Clinical and genetic characteristics of children with dopa-responsive dystonia caused by tyrosine hydroxylase gene variations / 中华儿科杂志

Objective: To explore the clinical and genetic characteristics of children with dopa-responsive dystonia (DRD) caused by tyrosine hydroxylase (TH) gene variations. Methods: Clinical data of 9 children with DRD caused by TH gene variations diagnosed in the Department of Children Rehabilitation, the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2022 were retrospectively collected and analyzed, including the general conditions, clinical manifestations, laboratory tests, gene variations and follow-up data. Results: Of the 9 children with DRD caused by TH gene variations, 3 were males and 6 were females. The age at diagnosis was 12.0 (8.0, 15.0) months. The initial symptoms of the 8 severe patients were motor delay or degression. Clinical symptoms of the severe patients included motor delay (8 cases), truncal hypotonia (8 cases), limb muscle hypotonia (7 cases), hypokinesia (6 cases), decreased facial expression (4 cases), tremor (3 cases), limb dystonia (3 cases), diurnal fluctuation (2 cases), ptosis (2 cases), limb muscle hypertonia (1 case) and drooling (1 case). The initial symptom of the very severe patient was motor delay. Clinical symptoms of the very severe patient included motor delay, truncal hypotonia, oculogyric crises, status dystonicus, hypokinesia, decreased facial expression, and decreased sleep. Eleven TH gene variants were found, including 5 missense variants, 3 splice site variants, 2 nonsense variants, and 1 insertion variant, as well as 2 novel variants (c.941C>A (p.T314K), c.316_317insCGT (p.F106delinsSF)). Nine patients were followed up for 40 (29, 43) months, and no one was lost to follow-up. Seven of the 8 severe patients were treated by levodopa and benserazide hydrochloride tablets and 1 severe patient was treated by levodopa tablets. All the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets. Although the weight of the patients increased and the drug dosage was not increased, the curative effect remained stable and there was no obvious adverse reaction. One severe patient developed dyskinesia in the early stage of treatment with levodopa and benserazide hydrochloride tablets and it disappeared after oral administration of benzhexol hydrochloride tablets. Until the last follow-up, motor development of 7 severe patients returned to normal and 1 severe patient still had motor delay due to receiving levodopa and benserazide hydrochloride tablets for only 2 months. The very severe patient was extremely sensitive to levodopa and benserazide hydrochloride tablets and no improvement was observed in this patient. Conclusions: Most of the DRD caused by TH gene variations are severe form. The clinical manifestations are varied and easily misdiagnosed. Patients of the severe patients responded well to levodopa and benserazide hydrochloride tablets or levodopa tablets, and it takes a long time before full effects of treatment become established. Long-term effect is stable without increasing the drug dosage, and no obvious side effect is observed.

Efeito da levodopa na mecânica coclear e no sistema auditivo eferente de indivíduos com doença de Parkinson / Effect of levodopa on cochlear mechanics and efferent auditory system of Parkinson's disease individuals

RESUMO Objetivo Analisar o efeito da levodopa na dinâmica coclear, bem como na via eferente olivococlear medial de indivíduos com doença de Parkinson idiopática (DP). Método Indivíduos com e sem DP, acompanhados em um hospital universitário, realizaram a pesquisa das emissões otoacústicas por produto de distorção (EOAPD) e do efeito inibitório das EOAPD (EIEOA) na presença de ruído contralateral. Foram estabelecidas as medidas de correlação entre os resultados das EOAPD e do EIEOA com estágio Hoehn&Yahr (H&Y), dose diária de levodopa e tempo de diagnóstico da DP. Além disso, as medidas eletroacústicas foram comparadas entre os indivíduos sem DP e com DP, estratificados de acordo com a dose de levodopa administrada diariamente. Resultados Foi identificada correlação fraca e negativa entre a amplitude das EOAPD com a dose diária de levodopa e correlações positivas, de força moderada e fraca, entre o EIEOA com a dose diária de levodopa e o tempo de diagnóstico da DP, respectivamente. A amplitude das EOAPD foi maior nos indivíduos com DP em uso de levodopa ≤ 600 miligramas quando comparada à de indivíduos sem DP e com DP, em uso de dose superior. Já o EIEOA foi menor nos indivíduos em uso de doses ≤ 600 miligramas, quando comparado aos demais grupos. Conclusão Doses diárias de levodopa iguais ou inferiores a 600 mg/dia aumentam as respostas mecanotransdutoras cocleares nas frequências de 2 e 3 kHz, enquanto que a ação dos sistemas eferentes olivococleares é reduzida nesta região.

ABSTRACT Purpose To evaluate the effect of levodopa on cochlear dynamics and on the medial olivocochlear efferent pathway of idiopathic Parkinson's disease (PD) individuals. Methods Individuals with and without PD, followed at a University Hospital, were submitted to Distortion Product Otoacoustic Emissions (DPOAE) and DPOAE Inhibitory Effect (OAEIE) in the presence of contralateral noise. Correlation measures between DPOAE and OAEIE results with Hoehn&Yahr (H&Y) stage, daily dose of levodopa and PD diagnosis period were established. Furthermore, electroacoustic measures were compared between individuals without and those with PD, stratified by dose of levodopa daily administered. Results Weak negative correlation between DPOAE amplitude and daily dose of levodopa was found, as well positive correlations between EIEOA with daily dose of levodopa and time of PD diagnosis, respectively. Higher DPOAE amplitude was found in individuals with PD using daily doses of levodopa ≤ 600 milligrams when compared to individuals without PD and those with PD using higher doses. EIEOA was lower in individuals using doses ≤ 600 milligrams, when compared to the other groups. Conclusion Daily doses of levodopa up to 600 mg / day increase the cochlear mechanical-transducer responses in 2 and 3 kHz frequencies, while the action of olivocochlear efferent systems is reduced in this region.

Impact of levodopa treatment in the voice pattern of Parkinson's disease patients: a systematic review and meta-analysis / O impacto do tratamento com levodopa na voz de pacientes com doença de Parkinson: revisão sistemática e meta-análise

Abstract Purpose Investigate the association between levodopa therapy and vocal characteristics in Parkinson's disease patients. Search strategy Studies published at MEDLINE, LILACS, and SciELO, from 1960 to December 2016. A systematic review and meta-analysis was performed using the following keywords: Parkinson's disease; levodopa; L-dopa; voice; speech disorders; dysphonia; dysarthria. After analyzing titles and abstracts, two independent reviewers selected all clinical trials that met the eligibility criteria and selected the articles and the data recorded in a previously standardized table. Selection criteria Trials published in English between 1960 and December 2016 individuals with clinical diagnosis of Parkinson's disease; use of levodopa therapy in stable doses; acoustic analysis combined or not with auditory-perceptual analysis to evaluate the vocal parameters under investigation. Data analysis The following vocal parameters were analyzed: fundamental frequency (F 0), jitter, and vocal intensity. Standardized mean differences (SMD) were calculated using the Comprehensive Meta-analysis V2 software. Results Nine articles met the eligibility criteria and were selected, with a total of 119 individuals. From these, six articles with 83 individuals were included in the meta-analysis. During the levodopa therapy "on" state, modifications in F 0 (SMD=0.39; 95% CI - 0.21-0.57) and jitter (SMD=0.23; 95% CI - 0.02-0.45) were observed. Vocal intensity was not affected (SMD=0.09; 95% CI - 0.22-0.39) by levodopa ingestion. Data of the included studies were controversial in the auditory-perceptual analysis of voice. Conclusion Levodopa therapy modifies F0 and jitter. No changes in vocal intensity were observed in either the "on" or "off" states of levodopa therapy.

RESUMO Objetivo investigar a associação entre o uso da levodopa e as características vocais em pacientes com doença de Parkinson. Estratégia de pesquisa estudos publicados nas bases MEDLINE, LILACS e SciELO, de 1960 a dezembro de 2016. Uso dos descritores: doença de Parkinson; levodopa; L-dopa; voz; distúrbios do discurso; disfonia e disartria. Depois de analisar os títulos e os resumos, dois revisores independentes selecionaram todos os ensaios clínicos que atendiam aos critérios de seleção, selecionaram os artigos e registraram os dados em uma tabela padronizada anteriormente. Critérios de seleção ensaios publicados em inglês entre 1960 e dezembro de 2016 assuntos com diagnóstico clínico de doença de Parkinson; uso de terapia com levodopa em doses estáveis; análise acústica combinada ou não com a análise auditiva-perceptiva para avaliar os parâmetros vocais sob investigação. Análise dos dados os parâmetros vocais analisados ​​foram: frequência fundamental (F0), Jitter e intensidade vocal. As diferenças de médias padronizadas (SMD) foram calculadas com o software Metanálise Abrangente V2. Resultados 9 artigos preencheram os critérios de elegibilidade e foram selecionados, com um total de 119 indivíduos. Desses 9 artigos, 6, com 83 indivíduos, foram incluídos na metanálise. Durante a fase "on", houve uma modificação no F0 (SMD = 0,39; IC 95% 0,21-0,57) e Jitter (SMD = 0,23; IC 95% 0,02-0,45). A intensidade vocal não foi afetada (SMD = 0,09; IC 95% -0,22-0,39) pela ingestão da levodopa. Ao considerar a análise auditiva-perceptiva, os dados foram controversos entre os estudos incluídos. Conclusão a terapia com levodopa modifica F0 e Jitter. Não houve alteração na intensidade vocal nas fases "on" e "off" da terapia com levodopa.

Effects and molecular mechanism of chitosan-coated levodopa nanoliposomes on behavior of dyskinesia rats

BACKGROUND: Chitosan, the N-deacetylated derivative of chitin, is a cationic polyelectrolyte due to the presence of amino groups, one of the few occurring in nature. The use of chitosan in protein and drug delivery systems is being actively researched and reported in the literature RESULTS: In this study, we used chitosan-coated levodopa liposomes to investigate the behavioral character and the expression of phosphorylated extracellular signal-regulated kinase (ERK1/2), dopamine- and cAMP-regulated phos-phoprotein of 32 kDa (DARPP-32) and FosB/AFosB in striatum of rat model of levodopa-induced dyskinesia (LID). We found that scores of abnormal involuntary movement (AIM) decreased significantly in liposome group (P < 0.05), compared with levodopa group. Levels of phospho-ERK1/2, phospho-Thr34 DARPP-32 and FosB/AFosB in striatum decreased significantly in liposome group lesion side compared with levodopa group (P < 0.05). However, both of two groups above have significantly differences compared with the control group (P < 0.05). CONCLUSION: Chitosan-coated levodopa liposomes may be useful in reducing dyskinesias inducing for Parkinson disease. The mechanism might be involved the pathway of signaling molecular phospho-ERK1/2, phospho-Thr34 DARPP-32 and AFosB in striatum

Análise de parâmetros pneumofuncionais em pacientes com doença de Parkinson: estudo piloto / Analysis of pneumofunctional parameters in patients with Parkinson´s disease: pilot study

A doença de Parkinson (DP) é uma doença crônica e degenerativa do sistema nervoso central (SNC) de causa desconhecida que provoca desordens do movimento. Alterações secundárias são encontradas, entre elas as respiratórias, que compreendem uma das principais causas de morte na DP, por diversas vezes negligenciadas. O objetivo deste estudo foi verificar alterações pneumofuncionais em pacientes com DP e sua relação com medidas de avaliação neurológica. Neste estudo participaram 10 indivíduos com diagnóstico de DP, que foram classificados nos estágios da escala modificada de estadia-mento de Hoehn e Yahr (HY) e avaliados pelo Questionário para Qualidade de Vida na DP (PDQ-39), Escala Unificada para a Avaliação da Doença de Parkinson (UPDRS) e função respiratória. Após obtenção dos dados, realizou-se análise da relação entre as variáveis. A idade dos indivíduos (3 homens e 7 mulheres) variou de 57 a 90 anos, e o tempo de evolução da doença entre 6 meses e 30 anos. Oito faziam uso do medicamento levodopa e não existiu relação deste com as variáveis pneumofuncionais. A maioria dos pacientes apresentou alterações respiratórias, entre elas sinais do desconforto respiratório, diminuição da mobilidade torácica e do pico de fluxo expiratório. Existiu correlação negativa significativa entre as medidas do Peak Flow e HY (r = - 0,842; p = 0,009) e do Peak Flow e PDQ-39 (r = - 0,707; p = 0,05). Nesse sentido, sugerem-se avaliação respiratória e intervenção precoce nos estágios iniciais da DP

Parkinson´s disease (PD) is a chronic and degenerative disease of the central nervous system of unknown origin that causes movement disorders. However, in addition to these, secondary problems are found, such as respiratory changes that include one of the main causes of death in PD, which are often overlooked. The aim of this study was to evaluate pneumofunctional changes in patients with PD and their relationship with measures of neurological evaluation. The study included 10 individuals diagnosed with PD, which were classified in stages of Hoehn and Yahr staging modified scale (HY) and evaluated by the Questionnaire for Quality of Life in PD (PDQ-39), Unified Scale for evaluation of Parkinson?s disease (UPDRS) and respiratory function. After obtaining the data, an analysis of the relationship between the variables was performed. The age of the individuals (3 men and 7 women) ranged from 57 to 90 years, and the progression of the disease between 6 months and 30 years. Eight individuals were using the drug levodopa, and there was no relation with the pneumofunctional variables. Most patients had respiratory disorders as signs of respiratory distress, decreased thoracic mobility and peak expiratory flow. There was a significant negative correlation between the measures of Peak Flow and HY (r = - 0.842; p = 0.009) and Peak Flow and PDQ-39 (r = - 0.707; p = 0.05). Therefore, it is suggested respiratory evaluation and early intervention in the early stages of PD

A Rat Model of Striatonigral Degeneration Generated by Simultaneous Injection of 6-Hydroxydopamine into the Medial Forebrain Bundle and Quinolinic Acid into the Striatum

A double toxin-double lesion strategy is well-known to generate a rat model of striatonigral degeneration (SND) such as multiple system atrophy-parkinsonian type. However, with this model it is difficult to distinguish SND from Parkinson's disease (PD). In this study, we propose a new rat model of SND, which is generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum. Stepping tests performed 30 min after intraperitoneal L-dopa administration at 6 weeks post-surgery revealed an L-dopa response in the PD group but not the SND group. Apomorphine-induced rotation tests revealed no rotational bias in the SND group, which persisted for 2 months, but contralateral rotations in the PD group. MicroPET scans revealed glucose hypometabolism and dopamine transporter impairment on the lesioned striatum in the SND group. Tyrosine hydroxylase immunostaining in the SND group revealed that 74.7% of nigral cells on the lesioned side were lost after lesion surgery. These results suggest that the proposed simultaneous double toxin-double lesion method successfully created a rat model of SND that had behavioral outcomes, multitracer microPET evaluation, and histological aspects consistent with SND pathology. This model will be useful for future study of SND.

THE COPPER INTERFERENCE WITH THE MELANOGENESIS OF Cryptococcus neoformans / A interferência de cobre na melanogênese de Cryptococcus neoformans

Melanin is a pigment produced by laccase, a phenoloxydase enzyme, and is related to the virulence of Cryptococcus neoformans as it is also considered an adaption mechanism to environmental conditions and protection against UV radiation, phagocytic system attack and antifungal drugs. Laccase synthesis is stimulated by several factors, including copper metabolism. The current study shows C. neoformans strains with higher melanization intensity when grown in L-dopa medium supplemented with different concentrations of copper sulfate. This increase shows that melanization rates may be enhanced in the presence of copper ions and may also enhance the virulence of C. neoformans in infected patients that present increasing copper concentrations in serum, such as those with HIV. The virulence of these strains may also be increased in the environment, where this metal is available as CuSO4 in algicidal and fungicidal compounds.

A melanina é um pigmento produzido pela enzima lacase, uma fenoloxidase, e está associada à virulência de Cryptococcus neoformans sendo considerada mecanismo de adaptação às condições ambientais e proteção contra a radiação UV, ataque do sistema fagocítico e antifúngicos. A lacase tem sua síntese estimulada por diversos fatores, incluindo o metabolismo de cobre. Este estudo mostra linhagens de C. neoformans com maior intensidade de melanização quando cultivadas em meio L-dopa suplementado com diferentes concentrações de sulfato de cobre. Este aumento demonstra que as taxas de melanização podem ser aumentadas na presença de íons cobre e também aumentar a virulência de C. neoformans em pacientes infectados que apresentam aumento nas concentrações séricas de íons cobre tais como pacientes com HIV. A virulência destas linhagens também pode ser incrementada no meio ambiente, onde este metal está disponível como CuSO4 em compostos algicidas e fungicidas.

La intoxicación con cobre disminuye la sobrevida e induce alteraciones neurológicas en Drosophila melanogaster / Copper intoxication decreases lifespan and induces neurologic alterations in Drosophila melanogaster

La enfermedad de Wilson, es un trastorno hereditario autosómico recesivo causado por mutaciones del gen de la trifosfatasa de adenosina (ATP7B). Dicha mutación ocasiona intoxicación con cobre, generando manifestaciones clínicas por los efectos tóxicos del metal, principalmente a nivel del hígado y el encéfalo. Recientemente se han desarrollado modelos genéticos de la enfermedad para su estudio clínico. Sin embargo, la utilidad de los mismos es limitada por el hecho de que en tales modelos no se observan manifestaciones neurológicas. El presente estudio tuvo como objetivo desarrollar un modelo de la enfermedad de Wilson en Drosophila melanogaster. Inicialmente se evaluó el efecto de la suplementación con concentraciones de 31 µM y 47 µM de cobre en la sobrevida. Posteriormente se realizaron estudios de conducta para determinar si existían alteraciones en el desempeño motor asociadas al tratamiento con la dosis de 47 µM de cobre. Los resultados obtenidos sugieren que el tratamiento con cobre disminuye la viabilidad de la Drosophila. La disminución de la sobrevida estuvo asociada a un aumento y una disminución de los registros de actividad motora en las etapas tempranas y tardías de la intoxicación respectivamente. Por último, se evaluó el papel del sistema de neurotransmisión dopaminérgico sobre las alteraciones conductuales inducidas por el cobre. El tratamiento con el precursor de la dopamina, L-dopa, indujo un aumento de la actividad motora similar al inducido por el cobre. Por el contrario, el tratamiento con Flufenazina, un antagonista de los receptores dopaminérgicos D2, fue capaz de impedir las alteraciones conductuales en todas las edades evaluadas. Estos resultados sugieren que la Drosophila melanogaster podría ser empleada como modelo para el estudio de posibles intervenciones con potencial terapéutico en la enfermedad de Wilson.

Wilson disease is a hereditary disorder caused by mutations of the ATP7B gene, which leads to intoxication with copper as a result of an unbalance of copper homeostasis. The clinical manifestations resulting from this intoxication are related to the affectation of liver and the encephalon in most cases. Several animal models are currently available for the study of the malady. However, in such models no neurological symptoms are observed, which limits their use for the study of pathogenic effects of this disease on the central nervous system. The aim of the present study was to evaluate if copper feeding could induce a disease state in Drosophila melanogaster to model Wilson disease. The effect of the feeding of copper at the doses of 31 µM and 47 µM on the survival was initially evaluated. Next, behavioral experiments were conducted to determine whether the motor performance was altered by the 47 µM concentration. The results suggest that copper treatment decreases the viability of the flies. In addition, the decrease of viability was associated to an increase and decrease of spontaneous motor activity at early and late stages of the intoxication, respectively. Finally, the role of the dopaminergic neurotransmission system on the observed motor alterations was evaluated. The dopamine precursor L-dopa increased motor activity. In contrast, D2 receptor antagonist, Fluphenazine, was able to block both the increase and decrease of motor activity scores induced by copper. These results suggest that Drosophila melanogaster could be used as a model organism for the study of possible interventions with potential neuroprotective effects in Wilson disease.

Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers

Parkinson's disease (PD) is characterized by selective and progressive degeneration of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNpc) and by abnormal aggregation of alpha-synuclein. Previous studies have suggested that DA can interact with alpha-synuclein, thus modulating the aggregation process of this protein; this interaction may account for the selective vulnerability of DA neurons in patients with PD. However, the relationship between DA and alpha-synuclein, and the role in progressive degeneration of DA neurons remains elusive. We have shown that in the presence of DA, recombinant human alpha-synuclein produces non-fibrillar, SDS-resistant oligomers, while beta-sheet-rich fibril formation is inhibited. Pharmacologic elevation of the cytoplasmic DA level increased the formation of SDS-resistant oligomers in DA-producing neuronal cells. DA promoted alpha-synuclein oligomerization in intracellular vesicles, but not in the cytosol. Furthermore, elevation of DA levels increased secretion of alpha-synuclein oligomers to the extracellular space, but the secretion of monomers was not changed. DA-induced secretion of alpha-synuclein oligomers may contribute to the progressive loss of the dopaminergic neuronal population and the pronounced neuroinflammation observed in the SNpc in patients with PD.

Lack of tolerance for the anti-dyskinetic effects of 7-nitroindazole, a neuronal nitric oxide synthase inhibitor, in rats

7-Nitroindazole (7-NI) inhibits neuronal nitric oxide synthase in vivo and reduces l-DOPA-induced dyskinesias in a rat model of parkinsonism. The aim of the present study was to determine if the anti-dyskinetic effect of 7-NI was subject to tolerance after repeated treatment and if this drug could interfere with the priming effect of l-DOPA. Adult male Wistar rats (200-250 g) with unilateral depletion of dopamine in the substantia nigra compacta were treated with l-DOPA (30 mg/kg) for 34 days. On the 1st day, 6 rats received ip saline and 6 received ip 7-NI (30 mg/kg) before l-DOPA. From the 2nd to the 26th day, all rats received l-DOPA daily and, from the 27th to the 34th day, they also received 7-NI before l-DOPA. Animals were evaluated before the drug and 1 h after l-DOPA using an abnormal involuntary movement scale and a stepping test. All rats had a similar initial motor deficit. 7-NI decreased abnormal involuntary movement induced by l-DOPA and the effect was maintained during the experiment before 7-NI, median (interquartile interval), day 26: 16.75 (15.88-17.00); day 28: 0.00 (0.00-9.63); day 29: 13.75 (2.25-15.50); day 30: 0.5 (0.00-6.25); day 31: 4.00 (0.00-7.13), and day 34: 0.5 (0.00-14.63), Friedman followed by Wilcoxon test,vs day 26, P < 0.05;. The response to l-DOPA alone was not modified by the use of 7-NI before the first administration of the drug (l-DOPA vs time interaction, F1,10 = 1.5, NS). The data suggest that tolerance to the anti-dyskinetic effects of a neuronal nitric oxide synthase inhibitor does not develop over a short-term period of repeated administration. These observations open a possible new therapeutic approach to motor complications of chronic l-DOPA therapy in patients with Parkinson’s disease.

Investigation of central mechanism of insulin induced hypoglycemic convulsions in mice.

Insulin produces seizures in healthy and diabetic animals. Amongst suggested mechanisms, the role of neuromodulators and neurotransmitters is not clear. The present study explores the mechanisms involved in insulin-induced convulsions. Convulsions were induced in Swiss male albino mice with graded doses of insulin. Blood sugar levels were measured prior to and after the first convulsion. Drugs like 5-HTP (5-HT precursor), pCPA (5-HT depletor), ondansetron (5-HT3 antagonist), ketanserin (5-HT, antagonist), ketamine (NMDA antagonist), 1-dopa (dopamine precursor) and reserpine (amine depletor) were studied for interaction with convulsive behaviour induced by insulin. Insulin in 2 IU/kg dose did not produce convulsions while 4 and 8 IU/kg doses produced convulsions in 50% and 100% of animals respectively. 5-HTP, ondansetron, ketanserin, ketamine and l-dopa significantly protected/inhibited animals from convulsions at all studied doses of insulin. On the contrary, pCPA and reserpine potentiated insulin induced convulsions. Insulin caused mortality in 40 and 100% animals with 4 and 8 IU/kg doses respectively. pCPA and reserpine treatments caused mortality at all doses of insulin, while other drugs did not influence insulin induced mortality. Blood sugar levels were reduced in all groups irrespective of the presence or absence of convulsions. A definitive link of serotonergic, dopaminergic and excitatory amino acid pathways in mediating insulin-induced hypoglycemic convulsions is suggested.

Role of adenosine in drug-induced catatonia in mice.

Parkinson's disease is one of the most common neurodegenerative disorders affecting large majority of population who are older than age of 65. Apart from dopamine, acetylcholine and glutamate, adenosinc has also been identified in the basal ganglia. Adenosine modulates the release of a variety of neurotransmitters including dopamine. In order to establish adenosine-dopamine interactions in drug-induced catatonia we studied the effect of adenosine in drug-induced catatonia in mice. In the present study adenosine dose dependently produced catatonia when assessed on rota-rod and bar tests in mice. Adenosine also potentiated the catatonic effect of perphenazine. L-dopa plus carbidopa or OR-486 (a potent centrally acting COMT inhibitor) completely reversed adenosine-induced catatonia. Since reversal by scopolamine of adenosine-induced catatonia was not to the same extent as with l-dopa and OR-486 it appears that catecholamines particularly dopamine rather than cholinergic modulation is more important in adenosine induced catatonia. The motor dysfunction (catatonia) could be easily assessed using rota-rod test apparatus in mice.

Evaluation of clonidine, insulin, L-Dopa, exercise tests on growth hormone in short children

Growth hormone stimulation tests have been used to assess the growth hormone reserve of the pituitary gland in both children and adults. We have assessed the effect of clonidine, insulin, L-Dopa and exercise on growth hormone secretion in 261 short children. The results found in this study revealed that there are no significant differences in these stimulation tests [P=0.28]

Tratamento neuroprotetor da doença de Parkinson / Neuroprotector treatment of Parkinson's disease

A doença de Parkinson foi descrita em 1817 e desde então os conhecimentos sobre sua patologia e formas de tratamento foram crescendo. A levodopaterapia constituiu um avanço significativo no tratamento sintomático desta doença. Os estudos sobre os possíveis mecanismos etiopatogênicos da doença de Parkinson (DP) formaram a base para proposição de um novo tipo de abordagem terapêutica: um tratamento possivelmente curativo ou neuroprotetor. Neste trabalho é feita uma revisão do uso do deprenil e tocoferol (Vit E) nas fases iniciais da DP. Os resultados mostraram que o tocoferol não apresentou efeito terapêutico e que o efeito do deprenil ainda não foi definido se neuroprotetor, sintomático ou ambos

Tratamento crônico com L-Dopa e MK-801: efeitos comportamentais e neuroquímicos em um modelo experimental de parkinsonismo / Chronic treatment with L-Dopa and MK-801: behavioral and neurochemical effects in animal model of parkinsonism

O presente estudo investigou o efeito dos tratamentos crônicos com L-DOPA e MK-801 no desenvolvimento do processo de supersensibilidade dopaminérgica, utilizando um modelo de hemiparkinsonismo. Rotaçoes contralaterais à lesao foram utilizadas como medida comportamental do processo de supersensibilidade. Ratos lesados unilateralmente com 6-OHDA na substância negra foram tratados sistemicamente com L-DOPA/carbidopa e MK-801 durante 13 dias consecutivos, seguidos por um período de retirada de droga de 10 dias. Após esse período, os animais foram testados com salina e no dia seguinte testados com L-DOPA. Resultados mostraram que o tratamento com L-DOPA e o pré-tratamento com MK-801 nao impediram o aparecimento do processo de supersensibilidade, mas retardaram o início do mesmo. Entretanto, uma vez iniciado, o processo se tornou mais acentuado, visto que, após um período de retirada, a administraçao de L-DOPA produziu rotaçoes contralaterais equivalentes àquelas do 13§ dia. O grupo pré-tratado com MK-801, entretanto, apresentou um número de rotaçoes contralaterais semelhante ao apresentado pelo grupo salina. Ensaios bioquímicos utilizando a técnica de cromatografia líquida de alta eficiência (HPLC-EC) indicaram que o tratamento com L-DOPA nao produziu mudanças nos níveis dopaminérgicos estriatais. Entretanto, as razoes dopaminérgicas DOPAC/DA e HVA/DA dos grupos tratados com L-DOPA se encontravam aumentadas. Houve aumento nos níveis dopaminérgicos corticais. Em conclusao, o presente trabalho sugere que a administraçao crônica de L-DOPA nao é suficiente para impedir o desenvolvimento do processo de supersensibilidade, porém retarda o aparecimento deste. O pré-tratamento com MK-801, além de retardo, produz também a atenuaçao do processo.

Flujo sanguíneo cerebral regional mediante Spect con [99m-Tc]-HM-PAO en pacientes con enfermedad de Parkinson / Regional cerebral blood flow by Spect whit [99m-Tc]-HM-PAO in patients whit Parkinson disease

Se correlacionó el flujo cerebral regional (FSCr) mediante SPECT con [99m-Tc]-HM-PAO con las características clínicas más importantes en 25 pacientes con enfermedad de Parkinson idiopática (EP) y se comparó con un grupo control de 9 individuos sanos apareados en edad. Se calcularon índices de actividad relativa en 11 pares de regiones de interés (ROIs) corticales y subcorticales. Además, se determinó un índice de asimetría izquierdo-derecha para cada par de ROIs. Aunque se observaron asimetrías y déficits de la perfusión estriatal en varios pacientes, los valores medios no fueron diferentes a los del grupo control. No se encontró una relación entre el FSCr y los siguientes parámetros clínicos: lateralidad, signo predominante, tiempo de evolución y estadío de la enfermedad. Sólo se observaron diferencias estadísticamente significativas en las regiones temporales de ambos hemisferios cerebrales (p < 0,05) y asociada al deterioro cognitivo global. En 7 casos con demencia asociada (DSM-III-R) se observó una disminución bilateral significativa del FSCr de las ROIs temporales (p < 0,01 - lado izquierdo, p < 0,05 - lado derecho), frontales (p < 0,05) y parietal posterior (p < 0,05). Estos resultados sugieren que la perfusión a nivel temporal está asociada a la función cognitiva global y que la técnica de SPECT con [99m-TE]-HM-PAO es especialmente útil para apoyar, junto a criterios clínicos y neuropsicológicos, la presencia de un síndrome demencial en pacientes con EP

Motor activation time in Parkinson 's disease

Se estudió el tiempo de activación motora (TAM), considerando para el presente trabajo como el intervalo de procesamiento intracerebral durante una prueba de Tiempo de Reacción (TR), en 17 pacientes con enfermedad de Parkinson y en 7 voluntarios sanos. El TAM fue calculado substrayendo al TR premotor los tiempos de conducción aferente y eferente obtenidos por medio de potenciales evocados somatosensitivos y motores. Comparados con los voluntarios sanos los pacientes con enfermedad de Parkinson presentaron valores de TAM significativamente prolongados (p < 0,02). En un grupo menor de 9 pacientes se estudiaron el TAM y el potencial cognitivo P300 mientras se encontraban bajo tratamiento antiparkinsoniano y también luego de un período de 12 horas de supresión medicamentosa. Durante el período de supresión los pacientes exhibieron un importante incremento en el TAM (P < 0,01) sin cambios significativos en la latencia o amplitud del potencial P300. Estos resultados sugieren que el enlentecimiento del TAM corresponde a un funcionamiento anormal de los circuitos dopaminérgicos involucrados en la iniciación del movimiento y no esté relacionado a cambios en la reactividad o en el estado cognitivo

The beta-2 receptor plays a role in the hypotensive effect of L-Dopa

La levodopa ejerce efectos cardiovasculares tanto por conversasión a dopamina como por mecanismos no bien dilucidados. Los receptores beta adrenérgicos intervienen en los efectos de levodopa sobre el Sistema Nervioso Central. La participación de los receptores ß adrenérgicos en el efecto hipotensor periférico de la levodopa motiva el presente trabajo. En ratas anestesiadas (uretano 1 ml/100 i.p. y heparinizadas 300 U.I./Kgi.i.v.) se registró en un polígrafo la frecuencia cardíaca y la presión arterial media intracarotídea, una cánula traqueal facilitó la ventilación pulmonar. Los fármacos se inyectaron mediante un catéter de polietileno en la vena femoral. Grupos Experimentales: Grupo Control: a) Se estudió el efecto de Dopamina (3, 12 a 25µg/100gi.v.) y levodopa (12.5 a 100gi.v.) sobre presión arterial y frecuencia cardíaca. Pretratados con Beta bloqueadores: b) Se estudió la influencia de propranolol (50µg/100g), atenolol (100µg/100g) e ICI118.55(25µg/100g) inyectados 20 min antes sobre el efecto hipotensor de la dopamina y levodopa. La dopamina produjo hipotensión arterial dosis-dependiente (p<0.02) que no se modificó por propranolol, atenolol o ICI118.55. El tratamiento con atenolol no modificó la respuesta hipotensora de levodopa. El propranolol e ICI118.55 aumentaron la presión arterial. Propranolol e ICI118.55 comparten la propiedad de bloquear el receptor ß2. Se sugiere que ese receptor juega un rol fundamental en la hipotensión producida por levodopa

Parkinsonismo: aspéctos clínicos, biológicos e terapêuticos / Parkinsonism: clinical, biological and therapeutical aspects

O parkinsonismo idiopático (doença de Parkinson) e secundário, ou seja, que apresenta etiologia conhecida (pós-encefalítico, por toxinas, por drogas ou por algumas doenças degenerativas) såo processos neurodegenerativos que afetam progressivamente as funçÆes motoras normais do indivíduo. Neste trabalho, os aspéctos clínicos, etiológicos, fisiopatológicos e principalmente a descriçåo do arsenal farmacológico e as medidas utilizadas no combate ou retardo medicamentoso do parkinsonismo såo abordados e discutidos