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1.
Mult Scler Relat Disord ; 42: 102163, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32388458

RESUMO

Facing the outbreak of coronavirus disease 2019 (COVID-19) pandemic, there is an urgent need to find protective or curable drugs to prevent or to stop the course of the coronavirus SARS-CoV-2 infection. Recent evidence accumulates that adamantanes, widely used in different neurological diseases, could be repurposed for COVID-19. We hereby report on a questionnaire-based study performed to assess severity of COVID-19 in patients suffering from multiple sclerosis (n=10), Parkinson's disease (n=5) or cognitive impairment (n=7). In all patients infection with SARS-CoV-2 was confirmed by rtPCR of nasopharyngeal swabs. They were receiving treatment with either amantadine (n=15) or memantine (n=7) in stable registered doses. All of them had two-week quarantine since documented exposure and none of them developed clinical manifestations of infectious disease. They also did not report any significant changes in neurological status in the course of primary nervous system disease. Above results warrant further studies on protective effects of adamantanes against COVID-19 manifestation, especially in subjects suffering from neurological disease.


Assuntos
Amantadina/uso terapêutico , Infecções Assintomáticas , Disfunção Cognitiva/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Dopaminérgicos/uso terapêutico , Memantina/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Adamantano/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Disfunção Cognitiva/complicações , Infecções por Coronavirus/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Pandemias , Doença de Parkinson/complicações , Pneumonia Viral/complicações , Fatores de Proteção , Índice de Gravidade de Doença
2.
Nat Commun ; 11(1): 1957, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327644

RESUMO

Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.


Assuntos
Neostriado/citologia , Neurônios/fisiologia , Núcleo Accumbens/citologia , Receptores de Dopamina D2/metabolismo , Anfetamina/farmacologia , Animais , Biomarcadores/metabolismo , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopaminérgicos/farmacologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Neostriado/metabolismo , Neostriado/fisiologia , Vias Neurais , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Receptores de Dopamina D2/genética
4.
Lancet Neurol ; 19(5): 452-461, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171387

RESUMO

Debate is ongoing regarding when, why, and how to initiate pharmacotherapy for Parkinson's disease. Early initiation of dopaminergic therapies does not convey disease-modifying effects but does reduce disability. Concerns about the development of motor complications arising from the early initiation of levodopa, which led to misconceived levodopa-sparing strategies, have been largely mitigated by the outcomes of the PD MED and Levodopa in Early Parkinson's Disease (LEAP) studies. The LEAP study also showed the potential for early improvement in quality of life, even when disability is negligible. Until more effective methods of providing stable dopamine concentrations are developed, current evidence supports the use of levodopa as initial symptomatic treatment in most patients with Parkinson's disease, starting with low doses and titrating to therapeutic threshold. Monoamine oxidase-B inhibitors and dopamine agonists can be reserved as potential adjunct treatments later in the disease course. Future research will need to establish effective disease-modifying treatments, address whether patients' quality of life is substantially improved with early initiation of treatment rather than a wait and watch strategy, and establish whether new levodopa formulations will delay onset of dyskinesia.


Assuntos
Antiparkinsonianos/uso terapêutico , Dopaminérgicos/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Humanos , Qualidade de Vida , Fatores de Tempo , Resultado do Tratamento
5.
Bratisl Lek Listy ; 121(3): 225-229, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115981

RESUMO

AIM: Nicotine at high concentrations induces apoptosis in trophoblastic cells through induction of cell cytotoxicity and Reactive Oxygen Species (ROS). Methamphetamine in low dose has pharmaceutical properties. It seems that this components in low dose can protect the trophoblastic cells from nicotine-induced cell death. METHOD: Trophoblastic (JEG-3) cells grown in DMEM culture medium. MTT assay test detected the cell viability and Lactate Dehydrogenase test measured the cells cytotoxicity. Griess reaction was used for NO production analysis. Cell migration traced by wounding technique. Human Cytokine Array Focused 13-plex was also used for analysis of IL-1α, IL-1ß, IL-6, INFγ, and TNFα pre-inflammatory cytokines. RESULTS: Methamphetamine, in very low dose (pM), increased the cell viability and NO production, and decreased cell cytotoxicity, IL-1α, IL-1ß, IL-6, INFγ, and TNFα pre-inflammatory cytokines of JEG-3 cell which were exposed to high dose of nicotine, respectively. Cell migration was enhanced by low dose of methamphetamine in JEG-3 cells. CONCLUSION: Methamphetamine in very low dose suppressed the JEG-3 cell death induced by high dose of nicotine (Fig. 5, Ref. 48) Keywords: methamphetamine, nicotine, cell death, NO.


Assuntos
Dopaminérgicos , Inflamação , Metanfetamina , Trofoblastos , Linhagem Celular Tumoral , Sobrevivência Celular , Dopaminérgicos/farmacologia , Humanos , Inflamação/tratamento farmacológico , Metanfetamina/farmacologia , Nicotina/toxicidade , Trofoblastos/efeitos dos fármacos
6.
Genes Dev ; 34(1-2): 37-52, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31831628

RESUMO

In animals, the brain regulates feeding behavior in response to local energy demands of peripheral tissues, which secrete orexigenic and anorexigenic hormones. Although skeletal muscle is a key peripheral tissue, it remains unknown whether muscle-secreted hormones regulate feeding. In Drosophila, we found that decapentaplegic (dpp), the homolog of human bone morphogenetic proteins BMP2 and BMP4, is a muscle-secreted factor (a myokine) that is induced by nutrient sensing and that circulates and signals to the brain. Muscle-restricted dpp RNAi promotes foraging and feeding initiation, whereas dpp overexpression reduces it. This regulation of feeding by muscle-derived Dpp stems from modulation of brain tyrosine hydroxylase (TH) expression and dopamine biosynthesis. Consistently, Dpp receptor signaling in dopaminergic neurons regulates TH expression and feeding initiation via the downstream transcriptional repressor Schnurri. Moreover, pharmacologic modulation of TH activity rescues the changes in feeding initiation due to modulation of dpp expression in muscle. These findings indicate that muscle-to-brain endocrine signaling mediated by the myokine Dpp regulates feeding behavior.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/genética , Drosophila/metabolismo , Comportamento Alimentar/fisiologia , Animais , Encéfalo/fisiologia , Proteínas de Ligação a DNA/metabolismo , Dopaminérgicos/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Drosophila/enzimologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Levodopa/farmacologia , Monoiodotirosina/farmacologia , Transdução de Sinais , Fatores de Transcrição/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Regulação para Cima
7.
Am J Cardiol ; 125(1): 127-134, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31699360

RESUMO

Anecdotal cases of reversible methamphetamine-associated cardiomyopathy (rMAC) have been reported, but not well understood. This study sought to determine the clinical characteristics, outcomes and predictors of reversibility among patients with rMAC as compared with patients with persistent MAC (pMAC). We retrospectively studied adult MAC patients with left ventricular ejection fraction (LVEF) ≤40% at a single center between 2004 and 2018. rMAC was defined as increase in LVEF by ≥20 points or to ≥50%. Those with persistent LVEF ≤40% constituted the pMAC group. 357 MAC cases were identified: 250 patients had pMAC and 107 had rMAC. After a median follow-up of 45 months (interquartile range 27 to 70), LVEF increased by 28.3 ± 6.9% in rMAC (p <0.001), whereas it was unchanged in pMAC (Δ: -0.5 ± 8.7%, p = 0.350). Heart failure hospitalizations and New York Heart Association Class III/IV heart failure were both significantly reduced for rMAC than the pMAC group. All-cause mortality was 21.6% overall, 28% in pMAC and 6.5% in the rMAC group (p <0.001). Kaplan-Meier survival curves demonstrated significantly higher cumulative survival for rMAC (Log Rank p <0.001). Multivariable logistic regression identified MA cessation (odds ratio/OR: 4.23, 95% confidence interval/CI: 2.47 to 7.38, p <0.001) and baseline right ventricular end systolic area (OR: 0.92, 95% CI: 0.87 to 0.97, p = 0.001) as strongly predictive of MAC reversal. In conclusion, MAC reversal is not uncommon and is associated with significant clinical improvement including reduced mortality. It can be facilitated by MA cessation when the cardiac chambers, especially the right ventricle, are not severely dilated.


Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico , Cardiomiopatias/induzido quimicamente , Ventrículos do Coração/diagnóstico por imagem , Metanfetamina/efeitos adversos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Transtornos Relacionados ao Uso de Anfetaminas/mortalidade , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , California/epidemiologia , Cardiomiopatias/diagnóstico , Cardiomiopatias/fisiopatologia , Causas de Morte/tendências , Dopaminérgicos/efeitos adversos , Ecocardiografia , Feminino , Seguimentos , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida/tendências
8.
Isr Med Assoc J ; 12(21): 812-816, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31814345

RESUMO

BACKGROUND: The effect of repeated intravenous amantadine (IVAM) in advanced Parkinsonism has not been studied in depth. OBJECTIVES: To report the experience of our medical center with repeated IVAM infusions in patients with advanced Parkinsonism. METHODS: Thirty patients with advanced Parkinsonism of various etiologies were enrolled in an open-label retrospective study. All patients were treated with IVAM infusions in a neurological daycare center. Treatment was initiated with a loading dose of 200/400 mg per day for 5 days followed by a once-daily maintenance dose of 200/400 mg every 1 to 3 weeks. Patients and their caregivers participated in a structured interview and independently completed a clinical global impression of changes scale questionnaire on various motor and non-motor symptoms. RESULTS: Patient mean age was 73.3 ± 9.7 years, average disease duration was 6.2 ± 5.7 years, and mean Hoehn and Yahr score was 3.2 ± 0.84. Mean duration of the IVAM treatment was 15.1 ± 11.6 months. An improvement in general function was reported by 91% of the patients and 89% of the caregivers. Most of the patients reported improvement in tremor and rigidity, as well as in gait stability, freezing of gait, and reduced falls. The treatment was safe with few side effects. CONCLUSIONS: Our data suggest that repeated IVAM infusions could be an effective treatment against various motor symptoms and for improvement of mobility in patients with advanced Parkinsonism. Further randomized clinical trials with a larger sample size using objective measures are warranted to validate our results.


Assuntos
Acidentes por Quedas/prevenção & controle , Amantadina , Destreza Motora/efeitos dos fármacos , Doença de Parkinson , Recuperação de Função Fisiológica/efeitos dos fármacos , Idoso , Amantadina/administração & dosagem , Amantadina/efeitos adversos , Progressão da Doença , Dopaminérgicos/administração & dosagem , Dopaminérgicos/efeitos adversos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Estudos Retrospectivos , Resultado do Tratamento
9.
J Med Case Rep ; 13(1): 389, 2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31874650

RESUMO

BACKGROUND: Atrial myxomas are generally considered benign neoplasms. The majority of tumors are sporadic and less than 10% are associated with an autosomal dominant condition known as the Carney complex, which is most often caused by germline mutation in the gene PRKAR1A. Whether this gene plays a role in the development of sporadic myxomas has been an area of debate, although recent studies have suggested that some fraction of sporadic tumors also carry mutations in PRKARIA. Extra-cardiac complications of atrial myxoma include dissemination of tumor to the brain; however, the dissemination of viable invasive tumor cells is exceedingly rare. CASE PRESENTATION: We present here a 48-year-old white woman who developed multiple intracranial hemorrhagic lesions secondary to tumor embolism that progressed to 'false' aneurysm formation and invasion through the vascular wall into brain parenchyma 7 months after resection of an atrial myxoma. Whole exome sequencing of her tumor revealed multiple mutations in PRKAR1A not found in her germline deoxyribonucleic acid (DNA), suggesting that the myxoma in this patient was sporadic. CONCLUSIONS: Our patient illustrates that mutations in PRKAR1A may be found in sporadic lesions. Whether the presence of this mutation affects the clinical behavior of sporadic tumors and increases risk for metastasis is not clear. Regardless, the protein kinase A pathway which is regulated by PRKAR1A represents a possible target for treatment in patients with metastatic cardiac myxomas harboring mutations in the PRKARIA gene.


Assuntos
Neoplasias Encefálicas/secundário , Complexo de Carney/diagnóstico , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Dopaminérgicos/uso terapêutico , Neoplasias Cardíacas/diagnóstico , Memantina/uso terapêutico , Mixoma/diagnóstico , Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/terapia , Complexo de Carney/genética , Quimiorradioterapia , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Mutação em Linhagem Germinativa , Neoplasias Cardíacas/fisiopatologia , Neoplasias Cardíacas/terapia , Humanos , Hemorragias Intracranianas , Pessoa de Meia-Idade , Mixoma/fisiopatologia , Mixoma/terapia , Resultado do Tratamento , Sequenciamento Completo do Exoma
10.
Pan Afr Med J ; 33: 229, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31692664

RESUMO

Introduction: Currently we have no precise data on the parkinsonian syndromes in Madagascar. This study aims to collect data on these diseases and to describe the frequency and the clinical profile of parkinsonian syndromes in our Department of Neurology. Methods: We conducted a retrospective and descriptive study in the Department of Neurology, in Befelatanana from January 2014 to June 2018. The demographic and clinical data of patients diagnosed as having a parkinsonian syndrome were collected. We assessed data rates and characteristics and then we compared patients with idiopathic Parkinson's disease and patients with other parkinsonian syndromes. Data were processed using R. software. Results: The study included 104 of 3528 patients, seen in our Department. Among the patients with parkinsonian syndrome, 67(64.42%) had idiopathic Parkinson's disease (PD) and 37 (35.47%) another parkinsonian syndrome. The average interval between the onset of the disease and the consultation or the hospitalization in the Department was 2.5 years. For MP, the median age at onset was 58.5 [23; 80] years, the median age at diagnosis was 62 [28; 83] years and the sex ratio were 1.97. The median Hoehn and Yahr score were 2.0. Tremor-dominant Parkinson's disease was found in 24 (35.42%) of cases, a mixed phenotype was found in 28 (41.71%) of cases while akineto-rigid Parkinson's disease was found in 15 (22.38%) of cases. The other parkinsonian syndromes ocuurred in 27 (72.97%) men, with a median age at onset of 57.5 [26; 83] years, a median age at diagnosis of 59.3 [26; 83] years. Etiologies were dominated by Multiple System Atrophy 17/37 (46.64%). Patients with other parkinsonian syndromes had several cognitive disorders (p=0,0306) and MPs were more sensitive to dopamine (p=0.006). Conclusion: The patients with idiopathic parkinsonian syndrome had features different from those of patients with parkinsonism. There was a diagnostic delay as in other developing countries.


Assuntos
Dopamina/administração & dosagem , Doença de Parkinson/epidemiologia , Transtornos Parkinsonianos/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Tardio , Dopamina/farmacologia , Dopaminérgicos/administração & dosagem , Dopaminérgicos/farmacologia , Feminino , Humanos , Madagáscar/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/fisiopatologia , Estudos Retrospectivos , Fatores de Tempo
11.
Medicine (Baltimore) ; 98(46): e17834, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725623

RESUMO

RATIONALE: Spinocerebellar ataxia 2 (SCA2) is a genetic disease, mainly characterized by ataxia. A number of other neurological symptoms also have been described, such as Parkinsonism, cognitive dysfunction, autonomic dysfunction, even the signs of motor neuron disease and so on. Mostly, In the same family, clinical performance is the same in most cases. Here, we describe a father and his son who suffered from SCA2, but their first manifestations were different. PATIENT CONCERNS: The father exhibited progressive bradykinesia and rigidity, which resulted in the dysfunction of walking and caring himself. He hoped to relieve his symptoms by taking medicine. But the son presented with ataxia which was mild that the discomfort did not affect his daily life with none treated. DIAGNOSIS: Both of them were given SCA2 tests. Briefly, we designed primers around the CAG trinucleotide, repeated the spinal cerebellar ataxia subtype gene, performed PCR expansion, and then calculated the specific number of repetitions by capillary electrophoresis. Abnormal expansion was detected in them through SCA2 sequencing with different repeat numbers of CAG, and then they were diagnosed with SCA2 sequencing. INTERVENTIONS: The father was treated with dopaminergic drugs, but the son was not administered treatment. OUTCOMES: The father's symptoms are improved and he can take care of himself. The son has none difficulty in his daily life. LESSONS: It is rare that different individuals in the same family with SCA2 have different manifestations. The genetic testing is a crucial method to diagnose the disease of SCA2.


Assuntos
Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/fisiopatologia , Adulto , Dopaminérgicos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Ataxias Espinocerebelares/tratamento farmacológico
12.
J Pharmacol Sci ; 141(3): 111-118, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31708401

RESUMO

Post-weaning social isolation of laboratory animals is known to induce many behavioural and neurochemical abnormalities, which resemble neuropsychiatric disorders such as depression and anxiety. Therefore, they can help provide a suitable animal model to investigate the pathophysiology of neuropsychiatric symptoms and explore potential drugs for the treatment of neuropsychiatric diseases. Our recent studies have demonstrated that post-weaning social isolation of mice for no less than one week causes behaviour changes such as reduced attention, impaired social affiliation behaviour, and impaired conditional fear memories. Our neuropharmacological analyses have revealed that these behavioural features are modulated by different neuronal mechanisms, suggesting that post-weaning social isolation of mice can help provide an animal model with comorbid symptoms of patients with developmental disorders, including attention-deficit hyperactivity disorder, autism spectrum disorder, and specific learning disability. In this review, we discuss the neuropharmacological features of developmental disorder-like behaviour induced by post-weaning social isolation in mice to offer new insights into the pathophysiology of developmental disorders and possible therapeutic strategies.


Assuntos
Antagonistas Colinérgicos/farmacologia , Dopaminérgicos/farmacologia , Transtornos da Memória/tratamento farmacológico , Transtornos do Neurodesenvolvimento/tratamento farmacológico , Isolamento Social/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Camundongos , Atividade Motora/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/psicologia , Neurogênese/efeitos dos fármacos , Comportamento Social
13.
Mymensingh Med J ; 28(4): 762-766, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31599238

RESUMO

Stroke is one of the leading cause of disability worldwide. Motor function deficits due to stroke contribute to overall low quality of life. The objective was of this study is to observe functional motor outcome after stroke with low dose Levodopa therapy. This prospective follow up study was carried out in the Department of Neurology, Mymensingh Medical College Hospital, Mymensingh, Bangladesh from July 2014 to June 2016 to see the effect of low dose of Levodopa (110mg) on motor outcome after stoke disability. Motor deficit was measured by Medical Research Council (MRC) grading and Rivermead Mobility Index (RMI) score. Two groups were selected by simple random method, consisted of both ischemic and hemorrhagic stroke. All the patients of both the groups were suffering from at least some post stroke motor disability and attended full course of physiotherapy. The group (L) received 110mg Levodopa with physiotherapy. On the other hand (NL) group received only physiotherapy. They were all followed up for four times within two months of time and were assessed for recovery of motor function. Mean age was 59.03±11.56 years in Levodopa (L) group and 57.10±12.41 years in the Non Levodopa (NL) group; Males were predominant in both groups. Ninety three (77.50%) cases had ischemic stroke and 27(22.50%) cases had hemorrhagic stroke. Most common risk factors were hypertension and smoking. No known risk factor was detected in 8 (6.67%) patients. Single or multiple risk factors were confirmed in 112 patients (93.33%). MRC score was significantly higher both in affected upper and lower limb in Levodopa group comparing non Levodopa group at 4th visit. RMI score was also significantly higher in Levodopa group comparing non Levodopa group at 4th visit. The Levodopa (L) group showed better recovery pattern than Non Levodopa (NL) group. It can be concluded that motor recovery was better with administration of a single low dose of Levodopa in combination with physiotherapy. Motor outcome was significantly higher in levodopa group than non-levodopa group.


Assuntos
Pessoas com Deficiência , Dopaminérgicos/uso terapêutico , Levodopa/uso terapêutico , Transtornos Motores/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Bangladesh , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida
14.
Neuron ; 104(1): 113-131, 2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600509

RESUMO

The brain faces various computational tradeoffs, such as the stability-flexibility dilemma. The major ascending neuromodulatory systems are well suited to dynamically regulate these tradeoffs depending on changing task demands. This follows from various general principles of chemical neuromodulation, which are illustrated with evidence from pharmacological neuroimaging studies on striatal dopamine's role in output gating and cost-benefit choice of cognitive tasks. The work raises open questions, including those regarding the top-down cortical control of the midbrain dopamine system, and begins to elucidate the mechanisms underlying the variability in catecholaminergic drug effects. Such drug effects depend on the baseline state of distinct target brain regions, reflecting, in part, the systems' self-regulatory capacity to maintain equilibrium. It is hypothesized that the basal tone of different dopaminergic projection systems reflects the perceived statistics of the environment computed in frontal cortex. By normalizing dopamine levels, dopaminergic drugs might counteract the bias elicited by the perceived environment.


Assuntos
Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Dopaminérgicos/farmacologia , Dopamina/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Homeostase , Humanos , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Neuroimagem
15.
Nat Commun ; 10(1): 4450, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575856

RESUMO

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental psychiatric disorder. Genome-wide association studies (GWAS) have identified several loci associated with ADHD. However, understanding the biological relevance of these genetic loci has proven to be difficult. Here, we conduct an ADHD transcriptome-wide association study (TWAS) consisting of 19,099 cases and 34,194 controls and identify 9 transcriptome-wide significant hits, of which 6 genes were not implicated in the original GWAS. We demonstrate that two of the previous GWAS hits can be largely explained by expression regulation. Probabilistic causal fine-mapping of TWAS signals prioritizes KAT2B with a posterior probability of 0.467 in the dorsolateral prefrontal cortex and TMEM161B with a posterior probability of 0.838 in the amygdala. Furthermore, pathway enrichment identifies dopaminergic and norepinephrine pathways, which are highly relevant for ADHD. Overall, our findings highlight the power of TWAS to identify and prioritize putatively causal genes.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Fenótipo , Transcriptoma , Tonsila do Cerebelo , Dopaminérgicos/isolamento & purificação , Dopaminérgicos/metabolismo , Elongases de Ácidos Graxos/genética , Expressão Gênica , Loci Gênicos , Genômica , Genótipo , Humanos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Norepinefrina/genética , Norepinefrina/isolamento & purificação , Norepinefrina/metabolismo , Polimorfismo de Nucleotídeo Único , Probabilidade , Fatores de Transcrição de p300-CBP/genética
16.
Fish Shellfish Immunol ; 94: 497-509, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541775

RESUMO

As a crucial neuroendocrine-immune factor, dopamine (DA) could regulate the immune system of Litopenaeus vannamei. To understand the immune mechanisms and regulatory pathways of DA in L. vannamei, the transcriptome analysis of hemocytes of L. vannamei with injection of DA (10-6 mol/shrimp) at 3 and 12 h were performed in this study. Moreover, quantitative real-time PCR (qPCR) method was applied to validate the accuracy of transcriptome sequencing and analyze the expression pattern of candidate differentially expressed genes (DEGs) at different time points (0, 3, 6, 12, and 24 h) after DA injection. The results showed that a total of 51382 unigenes with a N50 length of 2341 bp were generated. And 1397 and 457 DEGs were obtained by comparative transcriptome at 3 and 12h respectively. Moreover, the results of functional annotation and enriched pathway showed that the DEGs were involved in phagosome (ko04145), lysosome (ko04142), Endocytosis (ko04144), and NOD-like receptor signaling pathway (ko04621). Besides, the Pearson's correlation coefficient (R) between transcriptome sequencing and qPCR was 0.845, which confirmed the reliability of the transcriptome sequencing results and the accuracy of assembly. Furthermore, the expression pattern of 15 candidate DEGs, containing 9 up-regulated and 6 down-regulated DEGs at 3 h, indicated the regulation of DA in physiological functions especially in the immune system. Therefore, these results revealed that DA induced the expressions of membrane receptors or proteins, activated intracellular signaling pathways, regulated cellular and humoral immune systems, controlled antioxidation and apoptosis, and was involved in the regulation of neuroendocrine system. These findings are helpful to promote the understanding on the effects of biogenic amines on physiological functions and regulatory networks of crustacean, and offer a substantial material and foundation for researching the immune response of crustacean.


Assuntos
Dopaminérgicos/metabolismo , Dopamina/metabolismo , Hemócitos/imunologia , Imunidade Inata/genética , Penaeidae/imunologia , Transcriptoma/efeitos dos fármacos , Animais , Dopamina/administração & dosagem , Dopaminérgicos/administração & dosagem , Perfilação da Expressão Gênica , Imunidade Inata/efeitos dos fármacos , Penaeidae/genética
17.
Anim Reprod Sci ; 208: 106122, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405473

RESUMO

The vitellogenesis-inhibiting hormone (VIH), also known as gonad-inhibiting hormone, is a neuropeptide hormone in crustaceans that belongs to the crustacean hyperglycemic hormone (CHH)-family peptide. There is regulation vitellogenesis by VIH during gonad maturation in crustaceans. A full-length Scylla olivacea VIH (Scyol-VIH) was identified through reverse transcription polymerase chain reaction and rapid amplification of cDNA ends. The open reading frame consists of 378 nucleotides, which encodes a 126-amino acid precursor protein, including a 22-residue signal peptide and a 103-amino acid mature peptide in which 6 highly conserved cysteine residues are present. There was expression of the Scyol-VIH gene in immature female Scylla olivacea in the eyestalk, brain and ventral nerve cord. The Scyol-VIH gene expression was localized to the eyestalk X-organ, brain neuronal clusters 6 and 11, and in multiple neuronal clusters of the ventral nerve cord. The relative abundance of Scyol-VIH mRNA transcript in the eyestalk was relatively greater in immature stage females, then decreased as ovarian maturation progressed. Furthermore, eyestalk Scyol-VIH increased after dopamine (5 µg/g BW) injection. The present research provides fundamental information about Scyol-VIH and its potential effect in controlling reproduction.


Assuntos
Braquiúros/fisiologia , Dopamina/farmacologia , Hormônios de Invertebrado/metabolismo , Ovário/crescimento & desenvolvimento , RNA Mensageiro/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Braquiúros/genética , Clonagem Molecular , Dopamina/administração & dosagem , Dopaminérgicos/farmacologia , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios de Invertebrado/genética , Ovário/metabolismo , Filogenia , RNA Mensageiro/genética , Serotonina/administração & dosagem , Serotonina/farmacologia , Serotoninérgicos/administração & dosagem , Serotoninérgicos/farmacologia , Maturidade Sexual , Espiperona/administração & dosagem , Espiperona/farmacologia , Fatores de Tempo
18.
Int J Dev Neurosci ; 78: 28-32, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31419477

RESUMO

Tyrosine hydroxylase (TH) deficiency is a rare autosomal recessive inborn error of dopamine transmission, which the deficient gene is at the chromosome 11, also called'Segawa Syndrome'. TH converts tyrosine into L-DOPA, which is the direct precursor of catecholamine biosynthesis. TH deficiency causes a neurological disease with primary extrapyramidal signs and a variable response to L-DOPA. We report three patients in China who were diagnosed with Tyrosine hydroxylase (TH) deficiency by genetic testing and clinical manifestations. After L-DOPA treatment, their condition had sustained improvement.


Assuntos
Dopaminérgicos/uso terapêutico , Distúrbios Distônicos/congênito , Levodopa/uso terapêutico , China , Distúrbios Distônicos/tratamento farmacológico , Feminino , Humanos , Lactente , Masculino , Resultado do Tratamento
19.
Eur J Med Chem ; 181: 111572, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31404859

RESUMO

The discovery and development of multitarget-directed ligands (MTDLs) is a promising strategy to find new therapeutic solutions for neurodegenerative diseases (NDs), in particular for Alzheimer's disease (AD). Currently approved drugs for the clinical management of AD are based on a single-target strategy and focus on restoring neurotransmitter homeostasis. Finding disease-modifying therapies AD and other NDs remains an urgent unmet clinical need. The growing consensus that AD is a multifactorial disease, with several interconnected and deregulated pathological pathways, boosted an intensive research in the design of MTDLs. Due to this scientific boom, the knowledge behind the development of MTDLs remains diffuse and lacks balanced guidelines. To rationalize the large amount of data obtained in this field, we herein revise the progress made over the last 5 years on the development of MTDLs inspired by drugs approved for AD. Due to their putative therapeutic benefit in AD, MTDLs based on MAO-B inhibitors will also be discussed in this review.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Técnicas de Química Sintética , Desenho de Fármacos , Descoberta de Drogas , Animais , Técnicas de Química Sintética/métodos , Donepezila/análogos & derivados , Donepezila/síntese química , Donepezila/farmacologia , Dopaminérgicos/síntese química , Dopaminérgicos/química , Dopaminérgicos/farmacologia , Descoberta de Drogas/métodos , Humanos , Indanos/síntese química , Indanos/química , Indanos/farmacologia , Memantina/análogos & derivados , Memantina/síntese química , Memantina/farmacologia , Terapia de Alvo Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Nootrópicos/síntese química , Nootrópicos/química , Nootrópicos/farmacologia , Rivastigmina/análogos & derivados , Rivastigmina/síntese química , Rivastigmina/farmacologia , Tacrina/análogos & derivados , Tacrina/síntese química , Tacrina/farmacologia
20.
Continuum (Minneap Minn) ; 25(4): 919-935, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31356287

RESUMO

PURPOSE OF REVIEW: Patients who have parkinsonian features, especially without tremor, that are not responsive to levodopa, usually have one of these three major neurodegenerative disorders rather than Parkinson disease: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or corticobasal degeneration (CBD). Each of these disorders eventually develops signs and symptoms that distinguish it from idiopathic Parkinson disease, but these may not be present at disease onset. Although these conditions are not generally treatable, it is still important to correctly diagnose the condition as soon as possible. RECENT FINDINGS: In recent years, it has been increasingly recognized that the symptoms of these diseases do not accurately predict the pathology, and the pathology does not accurately predict the clinical syndrome. Despite this, interest has grown in treating these diseases by targeting misfolded tau (in the case of PSP and CBD) and misfolded α-synuclein (in the case of MSA). SUMMARY: Knowledge of the characteristic signs and symptoms of PSP, MSA, and CBD are essential in diagnosing and managing patients who have atypical parkinsonian syndromes.


Assuntos
Doenças dos Gânglios da Base/diagnóstico , Atrofia de Múltiplos Sistemas/diagnóstico , Paralisia Supranuclear Progressiva/diagnóstico , Idoso , Doenças dos Gânglios da Base/tratamento farmacológico , Doenças dos Gânglios da Base/fisiopatologia , Diagnóstico Diferencial , Dopaminérgicos/administração & dosagem , Feminino , Humanos , Levodopa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Atrofia de Múltiplos Sistemas/fisiopatologia , Paralisia Supranuclear Progressiva/tratamento farmacológico , Paralisia Supranuclear Progressiva/fisiopatologia
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