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利拉鲁肽对多柔比星诱导的大鼠睾丸毒性和行为异常的调节作用：睾丸-脑轴的作用。

Modulatory effect of liraglutide on doxorubicin-induced testicular toxicity and behavioral abnormalities in rats: role of testicular-brain axis.

机构信息

Pharmacology & Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.

Researcher of Pharmacology, Egyptian Drug Authority, Cairo, Egypt.

出版信息

Naunyn Schmiedebergs Arch Pharmacol. 2023 Nov;396(11):2987-3005. doi: 10.1007/s00210-023-02504-7. Epub 2023 May 10.

DOI:10.1007/s00210-023-02504-7
PMID:37162541
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10567954/
Abstract

Doxorubicin (DOX) is a powerful chemotherapeutic agent used in many types of malignancies. However, its use results in testicular damage. DOX-induced testicular damage results in low level of serum testosterone which may affect cognitive function. The current study investigated the protective effect of liraglutide (50, 100 μg/kg/day) in testicular toxicity and the consequent cognitive impairment induced by DOX. DOX treatment reduced sperm count (62%) and sperm motility (53%) and increased sperm abnormalities (786%), as compared to control group. DOX also reduced serum testosterone level (85%) and the gene expression of testicular 3β-HSD (68%) and 17β-HSD (82%). Moreover, it increased testicular oxidative stress (MDA and GSH) by 103% and 59%, respectively, apoptotic (caspase-3 and P53) by 996% and 480%, respectively. In addition, DOX resulted in increasing autophagic markers including PAKT, mTOR, and LC3 by 48%, 56%, and 640%, respectively. Additionally, rats' behavior in Y-maze (60%) and passive avoidance task (85%) was disrupted. The histopathological results of testis and brain supported the biochemical findings. Treatment with liraglutide (100 μg/kg/day) significantly abrogated DOX-induced testicular damage by restoring testicular architecture, increasing sperm count (136%) and sperm motility (106%), and decreasing sperm abnormalities (84%) as compared to DOX group. Furthermore, liraglutide increased serum testosterone (500%) and steroidogenesis enzymes 3β-HSD (105%) and 17β-HSD (181%) along with suppressing oxidative stress (MDA and GSH) by 23% and 85%, respectively; apoptotic (caspase-3 and P53) by 59% and55%, respectively; and autophagic markers including PAKT, mTOR, and LC3 by 48%, 97%, and 60%, respectively. Moreover, it enhanced the memory functions in passive avoidance and Y-maze tests (132%). In conclusion, liraglutide is a putative agent for protection against DOX-induced testicular toxicity and cognitive impairment through its antioxidant, antiapoptotic, and antiautophagic effects.

摘要

多柔比星（DOX）是一种用于多种恶性肿瘤的强效化疗药物。然而，其使用会导致睾丸损伤。DOX 诱导的睾丸损伤导致血清睾酮水平降低，可能会影响认知功能。本研究探讨了利拉鲁肽（50、100μg/kg/天）对 DOX 诱导的睾丸毒性和随之而来的认知障碍的保护作用。与对照组相比，DOX 治疗使精子数（62%）和精子活力（53%）降低，并使精子畸形率（786%）增加。此外，它还降低了血清睾酮水平（85%）和睾丸 3β-HSD（68%）和 17β-HSD（82%）的基因表达。此外，它使睾丸氧化应激（MDA 和 GSH）分别增加 103%和 59%，凋亡（caspase-3 和 P53）分别增加 996%和 480%。此外，DOX 导致自噬标志物 PAKT、mTOR 和 LC3 的表达分别增加 48%、56%和 640%。此外，大鼠在 Y 迷宫（60%）和被动回避任务（85%）中的行为受到干扰。睾丸和大脑的组织病理学结果支持生化发现。与 DOX 组相比，利拉鲁肽（100μg/kg/天）的治疗显著减轻了 DOX 诱导的睾丸损伤，恢复了睾丸结构，使精子数（136%）和精子活力（106%）增加，并使精子畸形率（84%）降低。此外，利拉鲁肽增加了血清睾酮（500%）和类固醇生成酶 3β-HSD（105%）和 17β-HSD（181%），同时使氧化应激（MDA 和 GSH）分别降低 23%和 85%；凋亡（caspase-3 和 P53）分别降低 59%和 55%；自噬标志物 PAKT、mTOR 和 LC3 分别降低 48%、97%和 60%。此外，它增强了被动回避和 Y 迷宫测试中的记忆功能（132%）。总之，利拉鲁肽通过抗氧化、抗凋亡和抗自噬作用，成为一种潜在的保护 DOX 诱导的睾丸毒性和认知障碍的药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f05/10567954/263fcb692f0c/210_2023_2504_Fig10_HTML.jpg
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本文引用的文献

[1]
Role of liraglutide in Alzheimer's disease pathology.

Alzheimers Res Ther. 2021-6-12

[2]
Doxorubicin-Induced Cognitive Impairment: The Mechanistic Insights.

Front Oncol. 2021-5-13

[3]
Mechanisms of doxorubicin-mediated reproductive toxicity - A review.

Reprod Toxicol. 2021-6

[4]
Liraglutide Protects Nucleus Pulposus Cells Against High-Glucose Induced Apoptosis by Activating PI3K/Akt/ mTOR/Caspase-3 and PI3K/Akt/GSK3β/Caspase-3 Signaling Pathways.

Front Med (Lausanne). 2021-2-19

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Hydrogen sulfide ameliorates doxorubicin‑induced myocardial fibrosis in rats via the PI3K/AKT/mTOR pathway.

Mol Med Rep. 2021-4

[6]
Protective effect of liraglutide on experimental testicular ischaemia reperfusion in rats.

Andrologia. 2021-5

[7]
Liraglutide suppresses the proliferation of endometrial cancer cells through the adenosine 5'-monophosphate (AMP)-activated protein kinase signaling pathway.

Chin Med J (Engl). 2021-1-19

[8]
Glucagon-like peptide-1 receptor is expressed in human and rodent testis.

Andrology. 2020-11

[9]
Portals to frailty? Data-driven analyses detect early frailty profiles.

Alzheimers Res Ther. 2021-1-4

[10]
Liraglutide activates nature killer cell-mediated antitumor responses by inhibiting IL-6/STAT3 signaling in hepatocellular carcinoma.

Transl Oncol. 2021-1

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