Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Mol Psychiatry ; 27(4): 2019-2029, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35125495

RESUMO

Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer's disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer 11C-BU99008, 18F-FDG and 18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired patients and healthy controls in regional and voxel-wise levels of astrocyte reactivity, glucose metabolism, grey matter volume and amyloid load were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Amyloid beta (Aß)-positive patients showed greater 11C-BU99008 uptake compared to controls, except in the temporal lobe, whilst further increased 11C-BU99008 uptake was observed in Mild Cognitive Impairment subjects compared to those with Alzheimer's disease in the frontal, temporal and cingulate cortices. BPM correlations revealed that regions which showed reduced 11C-BU99008 uptake in Aß-positive patients compared to controls, such as the temporal lobe, also showed reduced 18F-FDG uptake and grey matter volume, although the correlations with 18F-FDG uptake were not replicated in the ROI analysis. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced 11C-BU99008 uptake, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid deposition occurs later) was associated with increased 11C-BU99008 uptake. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early Aß-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism, although the evidence for glucose hypometabolism here is less strong.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo , Encéfalo/metabolismo , Fluordesoxiglucose F18/metabolismo , Glucose/metabolismo , Substância Cinzenta/metabolismo , Humanos , Imidazóis , Indóis , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos
2.
Mol Psychiatry ; 26(10): 5848-5855, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34267329

RESUMO

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer's disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aß)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer's brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer's disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aß load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Astrócitos/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Humanos , Imidazóis , Indóis , Tomografia por Emissão de Pósitrons
3.
Clin Sci (Lond) ; 131(9): 799-802, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28424374

RESUMO

Despite recent advances in basic and clinical science, dementia remains an area of high unmet medical need. The role of cerebrovascular mechanisms in the pathogenesis and progression of cognitive and functional impairment in dementia is being revived. In order to facilitate the development of therapeutic approaches, it is critical that a number of fundamental elements are integrated into research strategies investigating cerebrovascular pathologies as these will maximize the opportunity of bringing medicines to patients in a timely manner.


Assuntos
Doença de Alzheimer/fisiopatologia , Transtornos Cognitivos/fisiopatologia , Demência/fisiopatologia , Doenças Vasculares/fisiopatologia , Doença de Alzheimer/tratamento farmacológico , Transtornos Cerebrovasculares/tratamento farmacológico , Transtornos Cerebrovasculares/fisiopatologia , Transtornos Cognitivos/tratamento farmacológico , Demência/tratamento farmacológico , Demência Vascular/tratamento farmacológico , Demência Vascular/fisiopatologia , Progressão da Doença , Indústria Farmacêutica/métodos , Indústria Farmacêutica/tendências , Humanos , Doenças Vasculares/tratamento farmacológico
4.
J Pharmacol Exp Ther ; 350(1): 153-63, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24784567

RESUMO

Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe dose-limiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was >150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was >10 versus <1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.


Assuntos
Córtex Cerebral/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/efeitos dos fármacos , Nootrópicos/farmacologia , Oxidiazóis/farmacologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Inibidores da Fosfodiesterase 4/farmacologia , Tiazóis/farmacologia , Aminopiridinas/farmacologia , Animais , Ansiolíticos/efeitos adversos , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Callithrix , Córtex Cerebral/efeitos dos fármacos , Ciclopropanos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Furões , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Macaca fascicularis , Masculino , Nootrópicos/efeitos adversos , Nootrópicos/farmacocinética , Nootrópicos/uso terapêutico , Oxidiazóis/efeitos adversos , Oxidiazóis/farmacocinética , Oxidiazóis/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacocinética , Pica/tratamento farmacológico , Ratos , Rolipram/farmacologia , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Tiazóis/uso terapêutico
5.
Bioorg Med Chem Lett ; 24(23): 5493-6, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25455491

RESUMO

2-Aminopyrimidin-4(1H)-one was proposed as the novel bioisostere of urea. Bioisosteric replacement of the reported urea series of the CXCR2 antagonists with 2-aminopyrimidin-4(1H)-ones led to the discovery of the novel and potent CXCR2 antagonist 3e. 2-Aminopyrimidin-4(1H)-one derivative 3e demonstrated a good developability profile (reasonable solubility and high permeability) and superior chemical stability especially in simulated gastric fluid (SGF) compared with ureas.


Assuntos
Pirimidinas/síntese química , Receptores de Interleucina-8B/antagonistas & inibidores , Ureia/análogos & derivados , Humanos , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
6.
Eur J Pharmacol ; 536(1-2): 54-61, 2006 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-16571351

RESUMO

An increase in brain 5-HT levels is thought to be the key mechanism of action which results in an antidepressant response. It has been proven that selective serotonin re-uptake inhibitors are effective antidepressants but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT1A, and possibly 5-HT1B, autoreceptor desensitisation. Therefore an agent incorporating 5-HT re-uptake inhibition coupled with 5-HT1A and/or 5-HT1B autoreceptor antagonism may provide a fast acting clinical agent. The current studies describe the in vitro profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one), a novel compound which has high affinity for human recombinant 5-HT1A, 5-HT1B and 5-HT1D receptors (pKi values of 8.6, 8.0, 8.8, respectively) and the human recombinant 5-HT transporter (pKi value of 9.3). SB-649915 also displays high affinity for rat, guinea pig, mouse and marmoset native tissue 5-HT1A, 5-HT1B and 5-HT1D receptors and rat native tissue 5-HT transporters (pKi values>or=7.5). In functional [35S]GTPgammaS binding studies, SB-649915 (up to 1 microM) does not display intrinsic activity in HEK293 cells expressing human recombinant 5-HT1A receptors but acts as a partial agonist at human recombinant 5-HT1B and 5-HT1D receptors with intrinsic activity values of 0.3 and 0.7, respectively, as compared to the full agonist 5-HT. From Schild analysis, SB-649915 caused a concentration-dependent, rightward shift of 5-HT-induced stimulation of basal [35S]GTPgammaS binding in cells expressing human recombinant 5-HT1A or 5-HT1B receptors to yield pA2 values of 9.0 and 7.9, respectively. In electrophysiological studies in rat dorsal raphe nucleus, SB-649915 did not affect the cell firing rate up to 1 microM but attenuated (+)8-hydroxy-2-(di-n-propylamino) tetralin-induced inhibition of cell firing with an apparent pKb value of 9.5. SB-649915 (1 microM) significantly attenuated exogenous 5-HT-induced inhibition of electrically-stimulated [3H]5-HT release from guinea pig cortex. In studies designed to enhance endogenous 5-HT levels, and therefore increase tone at 5-HT1B autoreceptors, SB-649915 significantly potentiated [3H]5-HT release at 100 and 1000 nM. In LLCPK cells expressing human recombinant 5-HT transporters and in rat cortical synaptosomes, SB-649915 inhibited [3H]5-HT re-uptake with pIC50 values of 7.9 and 9.7, respectively. In summary, SB-649915 is a novel, potent 5-HT1A/1B autoreceptor antagonist and 5-HT re-uptake inhibitor in native tissue systems and represents a novel mechanism that could offer fast acting antidepressant action.


Assuntos
Piperidinas/farmacologia , Quinolinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Animais , Autorreceptores/agonistas , Autorreceptores/antagonistas & inibidores , Benzoxazinas , Ligação Competitiva/efeitos dos fármacos , Callithrix , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobaias , Humanos , Técnicas In Vitro , Camundongos , Ensaio Radioligante , Núcleos da Rafe/citologia , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1B de Serotonina/genética , Receptor 5-HT1D de Serotonina/genética , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/antagonistas & inibidores , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia
7.
Life Sci ; 93(1): 30-37, 2013 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-23727352

RESUMO

AIMS: Several studies suggested an association between dysregulation of immune mediators and behavioural, neuroendocrine and neurochemical features of depression. Available data showed that cytokines affect the serotonin transporter (SERT) activity through p38 MAP kinase (MAPK)-dependent mechanisms in some cell lines and mice neurons (Zhu et al., Neuropsychopharmacology, 2006; 31:2121-31). The aim of this study was to investigate the interaction of Interleukin-1ß (IL-1ß) or p38 MAPK with SERT activity in rat brain and cell lines. MAIN METHODS: Synaptosomes or cells were treated with IL-1ß or the p38 MAPK activator anisomycin at different concentrations and end-points and the modulation of SERT activity as Km and Vmax was evaluated. KEY FINDINGS: Treatments with IL-1ß or anisomycin did not affect serotonin uptake and p38 MAPK activation in rat synaptosomes, in contrast to reports in mice (Zhu et al., Neuropsychopharmacology, 2010; 35:2510-20). The same treatments activated p38 MAPK phosphorylation in HeLa cells used as positive controls. Similarly, no changes after anisomycin treatment could be detected in [(3)H]serotonin uptake rate in LLC-PK cells expressing human SERT, although phosphorylated p38 MAPK levels augmented significantly. Direct cytokine release in brain was induced by intracerebroventricular administration of bacterial lipopolysaccaride. Although pro-inflammatory cytokines, such as IL-1ß, IL6, and Tumor Necrosis Factor α, showed significant increases in brain cortex, modulation of SERT activity in term of Km and Vmax was not detected. SIGNIFICANCE: These results imply that the stimulation of serotonin uptake by cytokines may not be a unique and fundamental mechanism in the pathology of depression induced by altered immune response.


Assuntos
Encéfalo/metabolismo , Depressão/fisiopatologia , Comportamento de Doença/fisiologia , Serotonina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Análise de Variância , Animais , Anisomicina/farmacologia , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Citocinas/metabolismo , Depressão/imunologia , Depressão/metabolismo , Ativação Enzimática/fisiologia , Ensaio de Imunoadsorção Enzimática , Células HeLa , Humanos , Interleucina-1beta/farmacologia , Análise dos Mínimos Quadrados , Masculino , Ratos , Ratos Sprague-Dawley , Serotonina/farmacocinética , Sinaptossomos/metabolismo
8.
Prog Brain Res ; 172: 213-30, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18772035

RESUMO

A close interplay exists between the serotonergic and dopaminergic neuronal systems both at the anatomical and functional level. It has long been known, at least in mammals, that the central serotonergic system modulates the activity of dopaminergic neurons in both the nigrostriatal pathway and ventral tegmental area. Since the discovery that reserpine and amphetamine induce symptoms in man that resemble those associated with depression and schizophrenia respectively, much attention has focussed on the development of drugs which affect the serotonergic and dopaminergic systems in psychiatric disorders. In this chapter, we will review some of the current research strategies targeting this neurotransmitter interaction that have driven compounds into clinical development in an attempt to provide more effective and safe medicines for such debilitating diseases.


Assuntos
Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Dopamina/metabolismo , Transtornos Mentais/tratamento farmacológico , Serotonina/metabolismo , Animais , Humanos , Isoformas de Proteínas/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Serotonina/metabolismo , Esquizofrenia/tratamento farmacológico , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA