RESUMO
We report a 49-year-old patient suffering from spastic paraplegia with a novel heterozygous mutation and analyzed the levels of heat shock proteins (hsp)-27, dopamine (DA), and its metabolites in their cerebrospinal fluid (CSF). The hsp27 protein concentration in the patient's CSF was assayed by an ELISA kit, while DA levels and its metabolites in the CSF, 3,4-dihydroxyphenylacetic acid (DOPAC), Cys-DA, and Cys-DOPA were measured by HPLC. Whole exome sequencing demonstrated SPG-11 c.1951C>T and novel SYNJ1 c.2614G>T mutations, both heterozygous recessive. The patient's DA and DOPAC levels in their CSF were significantly decreased (53.0 ± 6.92 and 473.3 ± 72.19, p < 0.05, respectively) while no differences were found in their Cys-DA. Nonetheless, Cys-DA/DOPAC ratio (0.213 ± 0.024, p < 0.05) and hsp27 levels (1073.0 ± 136.4, p < 0.05) were significantly higher. To the best of our knowledge, the c.2614G>T SYNJ1 mutation has not been previously reported. Our patient does not produce fully functional spatacsin and synaptojanin-1 proteins. In this line, our results showed decreased DA and DOPAC levels in the patient's CSF, indicating loss of DAergic neurons. Many factors have been described as being responsible for the increased cys-DA/DOPAC ratio, such as MAO inhibition and decreased antioxidant activity in DAergic neurons which would increase catecholquinones and consequently cysteinyl-catechols. In conclusion, haploinsufficiency of spatacsin and synaptojanin-1 proteins might be the underlying cause of neurodegeneration produced by protein trafficking defects, DA vesicle trafficking/recycling processes, autophagy dysfunction, and cell death leading to hsp27 upregulation as a cellular mechanism of protection and/or to balance impaired protein trafficking.
Assuntos
Proteínas de Choque Térmico HSP27 , Proteínas de Choque Térmico , Humanos , Pessoa de Meia-Idade , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Dopamina , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico HSP27/genética , Mutação , Paraplegia , Regulação para CimaRESUMO
INTRODUCTION: There is intense interest in identifying cerebrospinal fluid (CSF) biomarkers of Parkinson's disease (PD), both for early diagnosis and to track effects of putative treatments. Nigrostriatal dopamine depletion characterizes PD. Predictably, CSF levels of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, are decreased in PD, even in patients with recent onset of the movement disorder. Whether low CSF DOPAC is associated specifically with parkinsonism has been unclear. In the neuronal cytoplasm dopamine undergoes not only enzymatic oxidation to form DOPAC but also spontaneous oxidation to form 5-S-cysteinyl-dopamine (Cys-DA). Theoretically, oxidative stress or decreased activity of aldehyde dehydrogenase (ALDH) in the residual nigrostriatal dopaminergic neurons would increase CSF Cys-DA levels with respect to DOPAC levels. PD, parkinsonian multiple system atrophy (MSA-P), and pure autonomic failure (PAF) are synucleinopathies; however, PAF does not entail parkinsonism. We examined whether an elevated Cys-DA/DOPAC ratio provides a specific biomarker of parkinsonism in synucleinopathy patients. METHODS: CSF catechols were assayed in PD (n = 24), MSA-P (n = 32), PAF (n = 18), and control subjects (n = 32). RESULTS: Compared to controls, CSF DOPAC was decreased in PD and MSA-P (p < 0.0001 each). In both diseases Cys-DA/DOPAC ratios averaged more than twice control (0.14 ± 0.02 and 0.13 ± 0.02 vs. 0.05 ± 0.01, p < 0.0001 each), whereas in PAF the mean Cys-DA/DOPAC ratio was normal (0.05 ± 0.01). CONCLUSIONS: CSF Cys-DA/DOPAC ratios are substantially increased in PD and MSA-P and are normal in PAF. Thus, in synucleinopathies an elevated CSF Cys-DA/DOPAC ratio seems to provide a specific biomarker of parkinsonism.
Assuntos
Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Dopamina/análogos & derivados , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Idoso , Animais , Catecóis/líquido cefalorraquidiano , Di-Hidroxifenilalanina/farmacologia , Dopamina/líquido cefalorraquidiano , Dopamina/farmacologia , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Células PC12/efeitos dos fármacos , Doença de Parkinson/diagnóstico por imagem , Putamen/diagnóstico por imagem , RatosRESUMO
Postoperative delirium is a common complication that often results in poor outcomes in surgical and elderly patients. Accumulating evidences suggest that the pathophysiology of delirium results from multiple neurotransmitter system dysfunctions. To further clarify the effects of the selective serotonin (5-HT) (1A) antagonist WAY-100635 on the behaviors in scopolamine induced-delirium rats and to explore the molecular mechanism, in this study, we investigated the change of monoamine levels in the cerebrospinal fluid (CSF) and different brain regions using high-performance liquid chromatography and assessed the behavioral retrieval of delirium rats treated with WAY-100635. It was found that 5-hydroxy-3-indoleacetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid concentrations in the CSF of scopolamine-induced delirium rats were significantly increased, among which 5-HIAA was also increased in hippocampus and basolateral amygdala (BLA), and 5-HT(1A) receptor was significantly higher in the hippocampuses and BLA than other brain regions. Furthermore, intrahippocampus and intra-BLA stereotactic injection of WAY-100635 improved the delirium-like behavior of rats. Mechanistically, after WAY-100635 treatment, significant reduction of IL-1ß release into CSF and NOD-like receptor family, pyrin domain containing 3 (NLRP3) expression, phosphorylated phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), and S6K was observed. Altogether, these results suggest that delirium rats induced by scopolamine may be correlated with an increased cerebral concentration of 5-HT and dopamine neurotransmitters system; the selective 5-HT(1A) antagoniszts can reverse the delirium symptoms at some extent through tendering PI3K/Akt/mammalian target of rapamycin complex 1 (mTOR) activation-induced NLRP3 activity and then reducing IL-1ß release.
Assuntos
Delírio do Despertar/prevenção & controle , Interleucina-1beta/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Piperazinas/farmacologia , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Animais , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Delírio do Despertar/líquido cefalorraquidiano , Delírio do Despertar/induzido quimicamente , Delírio do Despertar/fisiopatologia , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Injeções Intraventriculares , Interleucina-1beta/líquido cefalorraquidiano , Interleucina-1beta/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/líquido cefalorraquidiano , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fosfatidilinositol 3-Quinase/líquido cefalorraquidiano , Fosfatidilinositol 3-Quinase/genética , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/líquido cefalorraquidiano , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/genética , Escopolamina , Serotonina/líquido cefalorraquidiano , Transdução de Sinais , Técnicas Estereotáxicas , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/líquido cefalorraquidiano , Serina-Treonina Quinases TOR/genéticaRESUMO
A través del método de equilibrio batch se comparó la adsorción de las catecolaminas Dopamina (DA), Noradrenalina (NA) y Adrenalina (A), y de los metabolitos ácido dihidroxifenilacético (Dopac) y ácido indolacético (5- HIAA) en las fases sólidas octadecil (C18) hidrofóbica, diol (C Diol) hidrofílica y de intercambio catiónico débil (WCX). En la fase sólida WCX a pH 4,0 se observó un 78% de adsorción de catecolaminas y 68% de adsorción de Dopac. Las isotermas de adsorción de las catecolaminas en la fase WCX son de tipo Langmuir. La adrenalina tiene mayor afinidad que la dopamina por la fase WCX a pH 4,0 y la dopamina mayor afinidad que el Dopac y éste es coadsorbido sobre las catecolaminas adsorbidas en la fase WCX. Un ensayo con solventes orgánicos demostró que el tolueno extrajo selectivamente de una mezcla sintética el Dopac y el 5-HIAA coadsorbido, mientras que en una muestra de tejido cerebral de ratas experimentales fueron extraídos el Dopac y el ácido homovanílico (HVA). Estos resultados sirvieron para proponer un paso adicional de extracción con solventes orgánicos para la separación de metabolitos ácidos durante la extracción en fase sólida (EFS) en el análisis de catecolaminas.
The adsorptions of Dopamine (DA), Noradrenaline (NA), and Adrenaline (A) catecholamines were compared by using the batch equilibrium method, as well as those of the dihydroxyphenylacetic acid (Dopac) and indolacetic acid (5-HIAA) metabolites on the hydrophobic octadecyl (C18), hydrophilic diol (C Diol) and weak cation exchange (WCX) solid phases. On the WCX solid phase at pH 4.0, catecholamines adsorption of 78% and Dopac adsorption of 68% were observed. The adsorption isotherms of catecholamines on the for the WCX phase at pH 4.0 than dopamine, dopamine has greater affinity than Dopac, and this latter is coadsorbed over the adsorbed catecholamines on the WCX phase. A trial with organic solvents demonstrated that toluene selectively extracted Dopac and the coadsorbed 5-HIAA from a synthetic mix, while in a brain tissue specimen from experimental rats, Dopac and homovanilic acid (HVA) were extracted. These results served to propose an additional extraction step with organic solvents throughout the separation of acid metabolites during solid phase extraction (EFS) for the analysis of catecholamines.
Assuntos
Animais , Ratos , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Catecolaminas/química , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Dopamina , Epinefrina/química , Norepinefrina , Extração em Fase SólidaRESUMO
Central dopaminergic (DA) systems are affected during human immunodeficiency virus (HIV) infection. So far, it is believed that they degenerate with progression of HIV disease because deterioration of DA systems is evident in advanced stages of infection. In this manuscript we found that (a) DA levels are increased and DA turnover is decreased in CSF of therapy-naïve HIV patients in asymptomatic infection, (b) DA increase does not modulate the availability of DA transporters and D2-receptors, (c) DA correlates inversely with CD4+ numbers in blood. These findings show activation of central DA systems without development of adaptive responses at DA synapses in asymptomatic HIV infection. It is probable that DA deterioration in advanced stages of HIV infection may derive from increased DA availability in early infection, resulting in DA neurotoxicity. Our findings provide a clue to the synergism between DA medication or drugs of abuse and HIV infection to exacerbate and accelerate HIV neuropsychiatric disease, a central issue in the neurobiology of HIV.
Assuntos
Dopamina/metabolismo , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Transmissão Sináptica/fisiologia , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Adulto , Benzamidas , Antígenos CD4/metabolismo , Estudos de Casos e Controles , Quimiocina CCL2/metabolismo , Galactosefosfatos/metabolismo , HIV/genética , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/diagnóstico por imagem , Infecções por HIV/imunologia , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Pirrolidinas , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tropanos , Carga Viral/métodosRESUMO
Both during and after a period of iron deficiency (ID), iron-dependent neural processes are affected, which raises the potential concern that the anemia commonly experienced by many growing infants could have a protracted effect on the developing brain. To further investigate the effects of ID on the immature brain, 49 infant rhesus monkeys were evaluated across the first year of life. The mothers, and subsequently the infants after weaning, were maintained on a standardized diet containing 180 mg/kg of iron and were not provided other iron-rich foods as treats or supplements. As the infants grew, they were all screened with hematological tests, which documented that 16 (33.3%) became markedly ID between 4 and 8 months of age. During this anemic period and subsequently at 1 year of age, cerebrospinal fluid (CSF) specimens were collected to compare monoamine activity in the ID and iron-sufficient infants. Monoamine neurotransmitters and metabolite levels were normal at 4 and 8 months of age, but by 1 year the formerly anemic monkeys had significantly lower dopamine and significantly higher norepinephrine levels. These findings indicate that ID can affect the developmental trajectory of these two important neurotransmitter systems, which are associated with emotionality and behavioral performance, and further that the impact in the young monkey was most evident during the period of recovery.
Assuntos
Anemia Ferropriva/fisiopatologia , Encéfalo/fisiopatologia , Dopamina/líquido cefalorraquidiano , Norepinefrina/líquido cefalorraquidiano , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Fatores Etários , Animais , Emoções/fisiologia , Epinefrina/líquido cefalorraquidiano , Índices de Eritrócitos , Feminino , Hemoglobinometria , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Macaca mulatta , Masculino , Gravidez , Valores de Referência , Serotonina/líquido cefalorraquidiano , Fatores SexuaisRESUMO
Bradykinesia and rigidity are the symptoms that most directly correlate with loss of striatal dopamine in Parkinson's disease. In the hemiparkinsonian (HP) monkey, this is represented by paucity of movement as measured by coli puterized movement analysis, diminished manual dexterity on clinical examination, and diminished performance on operant behavioral tasks. The present study used an MPTP-induced HP model in rhesus monkeys to evaluate the effectiveness of adrenal medullary and peripheral nerve co-grafts in diminishing parkinsonian symptoms. Unoperated controls (N = 4), surgical controls with caudate lesioning (N = 4), and caudate co-grafted (N = 4) HP monkeys demonstrated diminished movement in the home cage following MPTP. This behavior persisted in unoperated controls, but improved in both surgical control and co-grafted monkeys. Functional hand dexterity evaluations demonstrated similar impairment in all three groups but only surgical controls and co-grafted monkeys demonstrated improvement. In general, rotational behavior in response to apomorphine was consistent with recovery of function in surgical controls and co grafted monkeys, but marked between-subject variability precluded group statistical analyses. None of the monkeys could perform the operant task using the affected limb following MPTP. However, the performance of two co-grafted animals demonstrated partial recovery. L-dopa improved operant performance, demonstrating a dopaminergic component to the task. The results demonstrate recovery of behavioral function after surgical treatment, with adrenal co-grafted monkeys showing the greatest degree of improvement.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Medula Suprarrenal/transplante , Comportamento Animal/efeitos dos fármacos , Dopaminérgicos , Doença de Parkinson/cirurgia , Nervo Sural/transplante , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Animais , Condicionamento Operante , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Levodopa/metabolismo , Macaca mulatta , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/metabolismo , Doença de Parkinson Secundária/induzido quimicamente , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The development of a validated primate model of progressive parkinsonism is a critical step in the evaluation of drugs that might halt or slow progression of Parkinson's disease. In this pilot study, we gradually exposed 14 cynomolgus monkeys to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), at a weekly dose of 0.5 mg/kg s.c. for 10 weeks, to determine their probability of not reaching a predetermined endpoint on a disability scale by Kaplan-Meier analysis. Four other MPTP-exposed animals were coadministered the potent free radical scavenger 7-hydroxy-1-[4-(3-methoxyphenyl)-1-piperazinyl]acetylamino-2,2,4,6- tetramethylindan (OPC-14117) as a single oral daily dose of 0.6 g/kg, starting 2 weeks before MPTP initiation. The risk of reaching endpoint by week 10 was 79% and mean time before reaching endpoint was 6 weeks. Global motor activity, recorded in a subset of animals using a portable activity monitor, declined following the first MPTP dose and never recovered. Several cerebrospinal fluid indices of central monoamine metabolism collected by suboccipital puncture at 0, 5, and 10 weeks, including HVA, DOPAC, and tetrahydrobiopterin but not MHPG, were found to be "trait" markers for MPTP exposure, whereas CSF DOPAC and tetrahydrobiopterin constituted potential "state" markers for reaching endpoint. The antioxidant OPC-14117 did not protect against MPTP-induced parkinsonism. Further attempts to validate this incremental model of neurotoxin-induced parkinsonism as a predictor of patient responses to putative neuroprotective agents appear warranted.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Sequestradores de Radicais Livres/farmacologia , Indanos/farmacologia , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/fisiopatologia , Piperazinas/farmacologia , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Animais , Biomarcadores/líquido cefalorraquidiano , Biopterinas/análogos & derivados , Biopterinas/líquido cefalorraquidiano , Modelos Animais de Doenças , Feminino , Sequestradores de Radicais Livres/sangue , Ácido Homovanílico/líquido cefalorraquidiano , Indanos/sangue , Macaca fascicularis , Masculino , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Doença de Parkinson Secundária/líquido cefalorraquidiano , Projetos Piloto , Piperazinas/sangueRESUMO
Children with the opsoclonus-myoclonus syndrome (OMS) usually respond to corticotropin (adrenocorticotrophic hormone, ACTH) treatment but the mechanism of benefit is unknown. We previously showed that both cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) concentrations are low in pediatric OMS. In this study, we measured levels of CSF Dopa, catecholamines, deaminated metabolites of catecholamines, as well as HVA and 5-HIAA in eight patients before and during treatment with ACTH. All the children were ACTH-responsive with 50-70% improvement in multiple clinical features of OMS. ACTH treatment reduced the HVA concentration in every child by a mean of 21% (p < 0.001). Treatment with ACTH was associated with significant correlations between dopaminergic markers such as HVA, dihydroxyphenylacetic acid (DOPAC), and Dopa. There were no significant changes in the CSF concentrations of the noradrenergic markers norepinephrine (NE) and dihydroxyphenylglycol (DHPG), or the serotonergic marker 5-HIAA. The only child with a marked inflammatory pattern in CSF, which was reversed by ACTH, was atypical for a large increase in NE and decrease in 5-HIAA during ACTH treatment. Beneficial effects of ACTH in OMS are not associated with normalization of HVA or 5-HIAA levels. The pattern of decreased HVA and unchanged DOPAC levels could reflect decreased extraneuronal uptake of catecholamines (which steroids inhibit) or decreased 0-methylation of catecholamines in nonneuronal cells.
Assuntos
Hormônio Adrenocorticotrópico/administração & dosagem , Mioclonia/tratamento farmacológico , Neurotransmissores/líquido cefalorraquidiano , Transtornos da Motilidade Ocular/tratamento farmacológico , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Catecolaminas/líquido cefalorraquidiano , Pré-Escolar , Di-Hidroxifenilalanina/líquido cefalorraquidiano , Feminino , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Lactente , Masculino , Mioclonia/líquido cefalorraquidiano , Transtornos da Motilidade Ocular/líquido cefalorraquidiano , Valores de ReferênciaRESUMO
Measurement of monoamine metabolites in cerebrospinal fluid (CSF) has been one of the few methods available to study monoamine transmitter function in the human central nervous system (CNS). It has steadily proved to be of much use in clinical research of neurological and psychiatric diseases, in which altered functions of central monoamine neurotransmitters have been identified. In this work 3-methoxy-4-hydroxyphenylethylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were quantified in normal CSF and in patients with untreated Parkinson's disease (PD) and olivopontocerebellar atrophy (OPCA). Normal CSF was obtained from 162 patients at the time of spinal anesthesia for surgery. Reference values for monoamine metabolites were established for normal adult lumbar CSF. Up to the age of 70 years no relation of monoamine metabolite concentration with age or sex were encountered. In individuals above 70 years of age higher levels of MHPG, HVA, and 5-HIAA were present in women, while in men only higher levels of MHPG could be detected. A strong correlation between 5-HIAA and HVA concentrations were observed in all groups. PD patients exhibited normal CSF metabolite levels, but an altered 5-HIAA/HVA ratio, favoring 5-HIAA. Dominant and recessive OPCA differed essentially in HVA concentration-diminished in the first group and elevated in the last. Comparing the results obtained in PD and dominant OPCA, we suggest that the decrease of CSF HVA in the latter group might not reflect nigrostriatal degeneration as we previously thought. Possibly another factor influencing dopamine function in the CNS is involved.
Assuntos
Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Atrofias Olivopontocerebelares/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Genes Dominantes , Genes Recessivos , Humanos , Masculino , Pessoa de Meia-Idade , Atrofias Olivopontocerebelares/classificação , Atrofias Olivopontocerebelares/genética , Valores de Referência , Fatores SexuaisRESUMO
The effects of icv administration of ß-endorphin on secretory activity of dopaminergic neurons is described. Homovanillic and dihydroxyphenyl acetic acid levels in cerebrospinal fluid and extracts of brain tissue were determined after administration of ß-endorphin to animals pretreated or not with saloxone. The results suggest that ß-endorphin interferes with formation of dopaminergic metabolites by acting on opioid receptors
Assuntos
Ratos , Animais , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , beta-Endorfina/fisiologia , Corpo Estriado/metabolismo , Ácido Homovanílico/líquido cefalorraquidiano , Substância Negra/metabolismo , Dopamina/metabolismo , Naloxona/uso terapêutico , Neurônios/fisiologiaRESUMO
A method for the assay of acidic catecholamine metabolites in biological fluids using capillary gas chromatography--electron-capture negative-ion mass spectrometry is described. The method combines acetylation of phenolic hydroxy groups in buffered aqueous solution followed by pentafluorobenzyl ester formation and acetylation of aliphatic hydroxy groups under anhydrous conditions. The resulting per-O-acetyl carboxypentafluorobenzyl esters provided excellent negative-ion mass spectra with intense and diagnostic anions. The sensitivity of the analysis using electron-capture negative-ion mass spectrometry exceeds that using electron-impact mass spectrometry by two to three orders of magnitude. Analysis of acidic catecholamine metabolites in human lumbar cerebrospinal fluid and plasma were performed with good precision (sigma rel less than 5%) at the low nanomoles per litre level.
Assuntos
Catecolaminas/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/sangue , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Acetilação , Adulto , Catecolaminas/sangue , Catecolaminas/líquido cefalorraquidiano , Cromatografia Gasosa-Espectrometria de Massas , Ácido Homovanílico/sangue , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Temperatura , Ácido Vanilmandélico/sangue , Ácido Vanilmandélico/líquido cefalorraquidianoRESUMO
The authors review the studies of spinal fluid monoamines and their metabolites with and without probenecid and during drug-free and medicated conditions. Although technical knowhow and understanding of the variable that influence the actual levels measured has dramatically increased over the last 20 years, many questions still remain. Despite or rather because of advances such as CT, PET, and MRI, CSF studies still carry great promise for understanding the illness, predicting drug response, and behavioral change following drug withdrawal.
Assuntos
Catecolaminas/metabolismo , Esquizofrenia/líquido cefalorraquidiano , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Antipsicóticos/farmacologia , AMP Cíclico/líquido cefalorraquidiano , Dopamina/metabolismo , Dopamina beta-Hidroxilase/líquido cefalorraquidiano , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Norepinefrina/líquido cefalorraquidiano , Esquizofrenia/metabolismo , Serotonina/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Ácido Vanilmandélico/líquido cefalorraquidianoRESUMO
Three, 4-dihydroxyphenylacetic acid (DOPAC); 3-methoxy, 4-hydroxyphenylacetic acid (HVA); 3-methoxy; 4-hydroxyphenylglycol (MHPG); adenosine 3', 5'-cyclic monophosphate (cyclic AMP); and guanosine 3', 5'-cyclic monophosphate (cyclic GMP) were measured in cerebrospinal fluid (CSF) of patients with dementia of Alzheimer type (DAT) and controls. DOPAC levels were lower and HVA levels were higher in DAT patients than in controls. In the most rostral fractions of CSF from DAT patients there was a negative correlation between DOPAC and cyclic AMP levels. In addition, patients with onset of DAT symptoms before the age of 65 had lower DOPAC levels, a higher HVA/DOPAC ratio, and higher cyclic nucleotide levels than patients with late onset of DAT. By combining DOPAC and cyclic AMP levels, we could clearly distinguish these two groups.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Catecolaminas/líquido cefalorraquidiano , Nucleotídeos Cíclicos/líquido cefalorraquidiano , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Idoso , AMP Cíclico/líquido cefalorraquidiano , GMP Cíclico/líquido cefalorraquidiano , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , Pessoa de Meia-IdadeRESUMO
The neuroleptic malignant syndrome remains an intriguing syndrome, yet its pathogenesis is unknown. Despite numerous analogies with peripheral disorders of aberrant calcium migration in the sacroplasmic reticulum, the probable loci are striatal and hypothalamic (preoptic) dopaminergic pathways. In order to clarify the characteristics of dopamine activity, analysis of the central metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid in one case revealed marked elevations. A possible role for postsynaptic dopamine receptor inhibition is discussed. These findings further suggest that the syndrome may be similar to other extrapyramidal disorders, and they lend credence to observations of its reported drug induction and management.
Assuntos
Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/induzido quimicamente , Dopamina/líquido cefalorraquidiano , Doenças Neuromusculares/líquido cefalorraquidiano , Ácido 3,4-Di-Hidroxifenilacético/líquido cefalorraquidiano , Doenças dos Gânglios da Base/líquido cefalorraquidiano , Feminino , Ácido Homovanílico/líquido cefalorraquidiano , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Pessoa de Meia-IdadeRESUMO
The acid metabolites of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined in lumbar cerebrospinal fluid (CSF) by a new procedure. After gas chromatographic separation, the pentafluoroprionyl 2,2,3,3,3-pentafluoro-1-propionyl esters of DOPAC and HVA were analyzed by electron capture detection. Normal HVA levels were quantitated in as little as 0.1 ml CSF. No significant amounts of DOPAC (less than 1 ng/ml) were found in any of the drug-free samples analyzed. Levels of DOPAC increased only marginally in the CSF of patients receiving acute or chronic doses of L-Dopa. Baseline HVA levels ranged from 4.5--50 ng/ml with a mean value of 23 ng/ml. These studies demonstrate that HVA is the major dopamine metabolite in human CSF.