Efeitos da exposição ao β-Cariofileno na próstata ventral de gerbilos adultos após a suplementação pela Testosterona
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Data
2021-08-30
Autores
Castro, Nayara Fernanda da Costa
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A glândula prostática é muito suscetível às alterações nos níveis dos andrógenos, que podem desempenhar um importante papel no desenvolvimento da hiperplasia prostática benigna (HPB). O uso de compostos naturais no tratamento da HPB vem crescendo e tem demonstrado efeitos benéficos à próstata. O β-Cariofileno (BCP) é um composto fitocanabinoide que está presente em diferentes espécies de plantas e possui efeitos anti-inflamatório, apoptótico, antiangiogênico e pode estar relacionado com a inibição da proliferação de uma variedade de células tumorais, inclusive da próstata. Porém, esses estudos, até o momento, se restringiam aos efeitos do BCP em células em cultura, sendo necessário o conhecimento desses efeitos em modelos animais. Dessa forma, o presente trabalho avaliou as alterações provocadas pela testosterona na próstata ventral e analisou os efeitos do BCP na HPB induzida pela testosterona na próstata ventral de gerbilos adultos. Para tal foram utilizados gerbilos machos adultos submetidos a diferentes condições experimentais: injeções subcutâneas de testosterona (3 mg/kg), em dias alternados, durante 4 semanas e eutanasiados, imediatamente (grupo 1) e 30 dias (grupo 2) após o término do experimento; administração diária de BCP (50 mg/kg/dia), via gavagem, por 4 semanas, em gerbilos intactos (grupo 3) e que receberam a suplementação pela testosterona por 30 dias (grupo 4), além dos animais pertencentes ao grupo controle (grupo 5), que não receberam nenhum tratamento ou suplementação. Foram realizadas análises morfológicas, morfométricas, estereológicas, imunohistoquímicas, sorológicas e da expressão de proteínas na próstata ventral. Os resultados obtidos demonstraram que a suplementação pela testosterona promoveu o estabelecimento de lesões, de proliferação, aumento da quantidade de células inflamatórias e alterou a proporção entre os compartimentos teciduais prostáticos nos grupos 1 e 2, que receberam somente a testosterona. A administração de BCP em gerbilos com HPB reduziu a frequência de células proliferativas e inflamatórias nos compartimentos epitelial e estromal e de macrófagos no estroma. As análises dos receptores hormonais mostraram o aumento da frequência da 5 α-redutase 2 na próstata de todos os grupos experimentais comparado ao controle, do receptor de andrógeno (AR) nos grupos 1 e 2 e a redução desse receptor nos grupos 3 e 4. Além disso, foi observado o aumento da expressão do receptor de estrógeno do tipo β (ERβ) no grupo 4 comparado ao grupo 2 indicando um possível efeito anti-proliferativo do BCP na hiperplasia prostática. Também foi verificado o aumento das células em apoptose após o tratamento com o fitocanabinoide em ambos os grupos 3 e 4. Assim, conclui-se que a suplementação pela testosterona foi suficiente para induzir a HPB e essa condição hiperplásica se manteve mesmo após 4 semanas do fim do experimento e, pela primeira vez demonstrado em modelo animal, que o BCP apresentou efeitos positivos para a próstata hiperplásica, como a redução da proliferação e inflamação, indicando resultados promissores no tratamento da HPB.
The prostate gland is very susceptible to changes in androgen levels, which can play an important role in the development of benign prostatic hyperplasia (BPH). The use of natural compounds in the treatment of BPH has been growing and has shown beneficial effects on the prostate. The phytocannabinoid β-Caryophyllene (BCP) is present in different plant species and has anti-inflammatory, apoptotic, antiangiogenic effects and may be related to the inhibition of proliferation of a variety of tumor cells, including the prostate. However, these studies have been restricted to the effects of BCP in cultured cells and the knowledge of these effects is necessary for the experimental models. Thus, the present study evaluated the changes caused by testosterone in the ventral prostate and analyzed the effects of BCP on testosterone--induced BPH in the ventral prostate of adult gerbils. In order, we used adult male gerbils submitted to different experimental conditions: subcutaneous applications of testosterone (3 mg/kg), on alternate days, for four weeks and euthanized, immediately (group 1) and 30 days (group 2) after the end of the experiment; daily administration of BCP (50 mg/kg/day), via gavage, for four weeks, in intact gerbils (group 3) and that received supplementation by testosterone during 30 days (group 4), and animals from the control group (group 5), which received no treatment or supplementation. Morphological, morphometric, stereological, immunohistochemical, serological, and protein expression analyses were performed on the ventral prostate. The results showed that testosterone supplementation promoted the establishment of lesions, cell proliferation, increased number of inflammatory cells and altered the proportion between prostatic tissue compartments in the groups 1 and 2 that received testosterone alone. BCP administration in gerbils with BPH reduced the frequency of proliferative and inflammatory cells in the epithelial and stromal compartments and macrophages in the stroma. Hormone receptor analyses showed an increase in the frequency of 5 α-reductase 2 in the prostate of all experimental groups compared to the control, of the androgen receptor (AR) in groups 1 and 2, and a reduction of this receptor in groups 3 and 4. In addition, the estrogen receptor type β (ER- β) expression increased in group 4 compared to group 2 indicating a possible anti-proliferative effect of BCP on prostatic hyperplasia. The increase of cells in apoptosis after the phytocannabinoid treatment was also observed in both groups 3 and 4. In conclusion, the testosterone supplementation was sufficient to induce BPH and this hyperplastic condition remained even four weeks after the end of the experiment and, for the first time demonstrated in an animal model, that BCP showed positive effects for the hyperplastic prostate, such as reduced proliferation and inflammation, indicating promising results in the treatment of BPH.
The prostate gland is very susceptible to changes in androgen levels, which can play an important role in the development of benign prostatic hyperplasia (BPH). The use of natural compounds in the treatment of BPH has been growing and has shown beneficial effects on the prostate. The phytocannabinoid β-Caryophyllene (BCP) is present in different plant species and has anti-inflammatory, apoptotic, antiangiogenic effects and may be related to the inhibition of proliferation of a variety of tumor cells, including the prostate. However, these studies have been restricted to the effects of BCP in cultured cells and the knowledge of these effects is necessary for the experimental models. Thus, the present study evaluated the changes caused by testosterone in the ventral prostate and analyzed the effects of BCP on testosterone--induced BPH in the ventral prostate of adult gerbils. In order, we used adult male gerbils submitted to different experimental conditions: subcutaneous applications of testosterone (3 mg/kg), on alternate days, for four weeks and euthanized, immediately (group 1) and 30 days (group 2) after the end of the experiment; daily administration of BCP (50 mg/kg/day), via gavage, for four weeks, in intact gerbils (group 3) and that received supplementation by testosterone during 30 days (group 4), and animals from the control group (group 5), which received no treatment or supplementation. Morphological, morphometric, stereological, immunohistochemical, serological, and protein expression analyses were performed on the ventral prostate. The results showed that testosterone supplementation promoted the establishment of lesions, cell proliferation, increased number of inflammatory cells and altered the proportion between prostatic tissue compartments in the groups 1 and 2 that received testosterone alone. BCP administration in gerbils with BPH reduced the frequency of proliferative and inflammatory cells in the epithelial and stromal compartments and macrophages in the stroma. Hormone receptor analyses showed an increase in the frequency of 5 α-reductase 2 in the prostate of all experimental groups compared to the control, of the androgen receptor (AR) in groups 1 and 2, and a reduction of this receptor in groups 3 and 4. In addition, the estrogen receptor type β (ER- β) expression increased in group 4 compared to group 2 indicating a possible anti-proliferative effect of BCP on prostatic hyperplasia. The increase of cells in apoptosis after the phytocannabinoid treatment was also observed in both groups 3 and 4. In conclusion, the testosterone supplementation was sufficient to induce BPH and this hyperplastic condition remained even four weeks after the end of the experiment and, for the first time demonstrated in an animal model, that BCP showed positive effects for the hyperplastic prostate, such as reduced proliferation and inflammation, indicating promising results in the treatment of BPH.
Descrição
Palavras-chave
Próstata, Testosterona, Hiperplasia, β-Cariofileno, Gerbilos, Prostate, Testosterone, Hyperplasia, β-Caryophyllene, Gerbils