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Doctoral Thesis
DOI
https://doi.org/10.11606/T.10.2020.tde-28012021-211715
Document
Author
Full name
Sarah Gomes de Menezes Benevenuto
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2020
Supervisor
Committee
Veras, Mariana Matera (President)
Assís Neto, Antônio Chaves de
Boylan, Fábio de Souza Menezes
Marques, Karina do Valle
Santos, Nathália Villa dos
Title in Portuguese
Efeitos da fumaça da Cannabis sativa e de compostos Canabinóides: uma avaliação in vivo e in vitro
Keywords in Portuguese
Canabinóides
Desenvolvimento cerebral
Função mitocondrial
Gestação
Abstract in Portuguese
Os efeitos do uso materno da maconha sobre o desenvolvimento do sistema nervoso central da prole não são bem esclarecidos. Neste estudo foram investigados os efeitos da inalação materna da fumaça da Cannabis sativa sobre o desenvolvimento cerebral e os efeitos de exo e endocanabinóides e do extrato da fumaça da maconha sobre a função mitocondrial em cultura celular. Camundongas grávidas (n=20) foram expostas diariamente durante 5 minutos à fumaça decorrente da queima de maconha (0,2 g de Cannabis), ou ao ar filtrado, a partir do 5,5° dia gestacional (DG) ao 17,5° DG. No 18,5° DG metade dos fetos foram eutanasiados e a outra metade foi eutanasiada com 20 e 60 dias pós-natal (DPN) para análises estereológicas, imunohistoquímicas e de Western blotting. Cultura de neurônios primários corticais de ratos e células PC12 diferenciadas foram tratados com AEA, THC e CBD para avaliação da viabilidade celular e da função mitocondrial (produção de estresse oxidativo, potencial de membrana e dinâmica mitocondrial). A caracterização de HPAs, da composição elementar e de canabinóides foram realizados no material particulado e na droga, respectivamente. Animais expostos à fumaça da maconha no período gestacional tiveram alteração no volume encefálico, no tálamo, no hipotálamo e cerebelo com 60DPN. Houve alteração do volume do bulbo olfatório e do diencéfalo em fetos. A espessura das camadas corticais foi alterada em animais com 20 e 60DPN. Houve aumento de BDNF no córtex de animais adultos e alteração na expressão das proteínas BDNF (18DPC e 60DPN), CB1 e NeuN (60DPN). Além disso, diferenças específicas ligadas ao sexo foram observadas. Diminuição da viabilidade celular e no potencial de membrana, aumento na produção de EROs e inibição da dinâmica mitocondrial foram observadas nas culturas celulares. Os resultados desse estudo demonstram que a exposição in vivo e in vitro à fumaça da Cannabis causa alterações morfológicas cerebrais em camundongos e na função da mitocondrial neuronal.
Title in English
Effects of Cannabis sativa smoke and cannabinoid compounds: an in vivo and in vitro evaluation
Keywords in English
Brain development
Cannabinoids
Gestation
Mitochondrial function
Abstract in English
The effects of maternal marijuana use on the development of central nervous system in offsprings are not completely understood. In this study, we have investigated the effects of maternal Cannabis smoke inhalation on the brain development and the effects of cannabinoids and Cannabis smoke extracts on in vitro mitochondrial function. Pregnant mice (n = 20) were exposed daily for 5 minutes to marijuana smoke (0.2 g of Cannabis), or filtered air from gestational day (GD) 5.5 to 17.5 GD. On GD 18.5 half of the dams (n=10) were euthanized and the other half (n៞) were euthanized at postnatal day (PND) 20 and 60 for stereological, immunohistochemical, and Western blotting analysis. Neurons culture from rats and differentiated PC12 cells were treated with AEA, THC, and CBD to assess cell viability and mitochondrial function (reactive oxygen species production i.e. ROS), membrane potential, and mitochondrial dynamic). PHAs, elemental composition, and cannabinoids characterization were carried out by using the particulate material and the drug, respectively. The animals exposed to marijuana smoke during gestation presented changes in encephalon total volume, thalamus, hypothalamus, and cerebellum at PND 60. There was an alteration in the volume of the olfactory bulb and the diencephalon in fetuses. The thickness of the cortical layers changed in animals with PND 20 and 60. There was an increase in BDNF in the cortex of adult animals and a change in the expression of BDNF proteins (GD18 and PND60), CB1, and NeuN (PND60). Also, sex- specific differences were found. Cell viability and membrane potential were decreased. On the other hand, increased ROS production was found, and inhibition of mitochondrial dynamics was observed in cell cultures. In summary, this study points out that smoke Cannabis exposure in vivo and in vitro may cause brain damage in mice and in neuronal mitochondrial function.
 
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Publishing Date
2021-03-02
 
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