Effects of carvacrol and physical exercise on motor and memory impairments associated with Parkinson's disease / Efeitos do carvacrol e do exercício físico sobre o comprometimento motor e de memória associados à doença de Parkinson

ABSTRACT The present study was undertaken to investigate the effects of carvacrol and treadmill exercise on memory deficit, rotational behavior and oxidative stress biomarkers in a 6-OHDA-lesioned rat model of Parkinson's disease. Wistar rats were treated with carvacrol at a dose of 25 mg/kg and/or ran on a treadmill for a week. Then, 6-OHDA was microinjected into the medial forebrain bundle and treatments continued for six more weeks. Aversive memory, rotational behavior and oxidative stress biomarkers were assessed at the end of week six. The 6-OHDA-lesioned group showed a significant increase in rotational behavior and a decrease in step-through latency in the passive avoidance test compared with the sham group. These behaviors were accompanied by increased lipid peroxidation levels and decreased total thiol concentration in the striatum and/or hippocampus of the hemiparkinsonian rats. Moreover, treatment with carvacrol and exercise reduced rotational behavior and improved aversive memory deficit, which was accompanied by decreased lipid peroxidation levels and increased total thiol concentration in the striatum and/or hippocampus. In conclusion, treatment with carvacrol and treadmill exercise ameliorated motor and memory deficits by modulating oxidative stress in the striatum and hippocampus of hemiparkinsonian rats. Therefore, the combination of carvacrol and treadmill exercise could be an effective therapeutic tool for treatment of neurobehavioral deficits in Parkinson's disease patients.

RESUMO O presente estudo foi realizado para investigar os efeitos do carvacrol e do exercício em esteira sobre o déficit de memória, comportamento rotacional e biomarcadores de estresse oxidativo em um modelo animal (ratos lesionados por 6-OHDA) da doença de Parkinson (DP). Ratos Wistar foram tratados com carvacrol na dose de 25 mg/kg e/ou correram em uma esteira por uma semana. Depois, 6-OHDA foi microinjetada no feixe do prosencéfalo medial e os tratamentos continuaram por mais seis semanas. A memória aversiva, o comportamento rotacional e biomarcadores de estresse oxidativo foram avaliados no final da semana 6. O grupo 6-OHDA mostrou um aumento significativo no comportamento rotacional e uma diminuição na latência no teste de esquiva passiva em comparação com o grupo "sham". Estes comportamentos foram acompanhados por aumento dos níveis de peroxidação lipídica e diminuição da concentração total de tiol no estriado e/ou hipocampo de ratos hemiparkinsonianos. Além disso, o tratamento com carvacrol e exercício reduziu o comportamento rotacional e melhorou o déficit de memória aversiva, que foi acompanhado pela diminuição dos níveis de peroxidação lipídica e aumento da concentração total de tiol no estriado e/ou hipocampo. Em conclusão, o tratamento com carvacrol e exercícios em esteira melhorou os déficits motor e de memória, modulando o estresse oxidativo no estriado e no hipocampo de ratos hemiparkinsonianos. Portanto, a combinação de carvacrol e exercício em esteira pode ser uma ferramenta terapêutica eficaz para o tratamento de déficits neurocomportamentais em pacientes com DP.

Apomorphine in the treatment of Parkinson's disease: a review / O uso da apomorfina no tratamento da doença de Parkinson: revisão da literatura

ABSTRACT Optimizing idiopathic Parkinson's disease treatment is a challenging, multifaceted and continuous process with direct impact on patients' quality of life. The basic tenet of this task entails tailored therapy, allowing for optimal motor function with the fewest adverse effects. Apomorphine, a dopamine agonist used as rescue therapy for patients with motor fluctuations, with potential positive effects on nonmotor symptoms, is the only antiparkinsonian agent whose capacity to control motor symptoms is comparable to that of levodopa. Subcutaneous administration, either as an intermittent injection or as continuous infusion, appears to be the most effective and tolerable route. This review summarizes the historical background, structure, mechanism of action, indications, contraindications and side effects, compares apomorphine infusion therapy with other treatments, such as oral therapy, deep brain stimulation and continuous enteral infusion of levodopa/carbidopa gel, and gives practical instructions on how to initiate treatment.

RESUMO A optimização do tratamento da doença de Parkinson idiopática se faz um desafio, pois tem impacto direto na qualidade de vida do paciente. O melhor esquema terapêutico é o que permite o melhor controle motor com os menores efeitos adversos, através de terapêutica individualizada. A apomorfina é o único medicamento antiparkinsoniano que pode ser comparável à potência da levodopa no controle dos sintomas motores. Trata-se de um agonista dopaminérgico empregado na terapia de resgate em pacientes com flutuações motoras e também contribui para a melhora de muitos sintomas não motores. A via subcutânea, com injeções intermitentes, ou com infusão contínua, parece ser a melhor opção pela eficácia e tolerabilidade. Essa revisão resume aspectos históricos, estrutura da molécula, mecanismo de ação, indicação, contra-indicação e efeitos colaterais, compara a terapia de infusão com apomorfina com outros tratamentos, como a terapia oral, estimulação cerebral profunda e infusão enteral contínua de levodopa/carbidopa gel, e fornece instruções práticas de como iniciar o tratamento.

Effect of apomorphine on rat motor activity induced by fencamfamine and other indirect psychostimulant drugs

We evaluated the effects of low doses of apomorphine on the stimulant behavioral effects induced by amphetamine (2.5 mg/Kg), fencamfamine (6.0 mg/Kg) and cocaine (15,0 mg/Kg). Rats received 0.02 mg/Kg of apomorphine (sc) and 30 min later were injected with one of the stimulants.Motor activity including locomotion, rearing and sniffing was quantified in the animals home cages for 60 min at 15-min intervals. All stimulant drugs induced hyperactivity. When apomorphine was administered before cocaine, but not when administered before fencmfamine or amphetamine, distinctive changes occurred. The behavioral pattern resulting from high stimulation was replaced by that related to low stimulation, suggesting that apomorphine induces a transfer in the predominant behvior in cocaine-, and partially in fencamfamine-, but not in amphetamine-treated animals, by decreasing the intensity of the stereotyped effect. While no changes occured when apomorphine was administered before amphetamine, the fencamfamine group showed intermediate alterations (nonsignificant changes in sniffing but a significant increase in rearing behavior). These results are discussed in terms of the different mechanisms of presynaptic action of the drugs studied

Apomorfina: uma alternativa no controle das flutuaçöes motoras na doença de Parkinson / Apomorphine: an alternative in the control of motor fluctuations in Parkinson's disease

As flutuaçöes motoras (FM) decorrentes do uso prolongado de levedopa säo uma das principais complicaçöes do tratamento da doença de Parkinson (DP). A utilizaçäo da apomorfina, um potente agonista de receptores dopaminérgicos, associada ao domperidone para bloquear seus efeitos eméticos, surge como uma alternativa para contornar as FM dos parkinsonianos. Para adquirirmos experiência inicial com essa droga, decidimos estudar a açäo e os efeitos adversos da apomorfina em um grupo de quatro pacientes do nosso ambulatório com o diagnóstico de DP e com flutuaçöes do rendimento da levodopa. A apomorfina foi administrada por via subcutânea, sendo obtido o estado "on" em todos os pacientes com doses entre 1,5 e 3mg por aplicaçäo. A latência para o início do efeito variou de 7 a 30 minutos e a duraçäo da açäo de 60 a 85 minutos. O estado "on" produzido com a apomorfina foi indistinguível do observado com a levodopa, inclusive com a ocorrência de discinesias. Näo foram observados efeitos colaterais significativos. Nossa experiência inicial mostra que a apomorfina, em doses relativamente baixa, é uma alternativa eficaz para as FM da DP, com poucos efeitos colaterais

Effect of manipulation of the GABA system on dopamine-related behaviors

The interaction between GABAergic and dopaminergic system within the central nervous system was investigated in rats using the open-field apparatus and apomorphine-induced stereotypy, and in mice using haloperidol-induced catalepsy. The single intraperitoneal adminsitration of baclofen 3.0 mg/kg, 4,5,6,7-tetrahydroisoxasolo-(5,4-c) piridin-3-ol (THIP) 10.0 mg/kg and picrotoxin 2.0 mg/kg decreased both ambulation and rearing frequencies of the rats in the open-field; only the GABA agonists increased the duration of animal immobility. THIP (10.0 mg/kg) increased the duration of haloperidol-induced catalepsy. For apomorphine-induced stereotypy, baclofen 3.0 mg/kg and picrotoxin 1.0 mg/kg induced a significant leftward displacement of the control dose-response curve constructed for apomorphine (0.1-10 mg/kg) in relation to the control. In addition, baclofen, THIP, picrotoxin and 3-mercaptopropionic acid (3-MPA) 10.0 mg/kg decreased both rearing and sniffing behaviors elicited by apomorphine and increased licking and/ or gnawing. Different mechanisms seem to be involved in the similar effects induced by GABA agonists and antagonists. Picrotoxin induced stereotyped movements per se with a dose-dependent effect, but baclofen and THIP did not. The present data suggest that GABA manipulation facilitates the progressive activation of the different dopaminergic pathways involved in stereotyped behaviors, thus increasing those stereotyped components (gnawing and licking) that appear after a high level of activation of dopaminergic pathways

Diferences between the motor effects induce by apomorphone and by amplhetamine in the male albin rat / Diferencias entre los efectos motores inducidos por la apomorfina y la anfetamina en ratones

Although apomorphine and amphetamine act via dopaminergic receptors, their motor effects have some unexplained differences, which have not been sufficiently studied. In this work either drug induced a quite similar pattern of stereotyped behavior which was antagonized by a low dose of haloperidol in both cases. The slight increase in locomotion seen after apomorphine appeared after stereotypies had completely developed and was also blocked by the same dose of haloperidol. In contrast, the amphetamine-induced locomotor stimulation preceded or acompanied the development of stereotypies and it was potentiated by the low dose of haloperidol. We concluded that apomorphine acts mainly at the striatal level to induce both locomotion and stereotyped behavior, whereas amphetamine acts in the striatum to produce stereotypies and in the accumben to increase locomotion.

Tratamiento de las fluctuaciones motoras de la enfermedad de Parkinson con inyecciones subcutaneas de apomorfina / Treatment of motor fluctuations in Parkinson's disease with subcutaneous injections of apomorfine

Dieciseis pacientes con enfermedad de Parkinson y severas fluctuaciones motoras fueron tratados con inyecciones subcutáneas de apomorfina y seguidos prospectivamente durante un año. La utilización de la droga mejoró el número de hroas "off" diarias en un 52 por ciento; la eficacia del tratamiento se mantuvo constante al cabo de un año sin la aparición de tolerancia (ANOVA con mediciones repetidas p=0.0002). No se registraron efectos adversos severos que justificaran la suspensión del tratamiento. La apomorfina demostró ser una droga segura y eficaz en el tratamiento de las fluctuaciones motoras

Effects of single and long-term administration of sulpiride on open-field and stereotyped behavior of rats

1. The effects of single (3.0 to 180.0 mg/Kg) and long-term (up to 90.1 mg/Kg) administration of sulpiride on open-field and apomorphine-induced stereotyped behavior of rats were studied. 2. when animals were studied 30 min after ip sulpiride administration and rearing frequencies in the open-field or apomorphine effects were not modified in a dose-dependent and consistentway by the single sulpiride administration. 3. In relation to control values, a significant decrease im apomorphine-induced stereotyped behavior was observed when rats were injected with a single sulpiride dose 2.5, 5.0, 7.5 and 10.0 h before the dopaminergic agonist. 4. Withdrawal from long-term ip sulpiride administration (up to 90.0 mg/Kg per injection, twice daily for 57 days) induced a significant increase in all parameters of activity recorded in the open-field, and the responsiveness to apomorphine was also augmented in sulpiride-withdrawn rats. 5. These results suggest that sulpiride, a benzamide drug that differs from classic neuroleptic agents by producing fewer extrapyramidal side effects, also supersensitivity of central dopaminergic receptors