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1.
Brain Res ; 1373: 240-52, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21147074

RESUMO

In Parkinson's disease (PD), there is a significant loss of noradrenergic neurons in the locus coeruleus (LC) in addition to the loss of dopaminergic neurons in the substantia nigra (SN). The goal of this study was to determine if the surviving LC noradrenergic neurons in PD demonstrate compensatory changes in response to the neuronal loss, as observed in Alzheimer's disease (AD). Tyrosine hydroxylase (TH) and dopamine ß-hydroxylase (DBH) mRNA expression in postmortem LC tissue of control and age-matched PD subjects demonstrated a significant reduction in the number of noradrenergic neurons in the LC of PD subjects. TH mRNA expression/neuron did not differ between control and PD subjects, but DBH mRNA expression/neuron was significantly elevated in PD subjects compared to control. This increase in DBH mRNA expression in PD subjects is not a response to neuronal loss because the amount of DBH mRNA expression/neuron in AD subjects was not significantly different from control. Norepinephrine transporter (NET) binding site concentration in the LC of PD subjects was significantly reduced over the cell body region as well as the peri-LC dendritic zone. In PD subjects, the loss of dendrites from surviving noradrenergic neurons was also apparent with TH-immunoreactivity (IR). This loss of LC dendritic innervation in PD subjects as measured by TH-IR was not due to LC neuronal loss because TH-IR in AD subjects was robust, despite a similar loss of LC neurons. These data suggest that there is a differential response of the noradrenergic nervous system in PD compared to AD in response to the loss of LC neurons.


Assuntos
Doença de Alzheimer/patologia , Locus Cerúleo/patologia , Neurônios/fisiologia , Doença de Parkinson/patologia , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/fisiologia , Contagem de Células/métodos , Dopamina beta-Hidroxilase/genética , Dopamina beta-Hidroxilase/metabolismo , Feminino , Fluoxetina/análogos & derivados , Fluoxetina/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/metabolismo , Trítio/farmacocinética , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
2.
Neurosci Lett ; 463(1): 93-7, 2009 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-19631722

RESUMO

Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by the loss of neurons in specific regions of the CNS including the locus coeruleus (LC), the major noradrenergic locus in the CNS. Several animal models of AD have been developed that exhibit some of the pathophysiological changes in the CNS that are observed in AD patients. The purpose of this study was to determine if the integrity of the LC noradrenergic system is altered in the amyloid precursor protein 23 (APP23) mouse model of AD at the age of 3, 6 and 12 months through quantification of tyrosine hydroxylase (TH) mRNA expression. Despite a previous study suggesting alterations in the noradrenergic transmission system of APP23 mice, the current study failed to show altered TH-positive neuronal numbers or expression in LC noradrenergic neurons of APP23 mice versus wild-type (WT) littermates. However, the present study did demonstrate an age-dependent effect on TH mRNA expression. Both the number of TH-containing neurons and the amount of TH-positive grains/neuron significantly increased between the age of 3 and 6 months with no difference between 6 and 12 months. These observations indicate that any study comparing the noradrenergic system between WT (C57Bl/6) and experimental mice must strictly choose the age to be tested and limit age differences between control and experimental groups to the absolute minimum. More importantly, when long-term therapeutic interventions targeting the noradrenergic system are applied to mouse models, and related parameters are studied longitudinally, care should be taken to distinguish between potential therapeutic and strain-specific developmental or age-related alterations.


Assuntos
Envelhecimento/metabolismo , Precursor de Proteína beta-Amiloide/genética , Locus Cerúleo/metabolismo , Norepinefrina/metabolismo , Animais , Locus Cerúleo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/enzimologia , RNA Mensageiro/biossíntese , Tirosina 3-Mono-Oxigenase/biossíntese , Tirosina 3-Mono-Oxigenase/genética
3.
Brain Res ; 1285: 109-18, 2009 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-19524553

RESUMO

An important factor in determining the adverse consequences of a stress experience is the degree to which an individual can exert control over the stressor. Stressor controllability is known to influence brain norepinephrine levels, but its impact on activity in noradrenergic cell bodies is unknown. In the present study we investigated whether noradrenergic neurons within the locus coeruleus (LC), the major source of forebrain norepinephrine, are sensitive to stressor controllability. We exposed adult male Sprague-Dawley rats to escapable or yoked inescapable tailshock and assessed LC activity by measuring changes in the immediate early gene c-fos and the enzyme tyrosine hydroxylase (TH). We used in situ hybridization to measure levels of c-fos mRNA, TH mRNA, and TH primary transcript in the LC. In all three cases stress exposure increased expression relative to an unstressed homecage control group, but expression did not differ between controllable and uncontrollable stress. To further examine whether stressor controllability influences the number of stress-responsive LC neurons we performed double-label immunohistochemistry for TH and Fos. Again we detected an overall effect of stress, which did not differ between controllable and uncontrollable stress. We conclude that exposure to stress robustly increases expression of TH and c-fos in the LC, but this effect is not influenced by stressor controllability. To the extent that the expression of these genes reflects degree of neuronal activation, our results suggest that stress-induced activity of noradrenergic cell bodies in the LC is not sensitive to stressor controllability.


Assuntos
Medo/fisiologia , Locus Cerúleo/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo , Estresse Psicológico/fisiopatologia , Volição/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Estimulação Elétrica , Regulação da Expressão Gênica/fisiologia , Desamparo Aprendido , Imuno-Histoquímica , Hibridização In Situ , Masculino , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima/fisiologia
4.
J Neurosci ; 26(2): 467-78, 2006 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-16407544

RESUMO

In Alzheimer's disease (AD), there is a significant loss of locus ceruleus (LC) noradrenergic neurons. However, functional and anatomical evidence indicates that the remaining noradrenergic neurons may be compensating for the loss. Because the noradrenergic system plays an important role in learning and memory, it is important to determine whether compensation occurs in noradrenergic neurons in the LC and hippocampus of subjects with AD or a related dementing disorder, dementia with Lewy bodies (DLB). We observed profound neuronal loss in the LC in AD and DLB subjects with three major changes in the noradrenergic system consistent with compensation: (1) an increase in tyrosine hydroxylase (TH) mRNA expression in the remaining neurons; (2) sprouting of dendrites into peri-LC dendritic zone, as determined by alpha2-adrenoreceptors (ARs) and norepinephrine transporter binding sites; and (3) sprouting of axonal projections to the hippocampus as determined by alpha2-ARs. In AD and DLB subjects, the postsynaptic alpha1-ARs were normal to elevated. Expression of alpha1A- and alpha2A-AR mRNA in the hippocampus of AD and DLB subjects were not altered, but expression of alpha1D- and alpha2C-AR mRNA was significantly reduced in the hippocampus of AD and DLB subjects. Therefore, in AD and DLB subjects, there is compensation occurring in the remaining noradrenergic neurons, but there does appear to be a loss of specific AR in the hippocampus. Because changes in these noradrenergic markers in AD versus DLB subjects were similar (except neuronal loss and the increase in TH mRNA were somewhat greater in DLB subjects), the presence of Lewy bodies in addition to plaques and tangles in DLB subjects does not appear to further affect the noradrenergic compensatory changes.


Assuntos
Doença de Alzheimer/patologia , Hipocampo/patologia , Doença por Corpos de Lewy/patologia , Locus Cerúleo/patologia , Proteínas do Tecido Nervoso/análise , Norepinefrina/fisiologia , RNA Mensageiro/análise , Receptores Adrenérgicos alfa 1/análise , Receptores Adrenérgicos alfa 2/análise , Tirosina 3-Mono-Oxigenase/análise , Antagonistas Adrenérgicos alfa/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Dendritos/ultraestrutura , Feminino , Fluoxetina/análogos & derivados , Fluoxetina/metabolismo , Hipocampo/química , Humanos , Idazoxano/análogos & derivados , Idazoxano/metabolismo , Hibridização In Situ , Doença por Corpos de Lewy/metabolismo , Locus Cerúleo/química , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/análise , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Prazosina/metabolismo , RNA Mensageiro/biossíntese , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos alfa 2/metabolismo , Tetralonas/metabolismo , Tirosina 3-Mono-Oxigenase/biossíntese , Tirosina 3-Mono-Oxigenase/genética
5.
Brain Res Mol Brain Res ; 139(2): 367-71, 2005 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-16039007

RESUMO

Alpha1-adrenoreceptors (AR), of which three subtypes exist (alpha1A-, alpha1B- and alpha1D-AR) are G-protein-coupled receptors that mediate the actions of norepinephrine and epinephrine both peripherally and centrally. In the CNS, alpha1-ARs are found in the hippocampus where animal studies have shown the ability of alpha1-AR agents to modulate long-term potentiation and memory; however, the precise distribution of alpha1-AR expression and its subtypes in the human brain is unknown making functional comparisons difficult. In the human hippocampus, 3H-prazosin (alpha1-AR antagonist) labels only the dentate gyrus (molecular, granule and polymorphic layers) and the stratum lucidum of the CA3 homogeneously. Human alpha1A-AR mRNA in the hippocampus is observed only in the dentate gyrus granule cell layer, while alpha1D-AR mRNA expression is observed only in the pyramidal cell layers of CA1, CA2 and CA3, regions where 3H-prazosin did not bind. alpha1B-AR mRNA is not expressed at detectable levels in the human hippocampus. These results confirm a difference in hippocampal alpha1-AR localization between rat and humans and further describe a difference in the localization of the alpha1A- and alpha1D-AR mRNA subtype between rats and humans.


Assuntos
Expressão Gênica/fisiologia , Hipocampo/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mudanças Depois da Morte , Ligação Proteica/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ensaio Radioligante/métodos , Receptores Adrenérgicos alfa 1/classificação , Receptores Adrenérgicos alfa 1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Trítio/farmacocinética
6.
Brain Res Mol Brain Res ; 135(1-2): 285-9, 2005 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-15857691

RESUMO

Seizure-induced activity has been shown to increase the expression of immediate early genes (IEGs) c-fos and c-Jun in the CNS. Anti-epileptic drugs (AEDs) can suppress the induction of a seizure, but it is unknown if AEDs affect the expression of seizure-induced IEGs. We found that valproic acid (VPA), but not lamotrigine (LTG), was capable of suppressing seizure-induced c-fos and c-Jun mRNA expression in rats despite a similar anticonvulsant effect. LTG in some regions of the CNS enhanced seizure-induced IEG expression. These studies indicate that the older AED (VPA), as compared to the newer AED (LTG), can suppress seizure-induced IEG expression. The consequence of this suppression of IEGs following a generalized seizure may be viewed either as a neuroprotective or detrimental effect upon the brain.


Assuntos
Anticonvulsivantes/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Convulsões/metabolismo , Ácido Valproico/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Flurotila , Regulação da Expressão Gênica/fisiologia , Hibridização In Situ/métodos , Lamotrigina , Masculino , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Convulsões/induzido quimicamente , Triazinas/farmacologia
7.
Epilepsy Res ; 62(1): 35-9, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15519130

RESUMO

Neuropeptide Y (NPY) and galanin are neuropeptides that are regulated by energy states and are also anticonvulsant. We tested the hypothesis that the anticonvulsant efficacy of the ketogenic diet (KD) is mediated by increased expression of NPY and galanin via alterations in food intake and energy metabolism. In situ hybridization revealed no effect of the KD on NPY or galanin mRNA expression, suggesting that increased expression of NPY and galanin do not contribute to the anticonvulsant effect of the KD.


Assuntos
Química Encefálica/efeitos dos fármacos , Epilepsia/dietoterapia , Galanina/biossíntese , Neuropeptídeo Y/biossíntese , Ácido 3-Hidroxibutírico/sangue , Animais , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Hibridização In Situ , Cetonas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Convulsões/induzido quimicamente , Convulsões/dietoterapia
8.
Dev Neurosci ; 24(4): 294-9, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12457067

RESUMO

Numerous studies have examined the brain regional distribution of the immediate early gene (IEG), c-fos, following seizures induced by a variety of chemical or electrical provocations in the rat. Very little is known concerning the regional and temporal distribution of IEG expression following seizures in mice, and even less regarding the effects of development. In the present study, seizures of varying severities were induced in immature (postnatal day 17-18) and mature male (postnatal day 55-60) C3H mice with flurothyl, a volatile convulsant. In the immature mouse, neither c-fos nor c-jun mRNA were statistically elevated following any type of acute seizure activity. In the mature mouse, seizures of different severity resulted in differential effects on regional c-fos and c-jun mRNA expression. We conclude that the c-fos and c-jun are not reliable indicators of seizure activity in immature mice, whereas they remain indirect markers of neuronal activity in mature mice.


Assuntos
Encéfalo/metabolismo , Convulsivantes/farmacologia , Flurotila/farmacologia , Genes fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-jun/efeitos dos fármacos , Convulsões/induzido quimicamente , Fatores Etários , Animais , Genes fos/genética , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-jun/genética , RNA Mensageiro/análise
9.
Brain Res ; 946(2): 239-46, 2002 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-12137927

RESUMO

The norepinephrine transporter (NET) regulates adrenoreceptor signaling by controlling the availability of synaptic norepinephrine (NE), and it is a direct target for some classes of antidepressant drugs. NET levels are normal in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE, demonstrating that the NET does not require endogenous NE for appropriate regulation under physiological conditions. In contrast, tyrosine hydroxylase knockout (Th -/-) mice that lack both NE and dopamine (DA) have reduced levels of NET, suggesting that it is down-regulated by a complete absence of catecholamines and not NE per se. Chronic treatment with the NET inhibitor, desipramine (DMI), reduced NET levels in both control and Dbh -/- mice, demonstrating that NE is not required for the regulation of NET by antidepressant drugs. There are some qualitative and quantitative differences in the down-regulation of the NET by catecholamine depletion and DMI treatment, suggesting that different mechanisms may be involved.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Catecolaminas/farmacologia , Desipramina/farmacologia , Simportadores/metabolismo , Animais , Dopamina/metabolismo , Dopamina beta-Hidroxilase/deficiência , Dopamina beta-Hidroxilase/genética , Hibridização In Situ , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Norepinefrina/fisiologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , RNA Mensageiro/biossíntese , Simportadores/biossíntese , Tirosina 3-Mono-Oxigenase/deficiência , Tirosina 3-Mono-Oxigenase/genética
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