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1.
Handb Clin Neurol ; 193: 347-360, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36803822

RESUMO

There is an exigent need for disease-modifying and symptomatic treatment approaches for Parkinson's disease. A better understanding of Parkinson's disease pathophysiology and new insights in genetics has opened exciting new venues for pharmacological treatment targets. There are, however, many challenges on the path from discovery to drug approval. These challenges revolve around appropriate endpoint selection, the lack of accurate biomarkers, challenges with diagnostic accuracy, and other challenges commonly encountered by drug developers. The regulatory health authorities, however, have provided tools to provide guidance for drug development and to assist with these challenges. The main goal of the Critical Path for Parkinson's Consortium, a nonprofit public-private partnership part of the Critical Path Institute, is to advance these so-called drug development tools for Parkinson's disease trials. The focus of this chapter will be on how the health regulators' tools were successfully leveraged to facilitate drug development in Parkinson's disease and other neurodegenerative diseases.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Desenvolvimento de Medicamentos , Biomarcadores
2.
Clin Transl Sci ; 14(1): 214-221, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32702147

RESUMO

Interest in drug development for rare diseases has expanded dramatically since the Orphan Drug Act was passed in 1983, with 40% of new drug approvals in 2019 targeting orphan indications. However, limited quantitative understanding of natural history and disease progression hinders progress and increases the risks associated with rare disease drug development. Use of international data standards can assist in data harmonization and enable data exchange, integration into larger datasets, and a quantitative understanding of disease natural history. The US Food and Drug Administration (FDA) requires the use of Clinical Data Interchange Consortium (CDISC) Standards in new drug submissions to help the agency efficiently and effectively receive, process, review, and archive submissions, as well as to help integrate data to answer research questions. Such databases have been at the core of biomarker qualification efforts and fit-for-purpose models endorsed by the regulators. We describe the development of CDISC therapeutic area user guides for Duchenne muscular dystrophy and Huntington's disease through Critical Path Institute consortia. These guides describe formalized data structures and controlled terminology to map and integrate data from different sources. This will result in increased standardization of data collection and allow integration and comparison of data from multiple studies. Integration of multiple data sets enables a quantitative understanding of disease progression, which can help overcome common challenges in clinical trial design in these and other rare diseases. Ultimately, clinical data standardization will lead to a faster path to regulatory approval of urgently needed new therapies for patients.


Assuntos
Desenvolvimento de Medicamentos/normas , Troca de Informação em Saúde/normas , Doença de Huntington/tratamento farmacológico , Distrofia Muscular de Duchenne/tratamento farmacológico , Doenças Raras/tratamento farmacológico , Pesquisa Biomédica/normas , Bases de Dados Factuais/normas , Aprovação de Drogas , Humanos , Produção de Droga sem Interesse Comercial/normas , Estados Unidos , United States Food and Drug Administration/normas
3.
Biochem Pharmacol ; 151: 291-306, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29410157

RESUMO

Central Nervous System (CNS) diseases represent one of the most challenging therapeutic areas for successful drug approvals. Developing quantitative biomarkers as Drug Development Tools (DDTs) can catalyze the path to innovative treatments, and improve the chances of drug approvals. Drug development and healthcare management requires sensitive, reliable, validated, and regulatory accepted biomarkers and endpoints. This review highlights the regulatory paths and considerations for developing DDTs required to advance biomarker and endpoint use in clinical development (e.g., consensus CDISC [Clinical Data Interchange Standards Consortium] data standards, precompetitive sharing of anonymized patient-level data, and continual alignment with regulators). Summarized is the current landscape of biomarkers in a range of CNS diseases including Alzheimer disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorders, Depression, Huntington's disease, Multiple Sclerosis and Traumatic Brain Injury. Advancing DDTs for these devastating diseases that are both validated and qualified will require an integrated, cross-consortium approach to accelerate the delivery of innovative CNS therapeutics.


Assuntos
Biomarcadores/análise , Doenças do Sistema Nervoso Central/tratamento farmacológico , Desenvolvimento de Medicamentos , Descoberta de Drogas , Doenças do Sistema Nervoso Central/metabolismo , Desenvolvimento de Medicamentos/legislação & jurisprudência , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/legislação & jurisprudência , Descoberta de Drogas/métodos , Guias como Assunto , Humanos , Estados Unidos , United States Food and Drug Administration
4.
Clin Transl Sci ; 11(1): 63-70, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28749580

RESUMO

Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/análise , Modelos Biológicos , Imagem Molecular/métodos , Neuroimagem/métodos , Doença de Parkinson/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Progressão da Doença , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Atividade Motora/fisiologia , Doença de Parkinson/fisiopatologia , Pacientes Desistentes do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Tomografia Computadorizada de Emissão de Fóton Único/métodos
5.
Mol Autism ; 4(1): 45, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24238429

RESUMO

BACKGROUND: Austism spectrum disorder (ASD) is a heterogeneous behavioral disorder or condition characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a core clinical disability. METHODS: Transcript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA constructs. Whole genome expression analysis was conducted for each of the knockdown cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing an anti-luciferase shRNA. Gene set enrichment and a causal reasoning engine was employed to identify pathway level perturbations generated by the transcript knockdown. RESULTS: Quantification of the shRNA targets confirmed the successful knockdown at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity. CONCLUSIONS: This work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the broadest efficacy across the diverse population of autism patients.

6.
Restor Neurol Neurosci ; 30(4): 283-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22596355

RESUMO

PURPOSE: Phosphodiesterase 5A (PDE5A) inhibitors improve functional recovery in experimental models of stroke in rats when treatment is delayed and without effect on infarct volume. PDE5A is expressed to only a very limited extent in forebrain tissues, raising the possibility that the locus of effect for the inhibitors is outside the brain. To start to address this question, we determined whether PDE5A inhibitors must have the ability to cross the blood brain barrier to improve recovery. METHOD: After permanent middle cerebral artery occlusion in rats, PF-5 and UK-489,791, PDE5A inhibitors that do or do not pass the blood brain barrier, were administered starting 24 h after occlusion and continued for 1 week. Motor function was assessed at intervals to 28 days using body swing and limb placement measures. RESULTS: Both PF-5 and UK-489,791 produced improvement in motor scores over 28 days that were significantly greater than in vehicle treated animals. There was no difference in efficacy between the two PDE5A inhibitors. CONCLUSIONS: Brain penetrability appears not to be critical to the ability of a PDE5A inhibitor to improve functional recovery after experimental stroke in rats. This finding is discussed with regard to the cellular target(s) for PDE5A inhibitors mediating this effect.


Assuntos
Infarto da Artéria Cerebral Média/tratamento farmacológico , Inibidores da Fosfodiesterase 5/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
7.
J Pharmacol Exp Ther ; 341(2): 396-409, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22328573

RESUMO

Cyclic nucleotides are critical regulators of synaptic plasticity and participate in requisite signaling cascades implicated across multiple neurotransmitter systems. Phosphodiesterase 9A (PDE9A) is a high-affinity, cGMP-specific enzyme widely expressed in the rodent central nervous system. In the current study, we observed neuronal staining with antibodies raised against PDE9A protein in human cortex, cerebellum, and subiculum. We have also developed several potent, selective, and brain-penetrant PDE9A inhibitors and used them to probe the function of PDE9A in vivo. Administration of these compounds to animals led to dose-dependent accumulation of cGMP in brain tissue and cerebrospinal fluid, producing a range of biological effects that implied functional significance for PDE9A-regulated cGMP in dopaminergic, cholinergic, and serotonergic neurotransmission and were consistent with the widespread distribution of PDE9A. In vivo effects of PDE9A inhibition included reversal of the respective disruptions of working memory by ketamine, episodic and spatial memory by scopolamine, and auditory gating by amphetamine, as well as potentiation of risperidone-induced improvements in sensorimotor gating and reversal of the stereotypic scratching response to the hallucinogenic 5-hydroxytryptamine 2A agonist mescaline. The results suggested a role for PDE9A in the regulation of monoaminergic circuitry associated with sensory processing and memory. Thus, PDE9A activity regulates neuronal cGMP signaling downstream of multiple neurotransmitter systems, and inhibition of PDE9A may provide therapeutic benefits in psychiatric and neurodegenerative diseases promoted by the dysfunction of these diverse neurotransmitter systems.


Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , 3',5'-GMP Cíclico Fosfodiesterases/metabolismo , Colinérgicos/farmacologia , GMP Cíclico/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Inibidores de Fosfodiesterase/farmacologia , 3',5'-AMP Cíclico Fosfodiesterases/genética , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Humanos , Macaca fascicularis , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Neurotransmissores/farmacologia , Ratos , Ratos Long-Evans , Ratos Wistar , Filtro Sensorial/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
8.
J Neurosci Methods ; 204(1): 179-188, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22019329

RESUMO

Advances in imaging technology have enabled automated approaches for quantitative image analysis. In this study, a high content object based image analysis method was developed for quantification of ß-amyloid (Aß) plaques in postmortem brains of Alzheimer's disease (AD) subjects and in transgenic mice over overexpressing Aß. Digital images acquired from immunohistochemically stained sections of the superior frontal gyrus were analyzed for Aß plaque burden using a Definiens object-based segmentation approach. Blinded evaluation of Aß stained sections from AD and aged matched human subjects accurately identified AD cases with one exception. Brains from transgenic mice overexpressing Aß (PS1APP mice) were also evaluated by our Definiens object based image analysis approach. We observed an age-dependent increase in the amount of Aß plaque load that we quantified in both the hippocampus and cortex. From the contralateral hemisphere, we measured the amount of Aß in brain homogenates biochemically and observed a significant correlation between our biochemical measurements and those that we measured by our object based Definiens system in the hippocampus. Assessment of Aß plaque load in PS1APP mice using a manual segmentation technique (Image-Pro Plus) confirmed the results of our object-based image analysis approach. Image acquisition and analysis of 32 stained human slides and 100 mouse slides were executed in 8 h and 22 h, respectively supporting the relatively high throughput features of the Definiens platform. The data show that digital imaging combined with object based image analysis is a reliable and efficient approach to quantifying Aß plaques in human and mouse brain.


Assuntos
Algoritmos , Encéfalo/patologia , Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Microscopia Confocal/métodos , Reconhecimento Automatizado de Padrão/métodos , Placa Amiloide/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Aumento da Imagem/métodos , Masculino , Camundongos , Camundongos Transgênicos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
9.
Mol Autism ; 2(1): 7, 2011 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-21575186

RESUMO

BACKGROUND: The inbred mouse strain BTBR T+ tf/J (BTBR) exhibits behavioral deficits that mimic the core deficits of autism. Neuroanatomically, the BTBR strain is also characterized by a complete absence of the corpus callosum. The goal of this study was to identify novel molecular and cellular changes in the BTBR mouse, focusing on neuronal, synaptic, glial and plasticity markers in the limbic system as a model for identifying putative molecular and cellular substrates associated with autistic behaviors. METHODS: Forebrains of 8 to 10-week-old male BTBR and age-matched C57Bl/6J control mice were evaluated by immunohistochemistry using free-floating and paraffin embedded sections. Twenty antibodies directed against antigens specific to neurons, synapses and glia were used. Nissl, Timm and acetylcholinesterase (AchE) stains were performed to assess cytoarchitecture, mossy fibers and cholinergic fiber density, respectively. In the hippocampus, quantitative stereological estimates for the mitotic marker bromodeoxyuridine (BrdU) were performed to determine hippocampal progenitor proliferation, survival and differentiation, and brain-derived neurotrophic factor (BDNF) mRNA was quantified by in situ hybridization. Quantitative image analysis was performed for NG2, doublecortin (DCX), NeuroD, GAD67 and Poly-Sialic Acid Neural Cell Adhesion Molecule (PSA-NCAM). RESULTS: In midline structures including the region of the absent corpus callosum of BTBR mice, the myelin markers 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and myelin basic protein (MBP) were reduced, and the oligodendrocyte precursor NG2 was increased. MBP and CNPase were expressed in small ectopic white matter bundles within the cingulate cortex. Microglia and astrocytes showed no evidence of gliosis, yet orientations of glial fibers were altered in specific white-matter areas. In the hippocampus, evidence of reduced neurogenesis included significant reductions in the number of doublecortin, PSA-NCAM and NeuroD immunoreactive cells in the subgranular zone of the dentate gyrus, and a marked reduction in the number of 5-bromo-2'-deoxyuridine (BrdU) positive progenitors. Furthermore, a significant and profound reduction in BDNF mRNA was seen in the BTBR dentate gyrus. No significant differences were seen in the expression of AchE, mossy fiber synapses or immunoreactivities of microtubule-associated protein MAP2, parvalbumin and glutamate decarboxylase GAD65 or GAD67 isoforms. CONCLUSIONS: We documented modest and selective alterations in glia, neurons and synapses in BTBR forebrain, along with reduced neurogenesis in the adult hippocampus. Of all markers examined, the most distinctive changes were seen in the neurodevelopmental proteins NG2, PSA-NCAM, NeuroD and DCX. Our results are consistent with aberrant development of the nervous system in BTBR mice, and may reveal novel substrates to link callosal abnormalities and autistic behaviors. The changes that we observed in the BTBR mice suggest potential novel therapeutic strategies for intervention in autism spectrum disorders.

10.
J Pharmacol Exp Ther ; 331(3): 842-50, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19729580

RESUMO

Phosphodiesterase 5A (PDE5A) inhibitors improve functional recovery after middle cerebral artery occlusion (MCA-o) in rats. We used the PDE5A inhibitor 3-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one hydrochloride (PF-5) to determine the timing, duration, and degree of inhibition that yields maximum efficacy. We also investigated the localization of PDE5A to determine the tissues and cells that would be targets for PDE5 inhibition and that may mediate efficacy. Nearly complete inhibition of PDE5A, starting 24 h after MCA-o and continued for 7 days, resulted in nearly complete recovery of sensorimotor function that was sustained for 3 months. Delaying administration until 72 h after MCA-o resulted in equivalent efficacy, whereas delaying treatment for 14 days was ineffective. Treatment for 7 days was equivalently efficacious to 28 or 84 days of treatment, whereas treatment for 1 day was less effective. In the normal forebrain, PDE5A immunoreactivity was prominent in smooth muscle of meningeal arteries and a few smaller blood vessels, with weak staining in a few widely scattered cortical neurons and glia. At 24 and 48 h after MCA-o, the number and intensity of blood vessel staining increased in the infarcted cortex and striatum. PDE5A immunoreactivity also was increased at 48 h in putative microglia in penumbra, whereas there was no change in staining of the scattered cortical neurons. Given the window for efficacy and the PDE5A distribution, we hypothesize that efficacy results from an effect on vasculature, and perhaps modulation of microglial function, both of which may facilitate recovery of neuronal function.


Assuntos
Encéfalo/efeitos dos fármacos , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/biossíntese , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Masculino , Microglia/efeitos dos fármacos , Microglia/enzimologia , Atividade Motora/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Inibidores de Fosfodiesterase/farmacologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
11.
J Histochem Cytochem ; 57(10): 933-49, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19506089

RESUMO

Phosphodiesterases (PDEs) comprise a family of enzymes that regulate the levels of cyclic nucleotides, key second messengers that mediate a diverse array of functions. PDE2A is an evolutionarily conserved cGMP-stimulated cAMP and cGMP PDE. In the present study, the regional and cellular distribution of PDE2A in tissues of rats, mice, cynomolgus monkeys, dogs, and humans was evaluated by immunohistochemistry. A polyclonal antibody directed to the C-terminal portion of PDE2A specifically detected PDE2A by Western blotting and by immunohistochemistry. The pattern of PDE2A immunoreactivity (ir) was consistent across all species. Western blot analysis demonstrated that PDE2A was most abundant in the brain relative to peripheral tissues. PDE2A ir was heterogeneously distributed within brain and was selectively expressed in particular peripheral tissues. In the brain, prominent immunoreactivity was apparent in components of the limbic system, including the isocortex, hippocampus, amygdala, habenula, basal ganglia, and interpeduncular nucleus. Cytoplasmic PDE2A staining was prominent in several peripheral tissues, including the adrenal zona glomerulosa, neurons of enteric ganglia, endothelial cells in all organs, lymphocytes of spleen and lymph nodes, and pituitary. These studies suggest that PDE2A is evolutionarily conserved across mammalian species and support the hypothesis that the enzyme plays a fundamental role in signal transduction.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/biossíntese , Animais , Western Blotting , Encéfalo/anatomia & histologia , Encéfalo/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/genética , Cães , Gânglios Espinais/anatomia & histologia , Gânglios Espinais/enzimologia , Humanos , Imuno-Histoquímica , Hibridização In Situ , Macaca fascicularis , Camundongos , Camundongos Knockout , Especificidade de Órgãos , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Medula Espinal/anatomia & histologia , Medula Espinal/enzimologia
12.
J Pain ; 9(7): 567-79, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18455479

RESUMO

UNLABELLED: Chronic pain conditions remain a high unmet medical need, and a significant number of patients are not effectively treated with currently available therapies. There is a significant challenge in developing more effective therapies to treat pain, particularly in chronic debilitating pain conditions such as neuropathic pain. Preclinical research has been beneficial in advancing mechanistic understanding of the pathophysiology of pain as well as in defining new therapeutic targets for intervention. However, the increased understanding of the neurobiology of pain has not yet translated into breakthroughs in pain therapies. Some debate exists as to how predictive the common animal models of pain are to the human condition. Translation animal model activity promises to be enhanced by application of novel neuroimaging technologies. It is well acknowledged throughout the industry that the application of preclinical to clinical translational biomarkers is an important strategy that holds promise in increasing the confidence in the translatability of the preclinical to clinical data. Imaging biomarkers have tremendous potential for affecting pain research from both diagnostic as well as therapeutic standpoints. Noninvasive imaging has the inherent advantage of being able to evaluate central mechanisms of pain and the effects of intervention both in animals and in humans. Because each subject serves as its own control, the inherent intersubject variabilities can be less of a confound. This review discusses both the promise and limitations of using imaging modalities to study pain processing and integrates it into the evolving drug discovery and development paradigm. Each section summarizes current clinical reports and, if applicable, preclinical translational findings. Emphasis is given to technical areas for future development and revealing neuroinflammation dynamics and targets that are influenced by genetics and cellular insults. With continued application of neuroimaging technologies, new therapeutic approaches to treat chronic pain as well as define tools to assess functional outcomes promise to emerge. PERSPECTIVE: This review discusses the promises and limitations of using noninvasive imaging modalities to study pain processing and integrates it into the evolving drug discovery and development paradigm. Emerging neuroimaging technologies may spawn new therapeutic approaches to treat chronic pain as well as define translational tools to assess functional clinical outcomes.


Assuntos
Diagnóstico por Imagem/métodos , Neuralgia/diagnóstico , Dor/diagnóstico , Animais , Biomarcadores/análise , Ensaios Clínicos como Assunto , Diagnóstico por Imagem/tendências , Indústria Farmacêutica/tendências , Previsões , Humanos , Modelos Animais , Neuralgia/metabolismo , Neuralgia/terapia , Dor/metabolismo , Manejo da Dor
13.
Cell Transplant ; 16(3): 229-44, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17503735

RESUMO

Assessment of dopamine nerve terminal function and integrity is a strategy employed to monitor deficits in Parkinson's disease (PD) patients and in preclinical models of PD. Dopamine replacement therapies effectively replenish the diminished supply of endogenous dopamine and provide symptomatic benefit to patients. Tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and amino acid decarboxylase (AADC) are widely used markers of dopaminergic neurons and terminals. The present studies were initiated to: (a) assess alterations in all four markers in the MPTP primate model of dopaminergic degeneration and (b) to determine whether L-DOPA treatment may itself modulate the expression of these markers. MPTP treatment induced a significant decline of dopaminergic immunoreactive fiber and terminal density in the basal ganglia. The amount of reduction varied between markers. The rank order of presynaptic marker loss, from most to least profound reduction, was TH > VMAT2 > DAT > AADC. Semiquantitative image analysis of relative dopaminergic presynaptic fiber and terminal density illustrated region-specific reduction of all four markers. Double immunofluorescence colocalization of two presynaptic markers on the same tissue section confirmed there was a more dramatic loss of TH than of VMAT2 or of DAT following MPTP treatment. L-DOPA treatment was associated with a significantly higher level of AADC and VMAT2 immunoreactivity in the caudate nucleus compared to placebo. These results illustrate that neurotoxic injury of the dopamine system in primates leads to altered and differential expression of presynaptic dopaminergic markers in the basal ganglia and that expression of such markers may be modulated by L-DOPA therapy. These findings have implications for the use of biomarkers of disease progression as well as for the assessment of neurorestorative strategies, such as cell replacement, for the treatment of PD.


Assuntos
Biomarcadores/metabolismo , Dopamina/metabolismo , Transtornos Parkinsonianos/metabolismo , Terminações Pré-Sinápticas/metabolismo , Animais , Antiparkinsonianos/uso terapêutico , Descarboxilases de Aminoácido-L-Aromático/metabolismo , Gânglios da Base/citologia , Gânglios da Base/metabolismo , Gânglios da Base/patologia , Progressão da Doença , Dopaminérgicos/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Levodopa/uso terapêutico , Masculino , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/patologia , Placebos , Terminações Pré-Sinápticas/patologia , Saimiri , Tirosina 3-Mono-Oxigenase/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
14.
J Histochem Cytochem ; 54(11): 1205-13, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16864896

RESUMO

A monoclonal antibody directed against the amino terminal of rat phosphodiesterase 10A (PDE10A) was used to localize PDE10A in multiple central nervous system (CNS) and peripheral tissues from mouse, rat, dog, cynomolgus macaque, and human. PDE10A immunoreactivity is strongly expressed in the CNS of these species with limited expression in peripheral tissues. Within the brain, strong immunoreactivity is present in both neuronal cell bodies and neuropil of the striatum, in striatonigral and striatopallidal white matter tracks, and in the substantia nigra and globus pallidus. Outside the brain, PDE10A immunoreactivity is less intense, and distribution is limited to few tissues such as the testis, epididymal sperm, and enteric ganglia. These data demonstrate that PDE10A is an evolutionarily conserved phosphodiesterase highly expressed in the brain but with restricted distribution in the periphery in multiple mammalian species.


Assuntos
Diester Fosfórico Hidrolases/metabolismo , Animais , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Cães , Humanos , Imuno-Histoquímica , Macaca fascicularis , Camundongos , Especificidade de Órgãos , Ratos , Especificidade da Espécie
16.
J Pharmacol Exp Ther ; 314(3): 1257-66, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15980058

RESUMO

In this study, we investigated antiparkinsonian activity of the novel, highly selective dopamine D(2) receptor agonist sumanirole compared with two clinically effective dopaminergic therapies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinson's disease. Squirrel monkeys were rendered parkinsonian by chronic administration of MPTP and subsequently dosed with vehicle, L-DOPA plus carbidopa (L-DOPA), ropinirole, or sumanirole over a duration of 8 weeks. Antiparkinsonian effects measured with a parkinsonian primate rating scale (PPRS) showed that sumanirole elicited improved functional outcome compared with vehicle. The dopamine D2/D3 agonist ropinirole improved behavioral outcome similar to sumanirole, whereas L-DOPA treatment yielded the most significant symptomatic improvement. The relative rank of therapies that elicited normalization of PPRS was L-DOPA > sumanirole; ropinirole did not normalize PPRS in any of the treated monkeys. Dyskinesias were present with L-DOPA treatment but were not observed in sumanirole-, ropinirole-, or placebo-treated primates. Pathologically, all MPTP-treated animals displayed neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and reactive astrocytosis. Neurons immunoreactive with antibodies to the nuclear transcription factor DeltaFosB were most significantly increased in the striatum of L-DOPA-treated monkeys. These results suggest that sumanirole can exert antiparkinsonian effects similar to L-DOPA without the behavioral and morphological consequences of the latter.


Assuntos
Benzimidazóis/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Intoxicação por MPTP/tratamento farmacológico , Receptores de Dopamina D2/agonistas , Animais , Gânglios da Base/patologia , Benzimidazóis/farmacocinética , Monoaminas Biogênicas/líquido cefalorraquidiano , Levodopa/uso terapêutico , Intoxicação por MPTP/patologia , Intoxicação por MPTP/psicologia , Masculino , Atividade Motora/efeitos dos fármacos , Saimiri , Substância Negra/patologia
17.
Neurobiol Dis ; 20(2): 347-59, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15882945

RESUMO

This study investigated the consequences of levodopa treatment on the expression of the 65- and 67-kDa isoforms of glutamate decarboxylase (GAD65 and GAD67) immunoreactivity in the basal ganglia and cortex of monkeys rendered Parkinsonian by systemic MPTP administration. All MPTP-treated monkeys showed Parkinsonian impairment and selective loss of tyrosine hydroxylase (TH) with sparing of GAD immunoreactive (-ir) fibers and terminals in basal ganglia. The distribution of GAD65- and GAD67-ir in the cortex, caudate, and putamen was not significantly different in MPTP vs. naïve monkeys nor as a function of L-DOPA treatment. In comparison, the expression of GAD67- but not GAD65-ir was augmented in the globus pallidus in MPTP-treated monkeys. Quantification revealed significant increases in number of GAD67-ir neurons in the external and internal segments of the globus pallidus while no significant difference in the number of GAD65-ir neurons was observed. L-DOPA treatment did not significantly change the number of GAD65- or GAD67-ir pallidal neurons following MPTP. These results support and extend the findings that transcriptional elevation of GAD67 occurs in the globus pallidus and demonstrate that GAD65 and GAD67 are differentially altered following lesion. The finding of elevated GAD67 expression in the pallidum is consistent with alterations in inhibitory neurocircuitry playing a key role in the pathophysiology of motor disturbances in Parkinson's disease.


Assuntos
Gânglios da Base/enzimologia , Glutamato Descarboxilase/metabolismo , Isoenzimas/metabolismo , Neurônios/enzimologia , Transtornos Parkinsonianos/enzimologia , Ácido gama-Aminobutírico/biossíntese , Animais , Gânglios da Base/efeitos dos fármacos , Gânglios da Base/fisiopatologia , Contagem de Células , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Modelos Animais de Doenças , Dopaminérgicos/farmacologia , Globo Pálido/efeitos dos fármacos , Globo Pálido/enzimologia , Globo Pálido/fisiopatologia , Glutamato Descarboxilase/efeitos dos fármacos , Imuno-Histoquímica , Isoenzimas/efeitos dos fármacos , Levodopa/farmacologia , Masculino , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurônios/efeitos dos fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Saimiri , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
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