Hepatic toxicity caused by PLGA-microspheres containing usnic acid from the lichen C ladonia substellata (AHTI) during pregnancy in Wistar rats

Abstract

This study aimed to evaluate the teratogenic and hepatotoxic potential of the usnic acid encapsulated into PLGA-microspheres. In total, 12 female Wistar rats in pregnancy were randomly distributed in the control group (n= 6) that received 1.0 mL of physiological solution and treatment group (n= 6) that received 25 mg/kg of encapsulated usnic acid by oral administration. All females were euthanized at day 20 of pregnancy and their fetuses were removed and analyzed. During the pregnancy was observed a reduction in weight gain. There was no difference in serum transaminases levels analyzed as well as any difference in liver weight in both groups. The histomorphometric analysis of the liver from the treatment group revealed an increase in number of hepatocytes and a decrease in nuclear area of these cells. Moreover, no alteration was observed in cell area of hepatocytes or number of Kupffer cells. The fetuses had an increase in total number of hepatocytes and a reduction in the amount of megakaryocytes. These results show the hepatotoxic potential of usnic acid during pregnancy. However, its toxicity can be minimized by encapsulation in microspheres.

Histomorfometric Analysis of the Endochondral Ossification of the limbs of Rats submitted to Usnic Acid from Cladonia Substellata (AHTI) encapsulated in Plga-Microspheres / Análise Histomorfométrica da Ossificação Endocondral dos membros de Ratos submetidos ao Ácido Úsnico de Cladonia Substellata (AHTI) encapsulado em Microesferas de Plga

“…Research into hepatic toxicity of 25 mg/kg/day PLGA microspheres containing usnic acid during gestation of Wistar rats reported toxicity of the encapsulated drug, but to a much lesser extent than that found for uric acid in its free form (MARINHO et al, 2017). Given these findings, it is concluded that the toxicity of the compound can be minimized by encapsulating it with PLGA microspheres.…”

“…Usnic acid [2,6-diacetyl-7,9-dihydroxy-8-9b-dimethyl-1,3 (2H, 9α / βH) dibenzofurandione; C18H16O7], is a secondary lichen metabolite, which has various pharmacological properties such as anti-tumor (BURLANDO et al, 2009), antiviral (SHTRO et al, 2014), anti-inflammatory (SU et al, 2014), antioxidant (SUWALSKY et al, 2015), and antifungal (NITHYANAND et al, 2015). However, there are some limitations that decrease its therapeutic efficacy, such as high hepatotoxicity, low water solubility and reproductive toxicity (SANCHEZ et al, 2006;SILVA et al, 2017;MARINHO et al, 2017;DA SILVA et al, 2020).…”

Nano- and Microcarriers as Drug Delivery Systems for Usnic Acid: Review of Literature

“…In addition, histopathological analysis of tumors and livers of the sacrificed animals revealed extensive necrosis after treatment with free, but not encapsulated usnic acid. Also, an in vivo investigation of Marihno et al [40] showed that encapsulation of usnic acid into PLGA microspheres minimized its hepatotoxic potential during pregnancy. Comparing the results of the study of Ribeiro-Costa et al (2004) [35] to the previously discussed inferences on PLGA nanocapsules loaded with usnic acid [32], while taking into account the same experimental setup in both studies, it can be concluded that encapsulation into nanocarriers may be considered more effective than encapsulation into microcarriers in the enhancement of antitumor activity of this drug.…”

Ação do ácido úsnico de cladonia substellata (AHTI) sobre a síntese de colágeno e a ossificação endocondral dos membros de ratos wistar

“…O ácido úsnico [2,6-diacetil-7,9-dihidroxi-8-9b-dimetil-1,3(2H,9α/βH)-dibenzofurandiona; C18H16O7], é um composto natural resultante do metabolismo secundário de liquens, descrito na literatura com várias propriedades farmacológicas, tais como antitumoral (BURLANDO et al, 2009), antiviral (SHTRO et al, 2014, anti-inflamatório ( SU et al, 2014), antioxidante ( SUWALSKY et al, 2015) e antifúngico ( NITHYANAND et al, 2015). Apesar das diversas atividades biológicas já relatadas na literatura sobre o composto, existem limitações para sua aplicação terapêutica, como a alta hepatotoxicidade, baixa hidrossolubilidade e toxicidade reprodutiva (FRAVEAU et al, 2002;RIBEIRO-COSTA et al, 2004;PRAMYOTHIN et al, 2004;SANCHEZ et al, 2006;SANTOS et al, 2006;SILVA et al, 2017;MARINHO et al, 2017).…”