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.

Chronic treatment with carvacrol improves passive avoidance memory in a rat model of Parkinson's disease / O tratamento com carvacrol melhora a memória de esquiva passiva em um modelo da doença de Parkinson em ratos

ABSTRACT The present study investigated the effects of carvacrol on motor and memory deficits as well as hyperalgesia in the 6-OHDA-lesioned rat model of Parkinson's disease. The animals were subjected to unilateral microinjection of 6-OHDA into the medial forebrain bundle and treated with carvacrol (25, 50 and 100 mg/kg, ip) for six weeks after surgery. The 6-OHDA-lesioned rats showed contralateral rotations towards the lesion side, which was accompanied by learning and memory deficits in a passive avoidance test and a decrease in tail withdrawal latency in a tail flick test at the end of week 6. The results also showed that treatment with carvacrol at a dose of 25 mg/kg ameliorated memory deficits, with no effect on rotations and hyperalgesia in lesioned rats. In conclusion, carvacrol improves memory impairments in rats with Parkinson's disease; therefore, it may serve as an adjunct therapy for the alleviation of memory deficits in Parkinson's disease patients.

RESUMO O presente estudo investigou os efeitos do carvacrol nos déficits motores e de memória, bem como na hiperalgesia, em um modelo da doença de Parkinson (DP) em ratos com lesões 6-OHDA. Os animais foram submetidos a microinjeção unilateral de 6-OHDA no feixe mediano do prosencéfalo e tratados com carvacrol (25, 50 e 100 mg / kg, ip) durante 6 semanas após a cirurgia. Os ratos com lesões 6-OHDA mostraram rotações contralaterais para o lado da lesão, que foram acompanhadas de déficits de aprendizagem e de memória em um teste de evitação passiva, e de uma diminuição da latência de retirada da cauda em um teste de cauda no final da semana 6. Os resultados também mostraram que o tratamento crônico com carvacrol a uma dose de 25 mg / kg aliviou os déficits de memória, sem efeito sobre rotações e hiperalgesia em ratos lesados. Em conclusão, o carvacrol melhora a deficiência de memória em ratos com DP e, portanto, pode servir como uma terapia complementar para aliviar os déficits de memória em pacientes com DP.

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.

Ropinirole alters gene expression profiles in SH-SY5Y cells: a whole genome microarray study

Ropinirole (ROP) is a dopamine agonist that has been used as therapy for Parkinson's disease. In the present study, we aimed to detect whether gene expression was modulated by ROP in SH-SY5Y cells. SH-SY5Y cell lines were treated with 10 µM ROP for 2 h, after which total RNA was extracted for whole genome analysis. Gene expression profiling revealed that 113 genes were differentially expressed after ROP treatment compared with control cells. Further pathway analysis revealed modulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway, with prominent upregulation of PIK3C2B. Moreover, batches of regulated genes, including PIK3C2B, were found to be located on chromosome 1. These findings were validated by quantitative RT-PCR and Western blot analysis. Our study, therefore, revealed that ROP altered gene expression in SH-SY5Y cells, and future investigation of PIK3C2B and other loci on chromosome 1 may provide long-term implications for identifying novel target genes of Parkinson's disease.

Between the foreign and the local: French midwifery, traditional practitioners, and vernacular medical knowledge about childbirth in Lima, Peru / Entre o estrangeiro e o local: obstetrizes francesas, médicos tradicionais e conhecimento médico vernáculo sobre partos em Lima, Peru

This article examines the politics of midwifery and the persecution of untitled female assistants in childbirth in early republican Peru. A close reading of late colonial publications and the works of Benita Paulina Cadeau Fessel, a French obstetriz director of a midwifery school in Lima, demonstrates both trans-Atlantic and local influences in the campaign against untitled midwives. Cadeau Fessel's efforts to promote midwifery built upon debates among writers in Peru's enlightened press, who vilified untrained midwives' and wet nurses' vernacular medical knowledge and associated them with Lima's underclass. One cannot understand the transfer of French knowledge about professional midwifery to Peru without reference to the social, political, and cultural context.

Este artigo analisa as políticas de práticas de parteiras profissionais e a condenação de parteiras leigas nos primórdios do Peru republicano. A leitura atenta de publicações de fins do período colonial e dos trabalhos de Benita Paulina Cadeau Fessel, obstetriz francesa diretora de uma escola de parteiras em Lima, revela influência tanto transatlântica como local na campanha contra as parteiras sem titulação. Cadeau Fessel promovia seu ofício com base em debates veiculados na imprensa peruana ilustrada, que aviltavam o conhecimento tradicional de amas de leite e parteiras leigas e as associavam às classes desfavorecidas. Só é possível compreender a transferência do conhecimento francês sobre trabalho de parteiras profissionais para o Peru relacionando-a ao contexto social, político e cultural.

Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

Apomorphine is a dopamine receptor agonist proposed to be a neuroprotective agent in the treatment of patients with Parkinson's disease. Both in vivo and in vitro studies have shown that apomorphine displays both antioxidant and pro-oxidant actions, and might have either neuroprotective or neurotoxic effects on the central nervous system. Some of the neurotoxic effects of apomorphine are mediated by its oxidation derivatives. In the present review, we discuss recent studies from our laboratory in which the molecular, cellular and neurobehavioral effects of apomorphine and its oxidized derivative, 8-oxo-apomorphine-semiquinone (8-OASQ), were evaluated in different experimental models, i.e., in vitro genotoxicity in Salmonella/microsome assay and WP2 Mutoxitest, sensitivity assay in Saccharomyces cerevisiae, neurobehavioral procedures (inhibition avoidance task, open field behavior, and habituation) in rats, stereotyped behavior in mice, and Comet assay and oxidative stress analyses in mouse brain. Our results show that apomorphine and 8-OASQ induce differential mutagenic, neurochemical and neurobehavioral effects. 8-OASQ displays cytotoxic effects and oxidative and frameshift mutagenic activities, while apomorphine shows antimutagenic and antioxidant effects in vitro. 8-OASQ induces a significant increase of DNA damage in mouse brain tissue. Both apomorphine and 8-OASQ impair memory for aversive training in rats, although the two drugs showed a different dose-response pattern. 8-OASQ fails to induce stereotyped behaviors in mice. The implications of these findings are discussed in the light of evidence from studies by other groups. We propose that the neuroprotective and neurotoxic effects of dopamine agonists might be mediated, in part, by their oxidized metabolites.

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.

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.

Current and emerging strategies in the management of Parkinson's disease: a critical reappraisal

The pharmacological treatment of Parkinson's disease [PD] can be subdivided into symptomatic treatment [e.g. levodopa combined with a peripheral decarboxylase inhibitor [PDI], direct-acting dopamine receptor agonists, amantadine, centrally-acting antimuscarinic drugs and catechol-0-methyltransferase [COMT] inhibitors] aimed at restoring striatal dopamine function and reversing functional disability, and neuroprotective treatment [e.g. monoamine oxidase-B [MAO-B] inhibitors] aimed at interfering either with the cause of the disease or pathophysiologic mechanism of substantia nigral cell death. Despite the controversy about the development of long-term side effects levodopa/PDI remains the gold standard for the symptomatic treatment of PD. Direct-acting dopamine receptor agonists are usually recommended as adjuvants to levodopa/PDI. There is no compelling evidence that newer generation dopamine receptor agonists have a greater therapeutic effect than existing ones. Amantadine has limited effectiveness and loss of its beneficial effect after several months seriously limits its usefulness. Centrally-acting antimuscarinic drugs all have low efficacy and high toxicity and should be restricted for young patients with tremor-predominant PD. COMT inhibitors improve the pharmacokinetic properties of levodopa, however data are still lacking about their long-term efficacy and safety. The neuroprotective effect claimed by MAO-B inhibitors can well be offset by the increased mortality reported in patients treated with these drugs. The clinical and pharmacokinetic properties of the current and emerging drugs used in the treatment of PD are reviewed and guidelines are provided for the management of early and advanced PD