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1.
Mol Psychiatry ; 23(4): 812-823, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29158584

RESUMO

Among neurobiological mechanisms underlying antidepressant properties of ketamine, structural remodeling of prefrontal and hippocampal neurons has been proposed as critical. The suggested mechanism involves downstream activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis. We evaluated whether ketamine elicits similar molecular events in dopaminergic (DA) neurons, known to be affected in mood disorders, using a novel, translational strategy that involved mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. Sixty minutes exposure to ketamine elicited concentration-dependent increases of dendritic arborization and soma size in both mouse and human cultures as measured 72 hours after application. These structural effects were blocked by mTOR complex/signaling inhibitors like rapamycin. Direct evidence of mTOR activation by ketamine was revealed by its induction of p70S6 kinase. All effects of ketamine were abolished by AMPA receptor antagonists and mimicked by the AMPA-positive allosteric modulator CX614. Inhibition of BDNF signaling prevented induction of structural plasticity by ketamine or CX614. Furthermore, the actions of ketamine required functionally intact dopamine D3 receptors (D3R), as its effects were abolished by selective D3R antagonists and absent in D3R knockout preparations. Finally, the ketamine metabolite (2R,6R)-hydroxynorketamine mimicked ketamine effects at sub-micromolar concentrations. These data indicate that ketamine elicits structural plasticity by recruitment of AMPAR, mTOR and BDNF signaling in both mouse mesencephalic and human induced pluripotent stem cells-derived DA neurons. These observations are of likely relevance to the influence of ketamine upon mood and its other functional actions in vivo.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Ketamina/metabolismo , Mesencéfalo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Ketamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo , Receptores de Dopamina D3/metabolismo , Receptores de Glutamato/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo
2.
Science ; 196(4296): 1343-5, 1977 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-17159

RESUMO

Nigral basal adenylate cyclase and dopamine-sensitive adenylate cyclase, glutamate decarboxylase, choline acetyltransferase, and tyrosine hydroxylase activities were measured in rats with hemitransections at various levels or with electrolytic lesions of the medial forebrain bundle or the crus cerebri. The loss of nigral dopamine-sensitive adenylate cyclase activity after the various brain lesions was correlated with loss of nigral glutamic acid decarboxylase but not that of tyrosine hydroxylase; nigral choline acetyltransferase was unaffected in all cases. The data indicate that the nigral dopamine-sensitive adenylate cylase activity may be localized on neurons afferent to the nigra, probably originating from the globus pallidus and possibly from the tail of the caudate. The results suggest that dopamine, released from nigral dendrites, may influence dopaminergic activity indirectly by modulating impulses transmitted to the nigrostriatal neurons through the crus cerebri.


Assuntos
Adenilil Ciclases/metabolismo , Corpo Estriado/enzimologia , Dopamina/farmacologia , Substância Negra/enzimologia , Animais , Encéfalo/cirurgia , Colina O-Acetiltransferase/metabolismo , Dopamina/fisiologia , Eletrocoagulação , Ativação Enzimática , Globo Pálido/enzimologia , Glutamato Descarboxilase/metabolismo , Masculino , Vias Neurais/enzimologia , Neurônios/enzimologia , Ratos , Tirosina 3-Mono-Oxigenase/metabolismo
3.
Mol Cell Endocrinol ; 284(1-2): 11-20, 2008 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-18280641

RESUMO

A dysregulation of the nerve growth factor (NGF)-mediated control of prostate cell growth is associated with the malignant progression of prostate epithelial cells. Exogenous NGF induced in prostate cancer (PCa) cell lines DU145 and PC3 the expression of p75(NGFR), accompanied by a reduction of the cell malignancy. The aim of this study was to analyze the profile of NGF-regulated genes the PCa cell line DU145 by using the cDNA microarray technique. NGF treatment of DU145 cells decreased the expression of 52 known genes, while the expression of 40 known genes was increased. NGF treatment of the DU145 cell line modified the expression profile of clusters of genes involved in invasion and metastasis, in cell proliferation and apoptosis, inflammation, cell metabolism and transcriptional activity. Interestingly, NGF induced the same pattern of gene modifications in both PCa cell lines. Data presented here may help to identify gene/proteins that dispose to PCa progression and to assess future markers that could allow the development of new clinic diagnostic and therapeutical approaches.


Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento Neural/metabolismo , Neoplasias da Próstata/genética , Apoptose/genética , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores de Fator de Crescimento Neural/metabolismo , Proteínas Recombinantes/metabolismo , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Fatores de Transcrição/genética
4.
Cell Death Differ ; 12(7): 761-72, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15818410

RESUMO

Opposite effects of nuclear factor-kappaB (NF-kappaB) on neuron survival rely on activation of diverse NF-kappaB factors. While p65 is necessary for glutamate-induced cell death, c-Rel mediates prosurvival effects of interleukin-1beta. However, it is unknown whether activation of c-Rel-dependent pathways reduces neuron vulnerability to amyloid-beta (Abeta), a peptide implicated in Alzheimer's disease pathogenesis. We show that neuroprotection elicited by activation of metabotropic glutamate receptors type 5 (mGlu5) against Abeta toxicity depends on c-Rel activation. Abeta peptide induced NF-kappaB factors p50 and p65. The mGlu5 agonists activated c-Rel, besides p50 and p65, and the expression of manganese superoxide dismutase (MnSOD) and Bcl-X(L). Targeting c-Rel expression by RNA interference suppressed the induction of both antiapoptotic genes. Targeting c-Rel or Bcl-X(L) prevented the prosurvival effect of mGlu5 agonists. Conversely, c-Rel overexpression or TAT-Bcl-X(L) addition rescued neurons from Abeta toxicity. These data demonstrate that mGlu5 receptor activation promotes a c-Rel-dependent antiapoptotic pathway responsible for neuroprotection against Abeta peptide.


Assuntos
Peptídeos beta-Amiloides/toxicidade , NF-kappa B/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-rel/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Córtex Cerebral/citologia , Inibidores Enzimáticos/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Deleção de Genes , Inativação Gênica , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/metabolismo , Fenilacetatos/farmacologia , Proteínas Proto-Oncogênicas c-rel/deficiência , Proteínas Proto-Oncogênicas c-rel/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores de Glutamato Metabotrópico/genética , Superóxido Dismutase/metabolismo
5.
Curr Top Med Chem ; 6(8): 801-8, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16719818

RESUMO

Dopamine and glutamate have been shown to extensively interact in the striatum, nucleus accumbens, hippocampus and prefrontal cortex, to regulate different physiological functions, including locomotor activity, positive reinforcement, attention and working memory. Although dysfunctions of dopamine transmission have long been identified as critical determinants of neurological and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, there is now increasing evidence that concurrent alterations of dopamine and glutamate function may play a central role in the pathophysiology of these diseases. Thus, defining the characteristics of dopamine-glutamate interactions may be crucial to identify alternative molecular targets for the development of novel pharmacological tools. At the postsynaptic level, interactions between the dopamine D1 and the glutamate NMDA receptors appear to be particularly relevant. Different mechanisms are involved in this interactions: 1) D1R-dependent, second messenger-mediated phosphorylation of NMDAR subunits; 2) coordinated regulation of receptor trafficking at synaptic sites; 3) formation of an heteromeric D1/NMDA receptor complex. In this paper we review the molecular mechanisms, functional implications and pharmacological significance of D1R/NMDAR interaction via direct protein-protein oligomerization.


Assuntos
Receptores de Dopamina D1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Desenho de Fármacos , Doença de Parkinson , Esquizofrenia
6.
Naunyn Schmiedebergs Arch Pharmacol ; 389(5): 529-38, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26905520

RESUMO

Preclinical data indicate a direct anti-tumor effect of zoledronic acid (ZA) outside the skeleton, but its molecular mechanism is still not completely clarified. The aim of this study was to investigate the anti-cancer effects of ZA in human breast cancer cell lines, suggesting that they may in part be mediated via the miR-21/PTEN/Akt signaling pathway. The effect of ZA on cell viability was measured by MTT assay, and cell death induction was analyzed using either a double AO/EtBr staining and M30 ELISA assay. A Proteome Profiler Human Apoptosis Array was executed to evaluate the molecular basis of ZA-induced apoptosis. Cell cycle analysis was executed by flow cytometry. The effect of ZA on miR-21 expression was quantified by qRT-PCR, and the amount of PTEN protein and its targets were analyzed by Western blot. ZA inhibited cell growth in a concentration- and time-dependent manner, through the activation of cell death pathways and arrest of cell cycle progression. ZA downregulated the expression of miR-21, resulting in dephosphorilation of Akt and Bad and in a significant increase of p21 and p27 proteins expression. These results were observed also in MDA-MB-231 cells, commonly used as an experimental model of bone metastasis of breast cancer. This study revealed, for the first time, an involvement of the miR-21/PTEN/Akt signaling pathway in the mechanism of ZA anti-cancer actions in breast cancer cells. We would like to underline that this pathway is present both in the hormone responsive BC cell line (MCF-7) as well as in a triple negative cell line (MDA-MB-231). Taken together these results reinforce the use of ZA in clinical practice, suggesting the role of miR-21 as a possible mediator of its therapeutic efficacy.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Difosfonatos/farmacologia , Imidazóis/farmacologia , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Transdução de Sinais/efeitos dos fármacos , Ácido Zoledrônico
7.
Trends Pharmacol Sci ; 17(4): 155-60, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8984743

RESUMO

The concept of heterogeneity of Alzheimer's disease is based on molecular, neuropathological, clinical and neuropsychological features, and also supported by the observation that Alzheimer's patients differ in their response to pharmacological interventions. Recent investigations evaluating the therapeutic potential of cholinesterase inhibitors have disclosed the existence of at least two subsets of patients with dementia, defined as 'responders' and 'nonresponders' to this therapy. In this article, Paolo Liberini and colleagues suggest that the cluster of responders to the cholinesterase inhibitors might include a significant number of subjects with a rather selective dysfunction of the cholinergic system, as in the case of Lewy-body dementia. A neuropathological demonstration of this correlation should open up new therapeutic perspectives.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Demência/tratamento farmacológico , Corpos de Lewy , Doença de Alzheimer/patologia , Demência/patologia , Humanos
8.
Neurosci Lett ; 377(3): 147-51, 2005 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-15755516

RESUMO

NF-kappaB is a nuclear transcription factor involved in the control of fundamental cellular functions including cell survival. Among the many target genes of this factor, both pro- and anti-apoptotic genes have been described. To evaluate the contribution of NF-kappaB activation to excitotoxic insult, we analysed the effect of IkappaBalpha (IkappaBalpha) phosphorylation blockade on glutamate-induced toxicity in adult mouse hippocampal slices. By using immunocytochemical and EMSA techniques, we found that (i) acute exposure of hippocampal slices to NMDA induced nuclear translocation of NF-kappaB, (ii) NMDA-mediated activation of NF-kappaB was prevented by BAY 11-7082, an inhibitor of IkappaBalpha phosphorylation and degradation, and (iii) BAY 11-7082-mediated inhibition of NF-kappaB activation was associated with neuroprotection.


Assuntos
Hipocampo/efeitos dos fármacos , Proteínas I-kappa B/antagonistas & inibidores , N-Metilaspartato/antagonistas & inibidores , N-Metilaspartato/toxicidade , Nitrilas/farmacologia , Sulfonas/farmacologia , Animais , Hipocampo/metabolismo , Hipocampo/patologia , Proteínas I-kappa B/metabolismo , Técnicas In Vitro , Camundongos , Inibidor de NF-kappaB alfa , Fosforilação/efeitos dos fármacos
9.
Mol Endocrinol ; 10(3): 272-85, 1996 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8833656

RESUMO

Two different human prolactinoma phenotypes (responders and nonresponders), which are distinguished by different tumorigenic potential and different responsiveness to dopaminergic therapy, have recently been identified. Responders show low proliferation rate, low tumorigenic potential, and expression of D-2 receptors for dopamine (DA), while nonresponders are characterized by high proliferation rate, high tumorigenic potential, and lack of expression of DA D-2 receptors. In this study it has been shown that both gp140trk and gp75 components of nerve growth factor (NGF) receptor are expressed in responder prolactinoma cell lines. High levels of both NGF gene transcript and protein were also found in responders, and biologically active NGF was detectable in the media conditioned by these cells. Ablation of NGF production in responder cells by hybridization arrest of translation through NGF antisense oligonucleotides resulted in: 1) loss of secreted NGF; 2) loss of expression of gp75; 3) loss of expression of DA D-2 receptors; and 4) a remarkable increase in the cell proliferation rate. These results thus suggest that a NGF-mediated autocrine loop essential to control cell proliferation and to preserve some phenotypical characteristics of mammotroph cells is present in responder prolactinoma cell lines. Analysis of nonresponders showed that these cells express gp140trk but no detectable levels of gp75. In addition, no NGF mRNA or protein was detectable in nonresponders. Exposure of these cells to NGF resulted in the permanent expression of NGF mRNA and in the production and secretion of NGF protein, thus establishing the same NGF-mediated autocrine loop present in responders. As a result, it has been shown that nonresponder cells treated with NGF acquire and maintain most of the phenotypic characteristics of normal mammotroph cells. In conclusion, the present work reports that a NGF-mediated autocrine loop with an inhibitory role in the control of cell proliferation and tumor progression is active in the more differentiated DA-sensitive prolactinoma cell lines and is lost in the most malignant prolactinoma cells refractory to the dopaminergic therapy. Alterations in the expression of this autocrine loop thus may lead to cell transformation and tumor progression.


Assuntos
Proteínas de Neoplasias/fisiologia , Fatores de Crescimento Neural/fisiologia , Neoplasias Hipofisárias/patologia , Prolactinoma/patologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Proteína Tirosina Quinases/fisiologia , Receptores de Fator de Crescimento Neural/fisiologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Bromocriptina/farmacologia , Bromocriptina/uso terapêutico , Divisão Celular/efeitos dos fármacos , Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Fatores de Crescimento Neural/antagonistas & inibidores , Fatores de Crescimento Neural/biossíntese , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/farmacologia , Oligonucleotídeos Antissenso/farmacologia , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/metabolismo , Prolactinoma/classificação , Prolactinoma/tratamento farmacológico , Prolactinoma/metabolismo , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/efeitos dos fármacos , Receptor de Fator de Crescimento Neural , Receptor trkA , Receptores de Dopamina D2/biossíntese , Receptores de Dopamina D2/genética , Receptores de Fator de Crescimento Neural/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos
10.
Acta Neurochir Suppl ; 93: 59-63, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15986728

RESUMO

NF-kappaB is a nuclear transcription factor involved in the control of fundamental cellular functions including regulation of cell survival. We investigated NF-kappaB activation induced by two opposing modulators of cell viability: IL-1beta and glutamate. We found that IL-1beta activated p50, p65 and c-Rel subunits of NF-kappaB, while glutamate activated only p50 and p65 proteins. Cell stimulation by glutamate, correlated with expression of the pro-apoptotic genes Caspase-3, Caspase-2L and Bax. Conversely, IL-1beta induced the expression of the short anti-apoptotic isoform of Caspase-2. Finally, we analysed the effect of the inhibition of IkappaBalpha degradation on glutamate-induced toxicity by using BAY 11-7082, a selective inhibitor of IkappaBalpha phosphorylation. Our results suggest that BAY 11-7082 preserves neuron viability from the glutamate-mediated injury.


Assuntos
Apoptose/fisiologia , Ácido Glutâmico/farmacologia , Proteínas I-kappa B/metabolismo , Interleucina-1/farmacologia , Neurônios/metabolismo , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Cerebelo/citologia , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos , Proteínas I-kappa B/antagonistas & inibidores , Inibidor de NF-kappaB alfa , NF-kappa B , Neurônios/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
11.
Neuroscience ; 302: 112-20, 2015 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-25450955

RESUMO

Activation of microglia associated with neuroinflammation and loss of phagocytic activity is considered to play a prominent role in the pathogenesis of Alzheimer's disease (AD). CHF5074 (CSP-1103) has been shown to improve cognition and reduce brain inflammation in patients with mild cognitive impairment (MCI). CHF5074 was also found to reverse impairments in recognition memory and improve hippocampal long-term potentiation when administered to plaque-free Tg2576 mice (5-month-old) for 4 weeks. Though, no investigation has focused on the consequence of CHF5074 treatment on microglia polarization yet. In this study we evaluated the effect of CHF5074 administration (375 ppm in the diet) to 5-month-old Tg2576 mice on the expression of pro-inflammatory (M1) genes, Interleukin 1 beta (IL-1ß), Tumor Necrosis Factor alpha (TNFα) and inducible Nitric Oxide Synthase (iNOS), and anti-inflammatory/phagocytic (M2) markers Mannose Receptor type C 1 (MRC1/CD206), Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Chitinase 3-like 3 (Ym1). No changes of pro-inflammatory gene transcription but a reduced expression of MRC1/CD206, TREM2 and Ym1 were detected in the hippocampus of young Tg2576 mice receiving normal diet, when compared to wild-type littermates. CHF5074 did not affect the pro-inflammatory transcription but significantly increased the expression of MRC1/CD206 and Ym1. CHF5074 effects appeared to be hippocampus-specific, as the M2 transcripts were only slightly modified in the cerebral cortex. In primary cultures of mouse astrocyte-microglia, CHF5074 totally suppressed the expression of TNF-α, IL-1ß and iNOS induced by 10 µM ß-amyloid1-42 (Aß42). Moreover, CHF5074 significantly increased the expression of anti-inflammatory/phagocytic markers MRC1/CD206 and TREM2, reduced by the Aß42 application alone. The effect of CHF5074 was not reproduced by ibuprofen (3 µM or 500 µM) or R-flurbiprofen (3 µM or 100 µM), as both compounds limited the pro-inflammatory gene expression but did not modify the anti-inflammatory/phagocytic transcription. These data show that CHF5074 specifically drives the expression of microglia M2 markers either in young Tg2576 hippocampus or in primary astrocyte-microglia cultures, suggesting its potential therapeutic efficacy as microglial modulator in the early phase of AD.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Encéfalo/patologia , Ciclopropanos/uso terapêutico , Flurbiprofeno/análogos & derivados , Neuroglia/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Animais Recém-Nascidos , Anti-Inflamatórios não Esteroides/farmacologia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Estudos de Casos e Controles , Células Cultivadas , Ciclopropanos/farmacologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Flurbiprofeno/farmacologia , Flurbiprofeno/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fatores de Tempo
12.
Neurobiol Aging ; 4(2): 147-49, 1983.
Artigo em Inglês | MEDLINE | ID: mdl-6633783

RESUMO

Enkephalin like peptides seem to have an important regulatory role at ganglia level. The aim of the present study is to investigate whether the content of enkephalin-like peptides in sympathetic ganglia is affected by the aging process. The results show that the enkephalin like peptides content is low in superior cervical and coeliac ganglia of aged rats (25 months). The age-related decrease of enkephalin content in these structures may be of importance in determining an altered sympathetic control during aging.


Assuntos
Encefalina Metionina/análogos & derivados , Gânglios Simpáticos/análise , Fatores Etários , Animais , Encefalina Metionina/análise , Masculino , Peso Molecular , Peptídeos/análise , Ratos , Ratos Endogâmicos
13.
Neurobiol Aging ; 2(3): 229-31, 1981.
Artigo em Inglês | MEDLINE | ID: mdl-6273758

RESUMO

Parameters of dopaminergic transmission were studied in the retina of mature (3-4 months) and aged (23-24 months) rats. In the retina of senescent rats were found significantly higher dihydroxyphenylacetic acid (DOPAC) levels and a higher number of (3H-)spiroperidol binding sites. We detected also an increase of (3H)- methionine-enkephalin binding sites. The changes in the density of (3H)-spiroperidol and (3H)-Metenkephalin binding sites in the retina are opposite to those observed in the brain of aged rats.


Assuntos
Ácido 3,4-Di-Hidroxifenilacético/análise , Envelhecimento , Fenilacetatos/análise , Receptores Dopaminérgicos/análise , Retina/fisiologia , Animais , Sítios de Ligação , Corpo Estriado/análise , Corpo Estriado/fisiologia , Encefalinas/análise , Masculino , Ratos , Receptores Opioides/análise , Retina/análise
14.
Arch Neurol ; 34(1): 12-3, 1977 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-188401

RESUMO

Cyclic guanosine monophosphate (cGMP) levels have been measured in the cerebrospinal fluid of patients with various neurological diseases. The subjects with epilepsy or cerebrovascular diseases do not show any difference from the controls. Moreover, in the CSF of patients having cerebral tumors the levels of cGMP are markedly increased. This change is in line with previous in vitro studies on the increase of cGMP during cell growth and cell proliferation showing that the role of the nucleotide is important for the control of the life cycle of the cell.


Assuntos
Neoplasias Encefálicas/líquido cefalorraquidiano , Transtornos Cerebrovasculares/líquido cefalorraquidiano , GMP Cíclico/líquido cefalorraquidiano , Epilepsia/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Feminino , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/líquido cefalorraquidiano
15.
Mech Ageing Dev ; 12(1): 39-46, 1980 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-6243729

RESUMO

Dopamine and gamma-aminobutyric acid (GABA) receptor functions have been measured in various brain areas of aged rats. [3H] Spiroperidol binding is decreased in various dopaminergic brain areas, particularly in striatum and tuberculum olfactorium. In striatum the number of binding sites for [3H] spiroperidol is similar in both groups of animals, while the affinity is reduced in senescent rats. Moreover, in the pituitary a 50% increase of [3H] spiroperidol binding was detected in the group of senescent animals. On the other hand, [3H] GABA binding is significantly decreased in substantia nigra and hypothalamus of aged rats, while it is unmodified in cerebral cortex, cerebellum, striatum and nucleus accumbens.


Assuntos
Envelhecimento , Encéfalo/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores Dopaminérgicos/metabolismo , Animais , Corpo Estriado/metabolismo , Masculino , Bulbo Olfatório/metabolismo , Hipófise/metabolismo , Ratos , Espiperona/metabolismo , Ácido gama-Aminobutírico/metabolismo
16.
Pain ; 18(1): 25-31, 1984 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-6324054

RESUMO

Met-enkephalin levels were measured in various spinal cord regions of rats chronically suffering from the inflammation of a single paw following a treatment with Freund's adjuvant. The results indicate that chronic localized pain induces a selective increase of met-enkephalin immunoreactive material (ME-IR) in the dorsal horn of the spinal cord segment which receives a direct projection from the inflamed paw. In order to gain information on the functional meaning of these data, either the plexus brachialis or the sciatic nerve were sectioned peripherally before inducing inflammation. Denervation prevented the increase of ME-IR concentration induced by the injection of Freund's adjuvant. Our observations suggest that chronic localized pain in a limb induces a change in ME-IR content which is selective for the spinal cord segment receiving a direct projection from the inflamed paw. This increase depends on an intact innervation.


Assuntos
Encefalina Metionina/biossíntese , Dor/fisiopatologia , Medula Espinal/metabolismo , Vias Aferentes/fisiologia , Animais , Adjuvante de Freund , Inflamação/induzido quimicamente , Masculino , Fibras Nervosas/fisiologia , Dor/etiologia , Ratos , Ratos Endogâmicos , Transmissão Sináptica
17.
Neuropharmacology ; 24(3): 199-206, 1985 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-4039419

RESUMO

To investigate whether prolonged pretreatment with the dopamine (DA) agonist lisuride would result in modification of some of its behavioural effects, food intake, locomotor activity, body temperature or stereotyped and mounting behaviour were evaluated after acute injections of different doses of lisuride into rats, pretreated daily for four weeks with either saline or lisuride. Rats pretreated with lisuride developed tolerance to its anorexigenic and hypothermic effects, and reverse tolerance to its effects on locomotor activity, stereotyped and mounting behaviour. Pretreatment with lisuride did not modify the activity of drug-metabolizing enzymes in the liver. These results, in addition to revealing the pattern of the changes in the behavioural effects of a DA agonist drug, after repeated administration, may be taken as evidence for the existence of different DA receptor systems in different areas of the brain, that mediate different behavioural effects, and that differ markedly in their reactions to prolonged stimulation with an agonist drug.


Assuntos
Comportamento Animal/efeitos dos fármacos , Ergolinas/farmacologia , Lisurida/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Animais , Temperatura Corporal/efeitos dos fármacos , Tolerância a Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Lisurida/administração & dosagem , Masculino , Microssomos Hepáticos/enzimologia , Oxigenases de Função Mista/metabolismo , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Comportamento Sexual Animal/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos
18.
Neuropharmacology ; 39(5): 903-10, 2000 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-10699456

RESUMO

Research has provided evidence about the role of excitotoxicity in the pathophysiology of sporadic amyotrophic lateral sclerosis and suggests that AMPA/kainate receptor activation contributes greatly in mediating glutamate injury to motor neurons. The recent finding of variable expression of metabotropic glutamate (mGlu) receptor subtypes in adult rat spinal cord has prompted us to investigate their contribution to the excitotoxic process. We report here that stimulation of mGlu receptors efficiently prevents motor neuron degeneration induced by kainate. The application of kainate to lumbar spinal cord slices from adult rats induced a massive degeneration of motor neurons which became shrunken, dark and TUNEL-positive. On the contrary, no significant neurotoxicity was observed after NMDA application. A blockade of ionotropic non-NMDA receptors by CNQX, and mGlu receptor stimulation, efficiently counteracted kainate-mediated cell death. Among the various agonists for mGlu receptors, we tested 3-hydroxyphenylglycine (3HPG), which selectively stimulates group I mGlu receptors. In addition, we tested 2-(carboxycyclopropyl)glycine (L-CCG-I) and 4-carboxy-3-hydroxyphenylglycine (4C3HPG), two selective agonists for group II receptors, as well as L-amino-4-phosphonobutyrate (L-AP4), a preferential agonist for group III. The results suggest that all three groups of mGlu receptors are involved in inhibiting excitotoxic phenomena mediated by kainate on spinal cord motor neurons. This was despite being localized differently and, possibly, activating different neuroprotective pathways.


Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , Neurônios Motores/efeitos dos fármacos , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Receptores de Glutamato Metabotrópico/agonistas , Medula Espinal/efeitos dos fármacos , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Benzoatos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Cicloleucina/análogos & derivados , Cicloleucina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Marcação In Situ das Extremidades Cortadas , Técnicas In Vitro , Ácido Caínico , Masculino , Neurônios Motores/enzimologia , Neurônios Motores/patologia , N-Metilaspartato/farmacologia , Degeneração Neural/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Medula Espinal/enzimologia , Medula Espinal/patologia
19.
Neuropharmacology ; 26(5): 477-80, 1987 May.
Artigo em Inglês | MEDLINE | ID: mdl-2955241

RESUMO

With the aim of evaluating the possible functional modifications of both D1 and D2 dopamine receptor subpopulations after repeated administration of neuroleptics, the ability of selective D1 and D2 dopamine agonists to stimulate or inhibit, respectively, the activity of adenylate cyclase in the striatum and nucleus accumbens of rats treated with either saline or haloperidol for 21 days, was studied. It was found that stimulation of the activity of adenylate cyclase elicited by the selective D1 receptor agonist SKF 38393 was significantly greater in homogenates of striatum in rats treated with haloperidol, than in those of saline-treated rats. Similarly, the inhibitory effect on the activity of the enzyme elicited by the selective D2 agonist bromocriptine was much more evident in homogenates of the striatum from rats treated with neuroleptic than in those from saline-treated rats. When dopamine, sodium fluoride (NaF), or 5-guanylyl imidodiphosphate (Gpp(NH)p), were used as agonists to stimulate the activity of adenylate cyclase, the amount of cyclic AMP formed appeared the same in rats treated with haloperidol or saline. Dopamine receptors in nucleus accumbens behaved like those in the striatum in the pattern of modifications after repeated administration of haloperidol. Indeed, the inhibitory effect elicited by bromocriptine, as well as the stimulatory effect elicited by SKF 38393, was much more evident in nucleus accumbens from rats treated with haloperidol than in that from controls, whereas activation of adenylate cyclase induced by dopamine and sodium fluoride was similar in both experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Adenilil Ciclases/metabolismo , Corpo Estriado/efeitos dos fármacos , Haloperidol/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Núcleos Septais/efeitos dos fármacos , Animais , Corpo Estriado/enzimologia , Masculino , Núcleo Accumbens/enzimologia , Ratos , Ratos Endogâmicos , Receptores de Dopamina D1 , Receptores de Dopamina D2
20.
Neuropharmacology ; 38(10): 1477-84, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10530809

RESUMO

The role of group-I metabotropic glutamate receptors (mGlu1 and 5) in neurodegeneration is still controversial. While antagonists of these receptors are consistently neuroprotective, agonists have been found to either amplify or attenuate excitotoxic neuronal death. At least three variables affect responses to agonists: (i) the presence of the NR2C subunit in the NMDA receptor complex; (ii) the existence of an activity-dependent functional switch of group-I mGlu receptors, similar to that described for the regulation of glutamate release; and (iii) the presence of astrocytes expressing mGlu5 receptors. Thus, a number of factors, including the heteromeric composition of NMDA receptors, the exposure time to drugs or to ambient glutamate, and the function of astrocytes clearing extracellular glutamate and producing neurotoxic or neuroprotective factors, must be taken into account when examining the role of group-I mGlu receptors in neurodegeneration/neuroprotection.


Assuntos
Ácido Glutâmico/fisiologia , Fármacos Neuroprotetores , Neurotoxinas , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Astrócitos/fisiologia , Humanos , Degeneração Neural/fisiopatologia
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