Análise dos possíveis efeitos preventivos do canabidiol em um modelo animal de esquizofrenia: a ativação imune pela administração de ácido poliinosínico-policitidílico.
Data
2015-11-30
Autores
Peres, Fernanda Fiel 
Orientadores
Abílio, Vanessa Costhek
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: A esquizofrenia é um transtorno psiquiátrico de alta prevalência cujo tratamento farmacológico está associado a efeitos colaterais importantes e a altas taxas de refratariedade. O desenvolvimento de novas estratégias terapêuticas e preventivas é, portanto, essencial. Recentemente, verificamos que o tratamento com canabidiol dos 30 aos 60 dias pós-natal previne o aparecimento de alterações comportamentais que modelam sintomas positivos e cognitivos da esquizofrenia no modelo da linhagem SHR. Esses dados sugerem a aplicação do canabidiol na prevenção deste transtorno. Objetivo: Padronizar o modelo de esquizofrenia da ativação imune pela administração de ácido poliinosínico-policiticílico (poly I:C) e verificar os efeitos preventivos do tratamento com canabidiol (dos dias 30 aos 60 pós-natal) neste modelo. Métodos: Nos experimentos 1, 2, 3 e 5, o poly I:C foi administrado no período pré-natal ? camundongas da linhagem C57Bl/6J foram tratadas com veículo ou poly I:C durante a gestação. As doses de poly I:C utilizadas, a via de administração e o período de gestação em que a administração aconteceu variaram ao longo dos experimentos: 2,5, 5 ou 10 mg/kg de poly I:C, no dia de gestação (GD) 9 por via intravenosa (experimentos 1 e 5); 20 mg/kg de poly I:C nos GDs 11, 12 e 13 por via intraperitoneal (experimento 2); 10 mg/kg de poly I:C nos GDs 9 e 17 por via intravenosa (experimento 3). No experimento 4, o poly I:C foi administrado em camundongos C57Bl/6J no período neonatal (dias 4-6 pós-natal), na dose de 5 mg/kg, por via intraperitoneal. Nos experimentos 4 e 5, avaliou-se também o efeito preventivo do tratamento com canabidiol (doses de 0,5 ou 1 mg/kg) durante a peri-adolescência (dias 30 aos 60 pós-natal). Em todos os experimentos, ao completarem três meses os animais machos foram submetidos às seguintes avaliações comportamentais: locomoção, interação social, alternação espontânea, reconhecimento de objetos, inibição pré-pulso, medo condicionado ao contexto e sensibilidade a psicoestimulantes. Resultados: O protocolo utilizado no experimento 1 induziu, na prole, hiperlocomoção e déficit de interação social ? alterações comportamentais que modelam, respectivamente, os sintomas positivos e negativos da esquizofrenia. A hiperlocomoção desse modelo é prevenida pelo tratamento com canabidiol (1 mg/kg) dos dias 30 aos 60 pós-natal (experimento 5). Os protocolos utilizados nos experimentos 2, 3 e 4 não induziram alterações comportamentais necessárias para a caracterização de um modelo animal de esquizofrenia. Conclusão: Os resultados indicam que modelo desenvolvido no experimento 1 pode ser utilizado no estudo dos sintomas positivos e negativos da esquizofrenia, e reforçam o potencial preventivo do canabidiol com relação aos sintomas positivos.
Background: Schizophrenia is a highly prevalent psychiatric disorder whose pharmacological treatment is associated with significant side effects and high rates of treatment resistance. Therefore, investigating new therapeutic and preventive strategies for schizophrenia is paramount. Recently, we showed that treatment with cannabidiol from 30 to 60 post-natal days prevents the emergence of behavioral abnormalities that model the positive and cognitive symptoms of schizophrenia in the SHR strain. These data suggest the use of cannabidiol in the prevention of schizophrenia. Aim: To standardize immune activation by the administration of polyinosinic:polycytidylic acid (poly I:C) animal model of schizophrenia and to verify the potential preventive effects of a treatment with cannabidiol (from 30 to 60 post-natal days) in this model. Methods: In experiments 1, 2, 3 and 5, poly I:C was administered in the pre-natal period ¿ female C57Bl/6J mice were injected with vehicle or poly I:C during gestation. The doses of poly I:C, the route and the day of administration varied among the experiments: 2,5, 5 or 10 mg/kg of poly I:C intravenously in gestation day (GD) 9 (experiments 1 and 5); de 20 mg/kg of poly I:C intraperitoneally in GDs 11, 12 and 13 (experiment 2); 10 mg/kg of poly I:C intravenously in GDs 9 and 17 (experiment 3). In experiment 4, poly I:C (5 mg/kg) was administered intraperitoneally in neonatal C57Bl/6J mice (4-6 post-natal days). In experiments 4 and 5, we also evaluated the preventive effects of treatment with cannabidiol (0,5 or 1 mg/kg) during peri-adolescence (30-60 post-natal days). In every experiment, the male mice were subject to the following behavioral assessments at three months of age: locomotion, social interaction, spontaneous alternation, object recognition, pre-pulse inhibition of startle, contextual fear conditioning and sensitivity to psychostimulants. Results: In experiment 1, the offspring of female mice treated with 10 mg/kg of poly I:C displayed hyperlocomotion and diminished social interaction. These behavioral abnormalities model the positive and negative symptoms of schizophrenia, respectively. The hyperlocomotion is prevented by treatment with cannabidiol (1 mg/kg) from 30 to 60 post-natal days (experiment 5). The protocols used in experiments 2, 3 and 4 did not induce any behavioral abnormalities important to the characterization of an animal model of schizophrenia. Conclusion: The animal model developed in experiment 1 may be useful in the study of the positive and negative symptoms of schizophrenia. In addition, the data reinforce the preventive potential of cannabidiol against the positive symptoms of this disorder.
Background: Schizophrenia is a highly prevalent psychiatric disorder whose pharmacological treatment is associated with significant side effects and high rates of treatment resistance. Therefore, investigating new therapeutic and preventive strategies for schizophrenia is paramount. Recently, we showed that treatment with cannabidiol from 30 to 60 post-natal days prevents the emergence of behavioral abnormalities that model the positive and cognitive symptoms of schizophrenia in the SHR strain. These data suggest the use of cannabidiol in the prevention of schizophrenia. Aim: To standardize immune activation by the administration of polyinosinic:polycytidylic acid (poly I:C) animal model of schizophrenia and to verify the potential preventive effects of a treatment with cannabidiol (from 30 to 60 post-natal days) in this model. Methods: In experiments 1, 2, 3 and 5, poly I:C was administered in the pre-natal period ¿ female C57Bl/6J mice were injected with vehicle or poly I:C during gestation. The doses of poly I:C, the route and the day of administration varied among the experiments: 2,5, 5 or 10 mg/kg of poly I:C intravenously in gestation day (GD) 9 (experiments 1 and 5); de 20 mg/kg of poly I:C intraperitoneally in GDs 11, 12 and 13 (experiment 2); 10 mg/kg of poly I:C intravenously in GDs 9 and 17 (experiment 3). In experiment 4, poly I:C (5 mg/kg) was administered intraperitoneally in neonatal C57Bl/6J mice (4-6 post-natal days). In experiments 4 and 5, we also evaluated the preventive effects of treatment with cannabidiol (0,5 or 1 mg/kg) during peri-adolescence (30-60 post-natal days). In every experiment, the male mice were subject to the following behavioral assessments at three months of age: locomotion, social interaction, spontaneous alternation, object recognition, pre-pulse inhibition of startle, contextual fear conditioning and sensitivity to psychostimulants. Results: In experiment 1, the offspring of female mice treated with 10 mg/kg of poly I:C displayed hyperlocomotion and diminished social interaction. These behavioral abnormalities model the positive and negative symptoms of schizophrenia, respectively. The hyperlocomotion is prevented by treatment with cannabidiol (1 mg/kg) from 30 to 60 post-natal days (experiment 5). The protocols used in experiments 2, 3 and 4 did not induce any behavioral abnormalities important to the characterization of an animal model of schizophrenia. Conclusion: The animal model developed in experiment 1 may be useful in the study of the positive and negative symptoms of schizophrenia. In addition, the data reinforce the preventive potential of cannabidiol against the positive symptoms of this disorder.
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Citação
PERES, Fernanda Fiel. Análise dos possíveis efeitos preventivos do canabidiol em um modelo animal de esquizofrenia: a ativação imune pela administração de ácido poliinosínico-policitidílico. 2015. 92 f. Dissertação (Mestrado em Farmacologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2015.