RESUMO
Positron emission tomography (PET) molecular imaging of brain targets is a powerful tool to diagnose, follow up, and develop treatments and personalized medicine for a number of acute and chronic brain disorders. The availability of ß+ emitter tracers labelled with [(11)C] or [(18)F] having optimal characteristics of affinity and selectivity for alpha-7 nicotinic receptors (α7R) has received considerable attention, due to the major implication of these receptors in brain functions. The aim of this review is to identify the interest and need for the in vivo exploration of α7R by PET molecular imaging, which tools are currently available for this and how to progress.
Assuntos
Encéfalo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Encéfalo/metabolismo , HumanosRESUMO
The double-stranded RNA-dependent protein kinase (PKR), an apoptotic inducer, regulates much pro-inflammatory cytokine production. The purpose of this study was to evaluate in vivo the effects of the specific PKR inhibitor C16 in the striatum in an acute excitotoxic rat model with an important neuroinflammatory component. Inflammation was induced by unilateral striatal injection of quinolinic acid (QA) in 10-week-old normotensive rats. Animals were separated into groups receiving either vehicle or C16 for both sham and QA rats. The effects were assessed in ipsi- and contralateral striata by immunoblotting for PKR activation, by Luminex assay for cytokine levels and by immunofluorescent staining for cleaved caspase-3 to detect neuronal apoptosis. The highest dose of C16 (600µg/kg; C16-2) in QA rats reduced expression of the active catalytic domain of the PKR vs. that in vehicle-injected QA rats. A robust increase of IL-1ß levels on the contralateral side of QA rats was prevented by C16-2 (97% inhibition). Macroscopic and microscopic observation of cerebral tissue (Hematoxylin & Eosin staining) revealed that tissue integrity was more preserved with C16-2 treatment than its vehicle in QA rats. Furthermore, C16-2 treatment decreased by 47% the neuronal loss and by 37% the number of positive cleaved caspase-3 neurons induced by QA injection. In conclusion, C16 prevented not only the PKR-induced neuronal loss but also the inflammatory response in this acute excitotoxic in vivo model, highlighting its promising neuroprotective properties to rescue acute brain lesions.
Assuntos
Apoptose/efeitos dos fármacos , Imidazóis/farmacologia , Indóis/farmacologia , Interleucina-1beta/biossíntese , Inibidores de Proteínas Quinases/farmacologia , eIF-2 Quinase/antagonistas & inibidores , Doença Aguda , Animais , Apoptose/fisiologia , Caspase 3/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Wistar , eIF-2 Quinase/metabolismoRESUMO
BACKGROUND/AIMS: Neuroinflammation plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Its relationship with underlying ß amyloid deposition remains unclear. In vivo visualization of microglial activation has become possible with the development of molecular imaging ligands when used with positron emission tomography (PET). The translocator protein (TSPO) is upregulated during neuroinflammation. Consequently, targeting TSPO with radiolabeled ligands for PET is an attractive biomarker for neuroinflammation. METHODS: A review of the research literature on PET imaging which studied in vivo neuroinflammation in AD subjects and its relationship with amyloid load was performed, including papers published between 2001 and 2012. RESULTS: Six studies were included using either [(11)C]PK-11195 or another non-TSPO radioligand that binds to the monoaminooxidase B. All the studies evaluated amyloid load with [(11)C]PIB. Microglial activation and astrocytosis are potentially early phenomena in AD. However, the individual levels of amyloid deposition and microglial activation were not correlated. CONCLUSION: Noninvasive in vivo molecular imaging to visualize neuroinflammation in AD may contribute to our understanding of the kinetics of neuroinflammation and its relationship to the hallmarks of the disease. Both are important for the development of future therapeutic modalities and for quantifying the efficacy of future disease-modifying treatments.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Inflamação/patologia , Imagem Molecular/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Benzotiazóis , Humanos , Isoquinolinas , Translocases Mitocondriais de ADP e ATP/metabolismo , Monoaminoxidase/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tiazóis , Proteínas tau/metabolismoRESUMO
Segmentation is often required for the analysis of dynamic positron emission tomography (PET) images. However, noise and low spatial resolution make it a difficult task and several supervised and unsupervised methods have been proposed in the literature to perform the segmentation based on semi-automatic clustering of the time activity curves of voxels. In this paper we propose a new method based on spectral clustering that does not require any prior information on the shape of clusters in the space in which they are identified. In our approach, the p-dimensional data, where p is the number of time frames, is first mapped into a high dimensional space and then clustering is performed in a low-dimensional space of the Laplacian matrix. An estimation of the bounds for the scale parameter involved in the spectral clustering is derived. The method is assessed using dynamic brain PET images simulated with GATE and results on real images are presented. We demonstrate the usefulness of the method and its superior performance over three other clustering methods from the literature. The proposed approach appears as a promising pre-processing tool before parametric map calculation or ROI-based quantification tasks.
Assuntos
Processamento de Imagem Assistida por Computador/métodos , Tomografia por Emissão de Pósitrons/métodos , Algoritmos , Animais , Radioisótopos de Flúor , Cinética , Método de Monte Carlo , Imagens de Fantasmas , Pirazóis , Pirimidinas , RatosRESUMO
There is a potential risk that 5-HT(1A) receptor blockade combined with blockade of the 5-HT transporter by an SSRI may cause a toxic increase in 5-HT within the synapse, sparking concern for 'serotonin syndrome', a rare but potentially life threatening condition. We evaluated the safety and pharmacodynamics of the combination of the 5-HT(1A) antagonist lecozotan and the SSRI citalopram in a well-controlled Clinical Pharmacology Unit setting using the Hunter Serotonin Toxicity Criteria (HSTC), a set of validated decision rules featuring neurological and body temperature measurements, to detect any clinically relevant serotonin toxicity. Forty-three young healthy male subjects were randomized, to 2 parallel double-blind treatment groups following a 10-day citalopram 40 mg run-in period: citalopram 40 mg/lecozotan 10mg or citalopram 40 mg/placebo for 9 days. Overall, the combined administration of active drugs was well tolerated, however, one subject experienced moderate hyperreflexia, tremor of the hands, and sweating of hands and feet after 3 days of combined treatment. The event prompted treatment withdrawal and was regarded as mild serotonin toxicity, as per the HSTC. The onset of the event was around the time of peak plasma concentrations (t(max)) of both lecozotan and citalopram, and its time course corresponds to the well-defined PK profile of lecozotan. No evidence of a PK interaction was detected trough lecozotan and citalopram plasma concentrations analysis. The utility of the HSTC in detecting the non-discrete group of symptoms commonly referred to as "serotonin toxicity" was demonstrated in this clinical pharmacology study combining two 5-HT agents in a clinically controlled setting.
Assuntos
Temperatura Corporal/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Síndrome da Serotonina/diagnóstico , Síndrome da Serotonina/fisiopatologia , Adulto , Citalopram/administração & dosagem , Citalopram/sangue , Estudos Cross-Over , Dioxanos/administração & dosagem , Dioxanos/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Interações Medicamentosas , Eletroencefalografia/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Piperazinas/administração & dosagem , Piperazinas/sangue , Antagonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT1 de Serotonina/sangue , Síndrome da Serotonina/induzido quimicamente , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Positron emission tomography (PET) images are corrupted by noise. This is especially true in dynamic PET imaging where short frames are required to capture the peak of activity concentration after the radiotracer injection. High noise results in a possible bias in quantification, as the compartmental models used to estimate the kinetic parameters are sensitive to noise. This paper describes a new post-reconstruction filter to increase the signal-to-noise ratio in dynamic PET imaging. It consists in a spatio-temporal robust diffusion of the 4D image based on the time activity curve (TAC) in each voxel. It reduces the noise in homogeneous areas while preserving the distinct kinetics in regions of interest corresponding to different underlying physiological processes. Neither anatomical priors nor the kinetic model are required. We propose an automatic selection of the scale parameter involved in the diffusion process based on a robust statistical analysis of the distances between TACs. The method is evaluated using Monte Carlo simulations of brain activity distributions. We demonstrate the usefulness of the method and its superior performance over two other post-reconstruction spatial and temporal filters. Our simulations suggest that the proposed method can be used to significantly increase the signal-to-noise ratio in dynamic PET imaging.
Assuntos
Tomografia por Emissão de Pósitrons/métodos , Anisotropia , Difusão , Processamento de Imagem Assistida por Computador , Modelos Teóricos , Distribuição Normal , Imagens de Fantasmas , Razão Sinal-Ruído , Fatores de TempoRESUMO
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model provides a valuable paradigm of the energy deficiency disorders found in childhood. In such disorders, anticonvulsants may provide neuroprotection by modulating cellular energy consumption and by exerting favorable pleiotropic effects on neuronal survival. To verify such hypothesis, we tested the effects of levetiracetam, vigabatrin, gabapentine, pregabaline, tiagabine, clonazepam and lamotrigine on neuroprotection in the MPTP mouse model. The membrane dopamine transporter (DAT) density, which provides a reliable index of dopaminergic neurons survival in the basal ganglia, was assessed by semi-quantitative autoradiography of the striatum. Unlike all other anticonvulsants tested, lamotrigine provided a significant and dose-dependent neuroprotection in these experimental conditions. Lamotrigine, a widely used and well-tolerated molecule in children, could provide neuroprotection in various energy deficiency disorders.
Assuntos
Anticonvulsivantes/farmacologia , Doenças dos Gânglios da Base/metabolismo , Doenças dos Gânglios da Base/prevenção & controle , Gânglios da Base/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/prevenção & controle , Fármacos Neuroprotetores , Animais , Autorradiografia , Doenças dos Gânglios da Base/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Relação Dose-Resposta a Droga , Lamotrigina , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/patologia , Triazinas/farmacologiaRESUMO
The basal ganglia, which are interconnected in the striato-nigral dopaminergic network, are affected in several childhood diseases including Leigh syndrome (LS). LS is the most common mitochondrial disorder affecting children and usually arise from inhibition of the respiratory chain. This vulnerability is attributed to a particular susceptibility to energetic stress, with mitochondrial inhibition as a common pathogenic pathway. In this study we developed a LS model for neuroprotection trials in mice by using the complex I inhibitor MPTP. We first verified that MPTP significantly inhibits the mitochondrial complex I in the brain (p = 0.018). This model also reproduced the biochemical and pathological features of LS: MPTP increased plasmatic lactate levels (p = 0.023) and triggered basal ganglia degeneration, as evaluated through dopamine transporter (DAT) autoradiography, tyrosine hydroxylase (TH) immunohistochemistry, and dopamine dosage. Striatal DAT levels were markedly decreased after MPTP treatment (p = 0.003). TH immunoreactivity was reduced in the striatum and substantia nigra (p = 0.005), and striatal dopamine was significantly reduced (p < 0.01). Taken together, these results confirm that acute MPTP intoxication in young mice provides a reproducible pharmacological paradigm of LS, thus opening new avenues for neuroprotection research.
Assuntos
Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/metabolismo , Doença de Leigh/enzimologia , Intoxicação por MPTP/enzimologia , Doenças Mitocondriais/induzido quimicamente , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Gânglios da Base/enzimologia , Gânglios da Base/patologia , Doenças dos Gânglios da Base/induzido quimicamente , Doenças dos Gânglios da Base/enzimologia , Doenças dos Gânglios da Base/patologia , Dopamina/metabolismo , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos , Ácido Láctico/sangue , Doença de Leigh/induzido quimicamente , Doença de Leigh/patologia , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/patologia , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Neostriado/patologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/enzimologia , Degeneração Neural/patologiaRESUMO
The aim of this study was to examine the effects of supplementation with n-3 polyunsaturated fatty acids (PUFAs) on stress responses in mice subjected to an unpredictable chronic mild stress (UCMS) procedure. Stress-induced modifications in coat and aggressiveness were evaluated, and phospholipid PUFA profiles and monoamine levels were analyzed in the frontal cortex, hippocampus, and striatum. The results showed that repeated exposure to mild stressors induced degradation in the physical state of the coat, lowered body weight gain, and increased aggressiveness, without any effect of n-3 PUFA supplementation. The UCMS induced a significant decrease in the levels of norepinephrine in the frontal cortex and striatum, and a nonsignificant decrease in the hippocampus. The tissue levels of serotonin (5-HT) were 40% to 65% decreased in the three brain regions studied. Interestingly, the n-3 PUFA supplementation reversed this stress-induced reduction in 5-HT levels. These findings showed that supplementation in n-3 long-chain PUFAs might reverse certain effects of UCMS in cerebral structures involved in stress-related behaviors.
Assuntos
Monoaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Estresse Psicológico/metabolismo , Animais , Comportamento Animal/fisiologia , Ácidos Graxos Ômega-3/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfolipídeos , Valor Preditivo dos Testes , Tempo de Reação/fisiologia , Estresse Psicológico/dietoterapiaRESUMO
The objective of this study was to measure the steady-state cerebrospinal fluid (CSF) concentration of LY450108 and LY451395 (positive modulators of AMPA receptors) in healthy subjects after the administration of 1 mg and 5 mg. Secondary objectives included the evaluation of safety, pharmacokinetics, and steady-state ratio of plasma:CSF concentrations of LY450108 and LY451395 after multiple dosing. This study was an open-label, multiple oral dose study evaluating 1 mg and 5 mg LY450108 and 1 mg and 5 mg LY451395 in 12 (3 subjects per dosing group) healthy subjects, aged 18 to 49 years. Twelve healthy male subjects completed the study. LY450108 and LY451395 were quantifiable in CSF after 1-mg and 5-mg multiple-dose administrations with plasma:CSF ratio of 82:1 and 44:1, respectively. LY450108 and LY451395 1 mg and 5 mg were measured in the CSF. Single and multiple oral doses of LY450108 and LY451395 were determined to be safe and well tolerated in healthy subjects.
Assuntos
Compostos de Bifenilo/efeitos adversos , Compostos de Bifenilo/farmacocinética , Receptores de AMPA/agonistas , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Adulto , Área Sob a Curva , Compostos de Bifenilo/líquido cefalorraquidiano , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Masculino , Taxa de Depuração Metabólica , Sulfonamidas/líquido cefalorraquidianoRESUMO
Membrane and vesicular monoaminergic transporters, responsible for the homeostasis of neurotransmitter pools at nerve endings, are very involved in the physiology and diseases of central nervous system. Recent progresses of cerebral molecular imaging using SPECT and PET methods allow the extend of in vivo exploration of these transporters. For this aim, an increasing number of radiopharmaceuticals labelled with [123I], [99mTc], [11C] or [18F] have been developed such as cocaine derivatives for the DAT, compounds from the diphenyl sulfide family for the SERT, and dihydrotetrabenazine derivatives for the VMAT2. These functional imaging methods can be very useful in several neurological and psychiatric disorders which involve the monoaminergic neurotransmission systems such as Parkinson's disease, ADHD, depression and autism. For example, the DAT is a specific index of the density of dopaminergic endings which progressively degenerate in Parkinson's disease. In vivo exploration of this transporter can therefore be a relevant way (i) to realize an early detection of the loss of dopaminergic neurons, (ii) to assess the progression of the disease, (iii) to validate and improve the efficacy of new therapeutic strategies such as neuroprotection and neuroreparation. In all, the extend of in vivo exploration of monoamine transporters will allow great progress for (1) knowledge of physiopathological mechanisms of brain disorders, (2) early diagnosis of cerebral dysfunctions, allowing early use of new therapies, (3) selection of homogenous classes of subjects for therapeutic assays, (4) objectiveness of drug-molecular target interaction, (5) follow-up of disease evolution and treatment.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/análise , Desenho de Fármacos , Tomografia por Emissão de Pósitrons , Proteínas da Membrana Plasmática de Transporte de Serotonina/análise , Tomografia Computadorizada de Emissão de Fóton Único , Proteínas Vesiculares de Transporte de Monoamina/análise , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno Autístico/diagnóstico por imagem , Transtorno Autístico/tratamento farmacológico , Depressão/diagnóstico por imagem , Depressão/tratamento farmacológico , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológicoRESUMO
The presence of alpha6 subunit containing nicotinic acetylcholine receptors on nigrostriatal dopaminergic neurons has been demonstrated in rodents and monkeys. [(125)I]alpha-conotoxinMII is a radioligand that binds to alpha6, and also alpha3 subunits of nicotinic acetylcholine receptors (nAChRs). In the present study, we have compared the distribution of [(125)I]alpha-conotoxinMII binding in post mortem human tissue from four groups of patients: individuals with dementia with Lewy bodies displaying extra-pyramidal features (DLB + EPF), DLB without extra-pyramidal features (DLB - EPF) Parkinson's disease without dementia (PD) and age-matched controls. Reduced binding was observed in the putamen and caudate in PD and both DLB groups. In DLB patients, the decline was greater in DLB + EPF compared to DLB - EPF group. The declines in nicotinic receptor binding in the striatum were in part paralleled by reductions in the striatal dopamine transporter. In the thalamus, [(125)I]alpha-conotoxinMII binding was significantly reduced in the centromedian nucleus in both DLB groups, and also in the parafascicular nucleus in the DLB - EPF group. In DLB + EPF and PD patients, there was decreased binding in the ventral lateral nucleus. This study demonstrates alterations of alpha6 and/or alpha3 nAChRs binding in DLB and PD, which are likely to relate to extra-pyramidal symptoms.
Assuntos
Conotoxinas/metabolismo , Doença por Corpos de Lewy/metabolismo , Neostriado/metabolismo , Receptores Nicotínicos/metabolismo , Tálamo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Autorradiografia , Ligação Competitiva , Conotoxinas/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Humanos , Radioisótopos do Iodo , Doença por Corpos de Lewy/patologia , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/análise , Proteínas de Membrana Transportadoras/metabolismo , Neostriado/química , Neostriado/patologia , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Receptores Nicotínicos/análise , Tálamo/química , Tálamo/patologiaRESUMO
Chronic dysregulation of dopamine homeostasis has been shown to induce behavioural impairment in dopamine transporter knockout mutant mice arising from the dysfunction of the mesolimbic and hypothalamo-infundibular system. Here, we assessed whether there are also any motor consequences of a chronic and constitutive hyperdopaminergia in the nigrostriatal system in dopamine transporter knockout mutant mice. For this, we analysed motor performances using tests assessing balance, coordinated motor skills (rotarod, pole test), stride lengths and locomotor activity. Dopamine transporter knockout mutant mice were markedly hyperactive in the open field with central compartment avoidance, as previously shown. However, sensorimotor integration was also found to be altered in dopamine transporter knockout mutant mice which displayed a reduced fore- and hind-limb mean stride length, impaired motor coordination on the pole test and reduced rearings in the open field. Moreover, dopamine transporter knockout mutant mice showed a slower task acquisition on the rotarod. Six-week-old dopamine transporter knockout wild type mice having the same femur size as adult dopamine transporter knockout mutant mice ruled out a possible size-effect bias. Whilst there was no significant difference in the striatal volume, we found a slight but significant reduction in neuronal density in the striatum but not in the nucleus accumbens of dopamine transporter knockout mutant mice. There was a reduced binding in the striatum and nucleus accumbens of dopamine(1) receptors ([(3)H]SCH 23390) and dopamine(2) receptors ([(3)H]YM-09151-2). There was no significant difference in the number of dopaminergic neurons in the substantia nigra between dopamine transporter knockout mutant mice and dopamine transporter knockout wild type mice. These results suggest an impaired functioning of the nigrostriatal system in dopamine transporter knockout mutant hyperdopaminergic mice, as illustrated by motor and sensorimotor integration deficits, despite their apparent hyperactivity. These dysfunctions may arise from combined striatal cell loss and/or functional changes of dopaminergic neurotransmission.
Assuntos
Corpo Estriado/patologia , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras/deficiência , Transtornos das Habilidades Motoras/fisiopatologia , Proteínas do Tecido Nervoso , Substância Negra/patologia , Animais , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Transtornos das Habilidades Motoras/genética , Transtornos das Habilidades Motoras/patologia , Substância Negra/metabolismoRESUMO
More and more reports in recent years have shown that the intake of polyunsaturated fatty acids (PUFA) constitutes an environmental factor able to act on the central nervous system (CNS) function. We recently demonstrated that the effects of PUFA on behavior can be mediated through effects on the monoaminergic neurotransmission processes. Supporting this proposal, we showed that chronic dietary deficiency in alpha-linolenic acid in rats induces abnormalities in several parameters of the mesocortical and mesolimbic dopaminergic systems. In both systems, the pool of dopamine stored in presynaptic vesicles is strongly decreased. This may be due to a decrease in the number of vesicles. In addition, several other factors of dopaminergic neurotransmission are modified according to the system affected. The mesocortical system seems to be hypofunctional overall [e.g., decreased basal release of dopamine (DA) and reduced levels of dopamine D2 (DAD2) receptors]. In contrast, the mesolimbic system seems to be hyperfunctional overall (e.g., increased basal release of DA and increased levels of DAD2 receptors). These neurochemical changes are in agreement with modifications of behavior already described with this deficiency. The precise mechanisms explaining the effects of PUFA on neurotransmission remain to be clarified. For example, modifications of physical properties of the neuronal membrane, effects on proteins (receptors, transporters) enclosed in the membrane, and effects on gene expression and/or transcription might occur. Whatever the mechanism, it is therefore assumed that interactions exist among PUFA, neurotransmission, and behavior. This might be related to clinical findings. Indeed, deficits in the peripheral amounts of PUFA have been described in subjects suffering from neurological and psychiatric disorders. Involvement of the monoaminergic neurotransmission function has been demonstrated or hypothesized in several of these diseases. It can therefore be proposed that functional links exist among PUFA status, neurotransmission processes, and behavioral disorders in humans. Animal models are tools of choice for the understanding of such links. Improved prevention and complementary treatment of neurological and psychiatric diseases can be expected from these studies.
Assuntos
Monoaminas Biogênicas/metabolismo , Encéfalo/fisiologia , Doenças do Sistema Nervoso Central/fisiopatologia , Ácidos Graxos Insaturados/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Doenças do Sistema Nervoso Central/metabolismo , Ácidos Graxos Ômega-3/metabolismo , HumanosRESUMO
123I-Iodolisuride has high specific affinity for binding on dopamine D2 receptors in the striatum and has been used in a few single photon emission computed tomography (SPECT) studies of extrapyramidal disorders. The diagnosis of Parkinson's disease (PD) is very difficult in the first 5 years of evolution, with 15-25% false positive diagnoses. The aim of this study was therefore to determine the value of iodolisuride SPECT in discriminating Parkinson's from the most frequent Parkinson-plus syndromes (PPS). Seventeen patients with an extrapyramidal syndrome had a SPECT examination 1 h after injection of 180-185 MBq of 123I-iodolisuride. They were followed under dopaminergic treatment for at least 2 years. After 2 years, they were separated in two groups according to specific clinical criteria and sensitivity to dopaminergic treatment: nine patients had PD (age = 59.8+/-8.8 years; Hoehn and Yahr = 1.8+/-0.7; evolution = 4.3+/-3 years) and eight had PPS (age = 71.6+/-7.3 years; Hoehn and Yahr = 2.9+/-2.0; evolution = 4.1+/-1.5 years). The binding potential of iodolisuride in the striatum was assessed by considering the striatum (S)/occipital lobe (O) ratio at the pseudo-equilibrium 1 h after injection. The S/O ratio was statistically different between PD and PPS (1.97+/-0.3 vs. 1.65+/-0.2 (P<0.02)). Iodolisuride SPECT could differentiate both groups with a sensitivity of 88.8% and a specificity of 75%. Iodolisuride is a good specific D2 receptor ligand for SPECT and complements specific clinical criteria for the diagnosis of Parkinson's disease and differentiation between different extrapyramidal disorders.
Assuntos
Doenças dos Gânglios da Base/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Radioisótopos do Iodo , Lisurida/análogos & derivados , Doenças Neurodegenerativas/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Receptores de Dopamina D2/análise , Tomografia Computadorizada de Emissão de Fóton Único , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Reações Falso-Positivas , Feminino , Humanos , Radioisótopos do Iodo/farmacocinética , Lisurida/farmacocinética , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico por imagem , Paralisia Supranuclear Progressiva/diagnóstico por imagemRESUMO
The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the mechanisms responsible for the threshold effect might be obtained. The present study was thus designed to determine (1) the relationship between Parkinsonian symptom appearance and level of degeneration of the nigrostriatal pathway and (2) the concomitant presynaptic and postsynaptic striatal response to the denervation, in monkeys treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that produces a progressive Parkinsonian state. The kinetics of the nigrostriatal degeneration described allow the determination of the critical thresholds associated to symptom appearance, these were a loss of 43.2% of tyrosine hydroxylase-immunopositive neurons at the nigral level and losses of 80.3 and 81.6% DA transporter binding and DA content, respectively, at the striatal level. Our data argue against the concept that an increase in DA metabolism could act as an efficient adaptive mechanism early in the disease progress. Surprisingly, the D(2)-like DA receptor binding showed a biphasic regulation in relation to the level of striatal dopaminergic denervation, i.e., an initial decrease in the presymptomatic period was followed by an upregulation of postsynaptic receptors commencing when striatal dopaminergic homeostasis is broken. Further in vivo follow-up of the kinetics of striatal denervation in this, and similar, experimental models is now needed with a view to developing early diagnosis tools and symptomatic therapies that might enhance endogenous compensatory mechanisms.
Assuntos
Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Glicoproteínas de Membrana , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Doença de Parkinson Secundária/fisiopatologia , Substância Negra/fisiopatologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Ácido 3,4-Di-Hidroxifenilacético/análise , Animais , Autorradiografia , Comportamento Animal/efeitos dos fármacos , Ligação Competitiva , Proteínas de Transporte/análise , Proteínas de Transporte/metabolismo , Núcleo Caudado/química , Contagem de Células , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Progressão da Doença , Dopamina/análise , Proteínas da Membrana Plasmática de Transporte de Dopamina , Esquema de Medicação , Feminino , Ácido Homovanílico/análise , Macaca fascicularis , Atividade Motora/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Putamen/química , Receptores de Dopamina D2/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Phospholipid fatty acids are major structural components of neuronal cell membranes, which modulate membrane fluidity and hence function. Evidence from clinical and biochemical sources have indicated changes in the metabolism of fatty acids in several psychiatric disorders. We examined the phospholipid fatty acids in the plasma of a population of autistic subjects compared to mentally retarded controls. Our results showed a marked reduction in the levels of 22: 6n-3 (23%) in the autistic subjects, resulting in significantly lower levels of total (n-3) polyunsaturated fatty acids (PUFA) (20%), without significant reduction in the (n-6) PUFA series, and consequently a significant increase in the (n-6)/(n-3) ratio (25%). These variations are discussed in terms of potential differences in PUFA dietary intake, metabolism, or incorporation into cellular membranes between the two groups of subjects. These results open up interesting perspectives for the investigation of new biological indices in autism. Moreover, this might have new therapeutic implications in terms of child nutrition.
Assuntos
Transtorno Autístico/sangue , Ácidos Graxos/sangue , Adolescente , Adulto , Ácido Araquidônico/sangue , Estatura , Peso Corporal , Criança , Pré-Escolar , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6 , Ácidos Graxos Insaturados/sangue , Feminino , Humanos , Deficiência Intelectual/sangue , Ácido Linoleico/sangue , Masculino , Fosfolipídeos/sangue , Ácido alfa-Linolênico/sangueRESUMO
Previous studies have shown a reduction of dopaminergic D(2) receptors (D(2)R) in the striatum after hypoxia-ischemia in newborn rats. We show here an early and transient reduction of mRNA D(2)R in nonatrophic brains following hypoxia-ischemia. The left carotid artery of P7 rats was ligated followed by hypoxia for 2 h. The rats were sacrificed after 24 h, 48 h and 14 days. D(2)R mRNA was studied by in situ hybridization, the cell number by conventional histology, and neuronal and astrocyte differentiation by immunohistochemistry. A 20% reduction of striatal mRNA D(2)R occurred 24 h after hypoxia-ischemia, whereas no reduction was observed after 48 h and 14 days. There were no differences in total cell number and in the expression of neuronal (MAP-1, MAP-2) and astrocyte (GFAP) markers between both brain hemispheres nor between control and hypoxia-ischemia animals. The early decrease in mRNA D(2)R could explain the delayed reduced D(2)R after neonatal hypoxia-ischemia.
Assuntos
Animais Recém-Nascidos , Expressão Gênica , Hipóxia-Isquemia Encefálica/metabolismo , RNA Mensageiro/análise , Receptores de Dopamina D2/genética , Animais , Astrócitos/química , Astrócitos/patologia , Contagem de Células , Corpo Estriado/química , Corpo Estriado/patologia , Proteína Glial Fibrilar Ácida/análise , Imuno-Histoquímica , Hibridização In Situ , Ratos , Ratos WistarRESUMO
The effects of structural modifications of 2 beta-carbomethoxy-3 beta-phenyl tropane analogues were evaluated on in vitro affinity to the dopamine (DAT) and serotonin (5-HTT) transporters in rat brain tissue. The introduction of a large alkyl group at the 4'-position of the phenyl ring, affording 2 beta-carbomethoxy-3 beta-(4'-alkylphenyl) tropane, diminished the affinity for the DAT whereas moderate 5-HTT affinity was obtained. The introduction of an iodine at the 3'-position of the 4'-alkylphenyl, affording 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-alkylphenyl) tropane, and N-demethylation, affording 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-alkylphenyl) nortropane, improved affinity and specificity for the 5-HTT. It could be assumed from these results that the combination of these three modifications of tropane structure yielded highly selective compounds for the 5-HTT. Of the new compounds synthesized, the most selective cocaine derivative, 2 beta-carbomethoxy-3 beta-(3'-iodo-4'-isopropylphenyl) nortropane (8d) labeled with iodine-123 or carbon-11, could be a potential ligand for exploration of the 5-HT transporter by SPET or PET.
Assuntos
Proteínas de Transporte/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Tropanos/química , Animais , Ligantes , Espectroscopia de Ressonância Magnética , Ratos , Proteínas da Membrana Plasmática de Transporte de Serotonina , Tropanos/síntese química , Tropanos/metabolismoRESUMO
A dopamine transporter-radioligand binding study demonstrated a dopaminergic innervation around the pallidal complex in the normal monkey (n=5), i.e. where a subpopulation of pallidal neurons known as "border cells" is classically identified. Surprisingly, this peripallidal binding persists in monkeys rendered parkinsonian (n=5) with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. The border cell electrophysiological activity was then analysed in normal and parkinsonian monkeys (n=2), either in the untreated state or following administration of levodopa. Pallidal border cell firing frequency was significantly decreased after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (8.9+/-0.7 vs 31.4+/-1.6Hz, P<0.05). This decrease was partly corrected by levodopa administration (19.2+/-1.0Hz, P<0.05 vs both normal and parkinsonian situations). The peripallidal dopaminergic innervation suggests that pallidal border cells are under a direct dopaminergic control, arising from the ventral tegmental area and/or the basal forebrain magnocellular complex, the role of which remains unknown. Moreover, the relative sparing of these dopaminergic fibers in parkinsonian monkeys suggests that they would exhibit specific adaptive properties totally different from those described in the nigrostriatal pathway.