Banca de QUALIFICAÇÃO: MARIA SANTANA DA SILVA

Uma banca de QUALIFICAÇÃO de MESTRADO foi cadastrada pelo programa.
STUDENT : MARIA SANTANA DA SILVA
DATE: 04/10/2024
TIME: 14:00
LOCAL: GoogleMeet: https://meet.google.com/npc-dhze-wyf
TITLE:

IN SILICO EVALUATION OF THE PHARMACOLOGICAL PROPERTIES OF TRAZODONE AND ITS IN VIVO EFFECTS ON REPRODUCTIVE PARAMETERS AND EPIDIDYMAL DUCT CONTRACTION IN RATS

KEY WORDS:

Trazodone, m-CPP, pharmacological properties, reproductive parameters, epididymis.

PAGES: 86
BIG AREA: Ciências Biológicas
AREA: Farmacologia
SUMMARY:

Trazodone is an antidepressant approved for the treatment of major depressive disorder, which, when metabolized, leads to the formation of an active metabolite, m-chlorophenyl piperazine (m-CPP). However, the pharmacological characteristics of trazodone and, in particular, of m-CPP are not fully understood. Another important point is the lack of information on the effects of trazodone on male reproductive health. Thus, this study aimed to evaluate, through in silico methods, the molecular, medicinal chemistry, physicochemical, pharmacokinetic, pharmacodynamic, and toxicological properties of trazodone and its active metabolite m-CPP. Additionally, we investigated the effects of trazodone on epididymal duct contraction and reproductive parameters in rats. The in silico predictions of molecular, physicochemical, medicinal chemistry, pharmacokinetic (absorption, distribution, metabolism, and elimination), and toxicological properties of trazodone and its active metabolite m-CPP were performed using ADMETlab3.0 and pred-hERG 5.0 servers. For the evaluation of trazodone's anti-reproductive effects, we used adult Wistar rats, which were treated orally for 21 days with trazodone at doses of 10 mg/kg and 20 mg/kg. After the treatment period, the animals were euthanized, the reproductive organs were weighed, and the testis and epididymis were isolated for sperm parameter assessment and evaluation of the distal cauda epididymal duct contraction. The in vitro effects of trazodone on epididymal duct contraction were also assessed. Our in silico analyses indicate that m-CPP is capable of inhibiting enzymes and transporters that are essential for the metabolism and distribution of drugs. Furthermore, both trazodone and m-CPP exhibit in silico predictors suggesting nonspecific interactions with pharmacological targets, which may contribute to an unfavorable toxicological profile, potentially compromising trazodone's safety in humans. We also observed that trazodone exerts anti-reproductive effects in rats, characterized by damage to testicular tissue, reduced sperm production, as well as a decrease in the quantity and quality of sperm collected from the cauda epididymis. The contraction of the isolated distal cauda epididymal duct was also affected by both in vivo and in vitro trazodone treatment. In conclusion, the in silico analyses raise concerns regarding the safety of trazodone use, due to its nonspecificity and broad toxicological profile. Additionally, trazodone exhibited significant anti-reproductive effects, which may impair male fertility.

COMMITTEE MEMBERS:
Presidente - 2985070 - JONAS IVAN NOBRE OLIVEIRA
Externa ao Programa - 1645202 - ELAINE CRISTINA GAVIOLI - UFRNExterno à Instituição - JULIO NETO DA SILVA