Efeitos neuroprotetores do canabidiol no parkinsonismo induzido pelo tratamento repetido com baixa dose de reserpina em camundongos
Arquivos
Data
2024-05-09
Autores
Lima, Alvaro da Costa 
Orientadores
Silva, Regina Helena da
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A doença de Parkinson (DP) é a segunda doença neurodegenerativa ligada ao envelhecimento mais comum na população. É caracterizada pela sua sintomatologia motora e não motora, como por exemplo, tremores, dificuldade em iniciar movimentos, alteração na locomoção, depressão, ansiedade, déficits cognitivos, entre outros. Como características fisiopatológicas da DP vemos a diminuição gradativa dos neurônios dopaminérgicos da substância negra, além de diminuição nos níveis dopaminérgicos estriatais, bem como o aumento em parâmetros inflamatórios e indicadores de estresse oxidativo nessas regiões. Dessa forma, diversas novas terapias estão sendo desenvolvidas, principalmente com foco em ações antioxidantes e anti-inflamatórias. Uma dessas terapias é o uso da Cannabis, em especial o canabidiol (CBD), um de seus princípios ativos. O CBD não apresenta efeitos psicotrópicos, além de apresentar uma ação abrangente no organismo, agindo por meio de receptores ou por outros mecanismos. Tendo em vista o desenvolvimento lento, progressivo da DP, foi desenvolvido o modelo de administração repetida de uma dose baixa de reserpina (0,1mg/kg), que além de promover aumento progressivo nos déficits motores e não motores também causa aumento em parâmetros inflamatórios e oxidantes. Sendo assim, o objetivo deste trabalho foi verificar o possível efeito protetor do CBD em camundongos submetidos ao protocolo de administração aguda e repetida de reserpina, utilizando duas abordagens: (1) administração concomitante ao desenvolvimento do parkinsonismo e (2) administração prévia visando investigar ação preventiva. O efeito do CBD (em diferentes doses 0,5; 1,0 e 10 mg/kg) foi verificado através dos testes comportamentais de catalepsia, campo aberto e mastigação ao vácuo, e da imuno marcação neuronal de tirosina hidroxilase (TH), enzima limitante da síntese de dopamina. De maneira geral, foi visto que o CBD é capaz de atenuar os efeitos da reserpina nos animais, tanto nos comportamentos de catalepsia quanto na mastigação ao vácuo. O tratamento concomitante com CBD na dose de 0,5 mg/kg promoveu um retardo no surgimento dos comportamentos de catalepsia e atenuação na mastigação ao vácuo. Com o uso preventivo do CBD na dose de 0,5 mg/kg é observado um retardo maior no surgimento do comportamento cataléptico, com atenuação mais eficiente dos movimentos orais. Além disso, o CBD (0,5 mg/kg) apresenta uma prevenção da diminuição da marcação de TH na substância negra pars compacta, tanto no uso concomitante, quanto no uso preventivo. De acordo com os dados aqui apresentados, verificamos um efeito protetor do CBD, principalmente atenuando o surgimento de alterações motoras, como também as atenuando, sendo que esses efeitos foram mais expressivos no tratamento preventivo com CBD. O resultado da análise neuroquímica sugere uma proteção do CBD contra a reserpina, tanto de forma concomitante quanto preventiva.
Parkinson's disease (PD) is the second most common agerelated neurodegenerative disease. It is characterized by both motor and nonmotor symptoms, such as tremors, difficulty in initiating movements, changes in locomotion, depression, anxiety, cognitive deficits, among others. As pathophysiological characteristics of PD, we observe a gradual decrease in dopaminergic neurons in the substantia nigra, as well as a decrease in striatal dopaminergic levels, along with an increase in inflammatory parameters and indicators of oxidative stress in these regions. Several new therapies are being developed with the aim of promoting antioxidant and antiinflammatory actions. One of these therapies is the use of Cannabis, especially cannabidiol (CBD), one of its active compounds. CBD does not have psychotropic effects and acts broadly on the body, either through receptor interactions or by other mechanisms. Given the slow, progressive development of PD, a model of repeated administration of a low dose of reserpine (0.1 mg/kg) was developed. This model not only causes a progressive increase in motor and nonmotor deficits but also leads to an increase in inflammatory and oxidative parameters. Therefore, the objective of this study was to investigate the potential protective effect of CBD in mice subjected to the reserpine repeated administration protocol, using two approaches: (1) concurrent administration during the development of parkinsonism and (2) preadministration to explore preventive action. The effect of CBD (at different doses: 0.5, 1.0, and 10 mg/kg) was assessed through behavioral tests, including catalepsy, open field, and vacuum chewing, as well as the neuronal immunolabeling of tyrosine hydroxylase (TH), the limiting enzyme in dopamine synthesis. Overall, it was observed that CBD can attenuate the effects of reserpine both in cataleptic behaviors and vacuous chewing. Concurrent treatment with CBD at a dose of 0.5 mg/kg delayed the onset of cataleptic behaviors and attenuated vacuous chewing. In the case of preventive use, 0.5 mg/kg CBD exhibited a greater delay in the onset of cataleptic behavior and a more efficient attenuation of oral movements. CBD (0.5 mg/kg) prevented the decrease in TH labeling in the substantia nigra pars compacta in both protocols, concomitant and preventive. Based on the data presented here, we observed a protective effect of CBD, especially in delaying the onset or attenuating motor alterations. These effects were more pronounced in the preventive CBD treatment. The neurochemical results suggest a potential protective role of CBD against reserpineinduced effects, in the concomitant and preventive protocols.
Parkinson's disease (PD) is the second most common agerelated neurodegenerative disease. It is characterized by both motor and nonmotor symptoms, such as tremors, difficulty in initiating movements, changes in locomotion, depression, anxiety, cognitive deficits, among others. As pathophysiological characteristics of PD, we observe a gradual decrease in dopaminergic neurons in the substantia nigra, as well as a decrease in striatal dopaminergic levels, along with an increase in inflammatory parameters and indicators of oxidative stress in these regions. Several new therapies are being developed with the aim of promoting antioxidant and antiinflammatory actions. One of these therapies is the use of Cannabis, especially cannabidiol (CBD), one of its active compounds. CBD does not have psychotropic effects and acts broadly on the body, either through receptor interactions or by other mechanisms. Given the slow, progressive development of PD, a model of repeated administration of a low dose of reserpine (0.1 mg/kg) was developed. This model not only causes a progressive increase in motor and nonmotor deficits but also leads to an increase in inflammatory and oxidative parameters. Therefore, the objective of this study was to investigate the potential protective effect of CBD in mice subjected to the reserpine repeated administration protocol, using two approaches: (1) concurrent administration during the development of parkinsonism and (2) preadministration to explore preventive action. The effect of CBD (at different doses: 0.5, 1.0, and 10 mg/kg) was assessed through behavioral tests, including catalepsy, open field, and vacuum chewing, as well as the neuronal immunolabeling of tyrosine hydroxylase (TH), the limiting enzyme in dopamine synthesis. Overall, it was observed that CBD can attenuate the effects of reserpine both in cataleptic behaviors and vacuous chewing. Concurrent treatment with CBD at a dose of 0.5 mg/kg delayed the onset of cataleptic behaviors and attenuated vacuous chewing. In the case of preventive use, 0.5 mg/kg CBD exhibited a greater delay in the onset of cataleptic behavior and a more efficient attenuation of oral movements. CBD (0.5 mg/kg) prevented the decrease in TH labeling in the substantia nigra pars compacta in both protocols, concomitant and preventive. Based on the data presented here, we observed a protective effect of CBD, especially in delaying the onset or attenuating motor alterations. These effects were more pronounced in the preventive CBD treatment. The neurochemical results suggest a potential protective role of CBD against reserpineinduced effects, in the concomitant and preventive protocols.
Descrição
Citação
LIMA, Alvaro da Costa. Efeitos neuroprotetores do canabidiol no parkinsonismo induzido pelo tratamento repetido com baixa dose de reserpina em camundongos. 2024. 98 f. Tese (Doutorado em Farmacologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo.(UNIFESP). São Paulo, 2024.