbB4 nuclear signaling in the brain beyond embryonic development. Taken together, these results show that ErbB4 is expressed by neuronal somatodendrites in cerebral cortex and hippocampus from birth to adulthood, and support a role for neuregulins in dendritic growth and plasticity.
Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Receptores ErbB/metabolismo , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Compartimento Celular/fisiologia , Diferenciação Celular/fisiologia , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Córtex Cerebral/ultraestrutura , Proteínas de Ligação a DNA , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Hipocampo/ultraestrutura , Imuno-Histoquímica , Masculino , Microscopia Confocal , Microscopia Imunoeletrônica , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Neuregulina-1 , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurônios/ultraestrutura , Proteínas Nucleares/metabolismo , Células Piramidais/metabolismo , Células Piramidais/ultraestrutura , Ratos , Ratos Sprague-Dawley , Receptor ErbB-4RESUMO
Since the formulation of the concept of "proteomics" in 1995, a plethora of proteomic technologies have been developed in order to study proteomes of tissues, cells and organelles. The powerful new technologies enabled by proteomic approaches have lead to the application of these methods to an exponentially increasing variety of biological questions for highly complex protein mixtures. Continuous technical optimization allows for an ever-increasing sensitivity of proteomic techniques. In this review, a brief overview of currently available proteomic techniques and their applications is given, followed by a more detailed description of advantages and technical challenges of two-dimensional electrophoresis (2-DE). Some solutions to circumvent currently encountered technical difficulties for 2-DE analyses are proposed.
Assuntos
Eletroforese em Gel Bidimensional/métodos , Proteoma/análise , Proteômica/métodos , Animais , Biologia Computacional , Bases de Dados Factuais , Eletroforese em Gel Bidimensional/instrumentação , Humanos , Focalização Isoelétrica/instrumentação , Focalização Isoelétrica/métodos , Proteínas/análise , Proteínas/isolamento & purificação , Proteômica/instrumentação , Proteômica/tendências , SolubilidadeRESUMO
The present study evaluated whether neurotensin (NT) binding sites were altered in the aged rat brain and if these alterations were related to the cognitive status of the animal. Aged (24-25 months old) Long-Evans rats were behaviorally screened using the Morris water maze task and were classified as either aged, cognitively impaired (AI) or cognitively unimpaired (AU) based on their relative performances in the task compared to young control (Y) animals. Decreases in specific [125I]NT binding were observed in the hippocampal formation, namely the dentate gyrus (DG), as well as in the septum and hypothalamus. Both aged groups also showed significant reductions in specific [125I]NT binding levels compared to the Y animals in the hippocampal CA3 sub-field, with the AI animals exhibiting the lowest levels. In the Substantia Nigra Zona Compacta (SNc) and the ventral tegmental area (VTA), specific [125I]NT binding was decreased as a function of age while binding in the paraventricular nucleus of the hypothalamus (PVNh) was decreased as a function of age and cognitive status. These alterations in the level of specific [125I] NT binding in the aged animals suggest decreases in NT receptor signaling as a function of age and potential involvement of NT-ergic systems in the etiology of age-related cognitive deficits.
Assuntos
Envelhecimento/metabolismo , Envelhecimento/psicologia , Encéfalo/metabolismo , Cognição/fisiologia , Receptores de Neurotensina/metabolismo , Animais , Autorradiografia , Encéfalo/anatomia & histologia , Masculino , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Long-Evans , Distribuição TecidualRESUMO
Neuropeptide Y (NPY) is considered to be an important neuromodulator in the regulation of emotional behavior. For example, NPY is consistently involved in anxiety-related behaviors and there is increasing support for a role of this peptide in mood disorders such as depression. Furthermore, recent evidence suggests that NPY has a significant role in the neurobiological response to alcohol, including alcohol consumption, dependence, and withdrawal. In addition, NPY is beginning to emerge as an important modulator in the etiology of alcoholism that is independent from the addictive and reinforcing properties of the traditional system commonly associated with dopamine and instead, is strongly associated with innate emotionality. The recent developments elucidating the role of NPY in emotion and alcohol dependence are reviewed and the potential of the NPY system as a novel therapeutic strategy in the treatment of anxiety, depression and alcohol-related disorders is examined.
Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Alcoolismo/metabolismo , Encéfalo/metabolismo , Transtornos do Humor/metabolismo , Neuropeptídeo Y/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/genética , Transtornos do Sistema Nervoso Induzidos por Álcool/fisiopatologia , Alcoolismo/genética , Alcoolismo/fisiopatologia , Animais , Transtornos de Ansiedade/genética , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Transtorno Depressivo/genética , Transtorno Depressivo/metabolismo , Transtorno Depressivo/fisiopatologia , Emoções/efeitos dos fármacos , Emoções/fisiologia , Humanos , Transtornos do Humor/genética , Transtornos do Humor/fisiopatologia , Receptores de Neuropeptídeos/efeitos dos fármacos , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologiaRESUMO
The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a multifunctional membrane glycoprotein, which binds different classes of ligands including IGF-II and M6P-bearing lysosomal enzymes. Besides participating in the process of endocytosis this receptor functions in the trafficking of lysosomal enzymes from the trans-Glogi network (TGN) or the cell surface to lysosomes. In Alzheimer's disease (AD) brain, marked overexpression of certain lysosomal enzymes in vulnerable neuronal populations and their association to beta-amyloid (Abeta) containing neuritic plaques has been correlated to altered metabolic functions. In the present study, we measured the levels of IGF-II/M6P receptor and characterized its distribution profile in selected regions of AD and age-matched normal postmortem brains. Western blot analysis revealed no significant alteration in the levels of IGF-II/M6P receptor either in the hippocampus, frontal cortex or cerebellum between AD and age-matched control brains. However, a significant gene dose effect of apolipoprotein E (APOE) epsilon4 allele on IGF-II/M6P receptor levels was evident in the hippocampus of the AD brain. At the cellular level, immunoreactive IGF-II/M6P receptors were localized in the neurons of the frontal cortex, hippocampus and cerebellum of control brains. In AD brains, the labeling of the neurons was less intense in the frontal cortex and hippocampus than in the age-matched control brains. Additionally, IGF-II/M6P receptor immunoreactivity was observed in association with a subpopulation of Abeta-containing neuritic plaques as well as tau-positive neurofibrillary tangles both in the frontal cortex and the hippocampus. Reactive glial cells localized adjacent to the plaques also occasionally exhibited IGF-II/M6P receptor immunoreactivity. These results, when analyzed in context of the established role of the IGF-II/M6P receptor in the regulation of the intracellular trafficking of lysosomal enzymes, suggest that alterations in IGF-II/M6P receptor levels/distribution are possibly associated with altered functioning of the lysosomal enzymes and/or loss of neurons observed in AD brains, especially in patients carrying APOE epsilon4 alleles.
Assuntos
Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Fator de Crescimento Insulin-Like II/metabolismo , Receptor IGF Tipo 2/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Apolipoproteína E4 , Apolipoproteínas E/metabolismo , Western Blotting/métodos , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Mudanças Depois da MorteRESUMO
Neonatal ventral hippocampal (nVH) lesions in rats result in adult onset of a number of behavioral and cognitive abnormalities analogous to those seen in schizophrenia, including hyperresponsiveness to stress and psychostimulants and deficits in working memory, sensorimotor gating and social interaction. Molecular and neurochemical alterations in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of nVH-lesioned animals suggest developmental reorganization of these structures following neonatal lesions. To determine whether nVH lesions lead to neuronal morphological changes, we investigated the effect of nVH lesion on dendritic structure and spine density of pyramidal neurons of the PFC and medium spiny neurons of the NAcc. Bilateral ibotenic acid-induced lesion of the VH was made in Sprague-Dawley pups at postnatal day 7 (P7); and at P70, neuronal morphology was quantified by modified Golgi-Cox staining. The results show that length of basilar dendrites and branching and the density of dendritic spines on layer 3 pyramidal neurons were significantly decreased in rats with nVH lesions. Medium spiny neurons from the NAcc showed a decrease in the density of dendritic spines without significant changes in dendritic length or arborization. The data, comparable to those observed in the PFC of schizophrenic patients, suggest that developmental loss of excitatory projections from the VH may lead to altered neuronal plasticity in the PFC and the NAcc that may contribute to the behavioral changes in these animals.
Assuntos
Dendritos/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/toxicidade , Hipocampo/efeitos dos fármacos , Ácido Ibotênico/toxicidade , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Fatores Etários , Animais , Animais Recém-Nascidos , Comportamento Animal , Feminino , Hipocampo/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Núcleo Accumbens/patologia , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiologia , Gravidez , Ratos , Ratos Sprague-Dawley , Coloração pela Prata/métodos , Fatores de TempoRESUMO
By its projections to the primary visual and the prefrontal cortices, the basal forebrain cholinergic system is involved in cognitive processing of sensory stimuli. It has been suggested that visual stimulus-induced cholinergic activation of the visual cortex may exert a permissive role on thalamocortical inputs. However, it is not known if visual stimulation elicits cholinergic activation of high-order brain areas in the absence of attentional need. In the present study, we measured the effects of patterned visual stimulation (horizontal grating) on the release of acetylcholine with dual-probe in vivo microdialysis in the visual and the prefrontal cortices of anesthetized rats. We also used retrograde tracing to determine the anatomical relationships of cholinergic neurons with neurons of the visual system and the prefrontal cortex. Finally, we evaluated a functional correlate of this stimulation, namely c-fos immunolabeling. Patterned visual stimulation elicited significant increases in acetylcholine release in the visual cortex, accompanied by an increased number of c-fos immunoreactive neurons in this brain area. In contrast, in the prefrontal cortex, neither the level of acetylcholine release nor the number of c-fos immunoreactive neurons was significantly changed because of the stimulation. Cholinergic basal forebrain neurons projecting to the visual or the prefrontal cortices were both localized within the horizontal limb of the diagonal band of Broca but were not immunoreactive for c-fos during visual stimulation. No parts of the visual system were found to directly project to these basal forebrain neurons. These results suggest the differential involvement of cholinergic projections in the integration of sensory stimuli, depending on the level of activity of the targeted cortical area.
Assuntos
Acetilcolina/metabolismo , Estimulação Luminosa , Córtex Pré-Frontal/metabolismo , Córtex Visual/metabolismo , Análise de Variância , Animais , Colina O-Acetiltransferase/metabolismo , Corantes Fluorescentes/metabolismo , Imuno-Histoquímica/métodos , Microdiálise/métodos , Vias Neurais/anatomia & histologia , Vias Neurais/metabolismo , Neurônios/metabolismo , Córtex Pré-Frontal/citologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Long-Evans , Córtex Visual/citologiaRESUMO
Alzheimer's disease (AD) is a pathological process characterized by neuron degeneration and, as recently suggested, brain plasticity. In this work, we compared the reactive plasticity in AD brains associated to O-glycosydically linked glycans, recognized by lectins from Amaranthus leucocarpus (ALL) and Macrobrachium rosenbergii (MRL), and the tau neuritic degeneration. The neuritic degenerative process was evaluated by the quantification of aggregated neuritic structures. Lesions were determined using antibodies against hyperphosphorylated-tau (AD2), amyloid-beta, and synaptophysin. In these conditions, we classified and quantified three pathological structures associated to the neuritic degenerative process: 1) Amyloid-beta deposits (AbetaDs), 2) Classic neuritic plaques (NPs), and 3) Dystrophic neurites clusters (DNCs) lacking amyloid-beta deposits. Reactive plasticity structures were constituted by meganeuritic clusters (MCs) and peri-neuronal sprouting in neurons of the CA4 region of the hippocampus, immunoreactive to synaptophysin (exclusively in AD brains) and GAP-43. Besides, MCs were associated to sialylated O-glycosydically linked glycans as determined by positive labeling with ALL and MRL. Considering that these lectins are specific for the synaptic sprouting process in AD, our results suggest the co-occurrence of of several areas of reactive plasticity and neuron degeneration in AD.
Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Degeneração Neural/patologia , Plasticidade Neuronal , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Histocitoquímica , Humanos , Imuno-Histoquímica , Lectinas , Masculino , Pessoa de Meia-Idade , Placa Amiloide/patologia , Polissacarídeos/metabolismoRESUMO
Neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD) diseases are defined by a progressive neuronal dysfunction and an ensuing behavioral dysfunction. Although protein aggregation (i.e beta-amyloid and alpha-synuclein) plays a pivotal role in both AD and PD, there is increasing evidence that excessive accumulation of reactive oxygen species (ROS) that occurs during normal and pathological brain aging contributes to neuronal losses and dysfunction. Based on these observations, it has been hypothesized that natural antioxidants derived from food, beverages and natural extracts may be beneficial to prevent or delay the occurrence of age-related cognitive deficits and neurodegenerative diseases. We will summarize in this review the role of oxidative stress in pathological brain aging, and provide evidence for a role for antioxidant molecules as therapeutic agents. We will also focus on the various mechanisms underlying their neuroprotective effects in in vivo and in vitro models of neurotoxicity.
Assuntos
Antioxidantes/farmacologia , Doenças Neurodegenerativas/metabolismo , Acetilcarnitina/metabolismo , Envelhecimento , Animais , Antioxidantes/metabolismo , Encéfalo/patologia , Alimentos , Ginkgo biloba/metabolismo , Humanos , Estresse Oxidativo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio , Transdução de Sinais , Ácido Tióctico/metabolismoRESUMO
The aim of the present study was to determine the effects of distinct categories of stressors on beta-endorphin (beta-EP) release in the arcuate nucleus (ArcN) and nucleus accumbens (NAcb) using in vivo microdialysis. Adult male rats were implanted with a cannula aimed at either the NAcb or the ArcN. On the day of testing, a 2 mm microdialysis probe was inserted into the cannula, and artificial cerebrospinal fluid was infused at 2.0 microl/min. After three baseline collections, animals either had a clothespin applied to the base of their tail for 20 min (a physical/tactile stressor), were exposed to fox urine odour for 20 min (a psychological stressor/species-specific threat), or were administered 2.4 g ethanol/kg body weight, 16.5% w/v, i.p. (a chemical/pharmacological stressor) with control animals receiving an equivalent volume of saline. Both tail-pinch and fox odour significantly increased beta-EP release from the ArcN (P<0.05), whilst only tail-pinch enhanced beta-EP release from the NAcb (P<0.01). On the other hand, alcohol stimulated beta-EP release in the NAcb as compared with saline-treated controls (P<0.01), but not in the ArcN. Although the increase in extracellular beta-EP produced by the other stressors was relatively rapid, there was a 90-min delay before alcohol administration caused beta-EP levels to exceed that of saline-injected controls. In conclusion, the fact that physical and fear-inducing psychological stressors stimulate beta-EP release in the ArcN and only physical stressors stimulate beta-EP release in the NAcb, indicates that stressors with different properties are processed differently in the brain. Also, an injection of alcohol caused a delayed increase of beta-EP in the NAcb but not the ArcN, indicating that alcohol may recruit a mechanism that is, at least partially, distinct from stress-related pathways.
Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Núcleo Accumbens/metabolismo , Estresse Fisiológico/metabolismo , beta-Endorfina/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Masculino , Microdiálise , Núcleo Accumbens/efeitos dos fármacos , Odorantes , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , CaudaRESUMO
Converging evidence in schizophrenia suggests prefrontal cortical neuronal deficits that correlate with exaggerated subcortical dopamine (DA) functions: Excitotoxic lesion of the ventral hippocampus (VH) in neonatal rats is widely considered a putative animal model of schizophrenia as they lead to characteristic post-pubertal emergence of behavioral and cognitive abnormalities suggesting a developmental change in the neural circuits comprising the prefrontal cortex (PFC) and subcortical DA. Nerve growth factor inducible-B (NGFI-B, also known as Nur77), an orphan nuclear receptor and transcriptional regulator, is constitutively expressed in the target structures of DA pathways. It acts as an immediate early gene with rapid modulation of its mRNA expression by stress, DA and antipsychotic drugs. The present study assessed the effects of neonatal VH (nVH) lesion and amphetamine treatment on the expression of NGFI-B mRNA in pre- and post-pubertal rats. Sprague-Dawley rat pups received bilateral injection of ibotenic acid or phosphate buffered saline in VH at postnatal (PD) 7. At PD35 and PD56, groups of sham and lesioned animals were administered with D-amphetamine (1.5 mg/kg) or saline and killed 20 min later. In situ hybridization analyses showed that the basal level of NGFI-B mRNA in saline-treated lesioned rats was significantly reduced in the medial PFC (mPFC) and cingulate cortex (CC) only at post-pubertal (PD56) age. No significant difference in NGFI-B mRNA levels was seen in the dorsal striatum or nucleus accumbens (NAcc). Amphetamine treatment increased the expression of NGFI-B mRNA in the mPFC, CC, striatum and NAcc in both control and lesioned animals of both ages. Interestingly, however, striatal and NAcc regions of lesioned rats showed a significantly greater effect of amphetamine at PD56. The data suggest that nVH lesions lead to delayed changes in PFC gene expression along with functional DAergic hyperactivity in subcortical regions.