Analysis of the finasteride treatment and its withdrawal in the rat hypothalamus and hippocampus at whole-transcriptome level.

IF 5.4 2区 医学 Q1 Medicine Journal of Endocrinological Investigation Pub Date : 2024-10-01 Epub Date: 2024-03-17 DOI:10.1007/s40618-024-02345-y
S Giatti, L Cioffi, S Diviccaro, R Piazza, R C Melcangi
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Abstract

Purpose: As reported in patients treated for androgenetic alopecia with finasteride (i.e., a blocker of the enzyme 5 alpha-reductase) and in an animal model, side effects affecting sexual, psychiatric, neurological, and physical domains, may occur during the treatment and persist with drug suspension. The etiopathogenesis of these side effects has been poorly explored. Therefore, we performed a genome-wide analysis of finasteride effects in the brain of adult male rat.

Methods: Animals were treated (i.e., for 20 days) with finasteride (1mg/rat/day). 24 h after the last treatment and 1 month after drug suspension, RNA sequencing analysis was performed in hypothalamus and hippocampus. Data were analyzed by differential expression analysis and Gene-Set Enrichment Analyses (GSEA).

Results: Data obtained after finasteride treatment showed that 186 genes (i.e., 171 up- and 15 downregulated) and 19 (i.e., 17 up- and 2 downregulated) were differentially expressed in the hypothalamus and hippocampus, respectively. Differential expression analysis at the drug withdrawal failed to identify dysregulated genes. Several gene-sets were enriched in these brain areas at both time points.

Conclusion: Some of the genes reported to be differentially expressed (i.e., TTR, DIO2, CLDN1, CLDN2, SLC4A5, KCNE2, CROT, HCRT, MARCKSL1, VGF, IRF2BPL) and GSEA, suggest a potential link with specific side effects previously observed in patients and in the animal model, such as depression, anxiety, disturbance in memory and attention, and sleep disturbance. These data may provide an important background for future experiments aimed at confirming the pathological role of these genes.

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从全转录组水平分析大鼠下丘脑和海马的非那雄胺治疗和停药情况。
目的:据报道,在使用非那雄胺(即 5 α-还原酶的阻断剂)治疗雄激素性脱发的患者中以及在动物模型中,可能会在治疗期间出现影响性、精神、神经和身体领域的副作用,并且在停药后仍会持续。对这些副作用的病因尚未进行深入研究。因此,我们对非那雄胺对成年雄性大鼠大脑的影响进行了全基因组分析:方法:用非那雄胺(1 毫克/只/天)对动物进行治疗(即 20 天)。在最后一次治疗 24 小时后和停药 1 个月后,对下丘脑和海马进行 RNA 测序分析。数据通过差异表达分析和基因组富集分析(Gene-Set Enrichment Analyses,GSEA)进行分析:结果:非那雄胺治疗后获得的数据显示,186个基因(即171个上调,15个下调)和19个基因(即17个上调,2个下调)分别在下丘脑和海马中差异表达。停药时的差异表达分析未能发现失调基因。在这两个时间点,这些脑区都富集了几个基因集:结论:报告的一些差异表达基因(即 TTR、DIO2、CLDN1、CLDN2、SLC4A5、KCNE2、CROT、HCRT、MARCKSL1、VGF、IRF2BPL)和 GSEA 表明,这些基因与之前在患者和动物模型中观察到的特定副作用(如抑郁、焦虑、记忆和注意力障碍以及睡眠障碍)存在潜在联系。这些数据可为今后旨在证实这些基因的病理作用的实验提供重要背景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Endocrinological Investigation
Journal of Endocrinological Investigation ENDOCRINOLOGY & METABOLISM-
CiteScore
8.10
自引率
7.40%
发文量
242
期刊介绍: The Journal of Endocrinological Investigation is a well-established, e-only endocrine journal founded 36 years ago in 1978. It is the official journal of the Italian Society of Endocrinology (SIE), established in 1964. Other Italian societies in the endocrinology and metabolism field are affiliated to the journal: Italian Society of Andrology and Sexual Medicine, Italian Society of Obesity, Italian Society of Pediatric Endocrinology and Diabetology, Clinical Endocrinologists’ Association, Thyroid Association, Endocrine Surgical Units Association, Italian Society of Pharmacology.
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