Repurposing of rebamipide as a neuroprotective agent to alleviate letrozole-induced depressive-like behaviors in female rats: Targeting SIRT1/FoxO1/wnt/ β-catenin, and related ferroptosis pathways

IF 5.1 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Aya Hamdy , Rabab H. Sayed , Mohammed F. El-Yamany , Gouda K. Helal , Mohmed I. Fahmy
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引用次数: 0

Abstract

Aims

Polycystic ovarian syndrome (PCOS) is a hormonal disorder affecting females worldwide. PCOS is associated with the development of depression, which is exacerbated by oxidative stress, neuro-inflammation, and ferropotosis. Rebamipide (Reba) is a potent antioxidant agent exhibiting cytoprotective effects. Reba notably activates SIRT1, which in turn plays a major role in ameliorating cellular iron deposition, thus preventing ferooptosis-related cell death. This study aimed to elucidate the neuroprotective effects of Reba against letrozole-induced depressive-like behaviour in female rats and further explore the role of SIRT1/FoxO/wnt/β-catenin and related ferroptosis pathways.

Materials and methods

Forty female Wistar rats were allocated into four groups: control group, a letrozole-treated group (1 mg/kg/day, p.o.), a Reba-treated group (80 mg/kg/day, p.o.) and a group receiving niacinamide (NAM), a selective SIRT1 blocker (100 mg/kg/day, i.p.) in addition to Reba.

Key findings

Reba restored the normal morphological structure of the hippocampi with significant improvement in the rats' behaviors. Reba up-regulated SIRT1, a key regulator of numerous antioxidant and anti-inflammatory cascades, including Nrf2, SOD, and HO-1. The anti-inflammatory activity of SIRT-1 was revealed by the downregulation of NF-κB-p65, TNF-α, and NLRP3 inflammasome, as well as the upregulation of FoxO/wnt/β-catenin signaling. Furthermore, the anti-ferroptosis effects were demonstrated by the inhibition of total iron and ferrous levels as well as the upregulation of Gpx4 and SLC7A11 genes. Pre-treatment with NAM abolished Reba's neuroprotective effects.

Significance

Reba has a major neuroprotective role via activating SIRT1 and inhibiting related oxidative, neuroinflammatory, and ferroptosis pathways.
利巴米胺作为神经保护剂的再利用以缓解来曲唑诱导的雌性大鼠抑郁样行为:靶向SIRT1/FoxO1/wnt/ β-catenin及其相关的铁下沉途径
目的:多囊卵巢综合征(PCOS)是一种影响全球女性的激素失调疾病。多囊卵巢综合征与抑郁症的发展有关,而抑郁症会因氧化应激、神经炎症和铁中毒而加剧。利巴米胺(Reba)是一种有效的抗氧化剂,具有细胞保护作用。热巴显著激活SIRT1, SIRT1反过来在改善细胞铁沉积中起主要作用,从而防止与光噬相关的细胞死亡。本研究旨在阐明热巴对来曲唑诱导的雌性大鼠抑郁样行为的神经保护作用,并进一步探讨SIRT1/FoxO/wnt/β-catenin及其相关的铁下沉通路的作用。材料与方法:将40只雌性Wistar大鼠分为4组:对照组、来曲唑治疗组(1 mg/kg/day,口服)、热巴治疗组(80 mg/kg/day,口服)和在热巴基础上给予选择性SIRT1阻断剂烟酰胺(NAM)(100 mg/kg/day,口服)。主要发现:热巴恢复了大鼠海马的正常形态结构,显著改善了大鼠的行为。热芭上调SIRT1, SIRT1是许多抗氧化和抗炎级联反应的关键调节因子,包括Nrf2、SOD和HO-1。SIRT-1的抗炎活性通过下调NF-κB-p65、TNF-α、NLRP3炎性小体以及上调FoxO/wnt/β-catenin信号传导而显现。此外,通过抑制总铁和亚铁水平以及上调Gpx4和SLC7A11基因,证明了抗铁下垂作用。NAM预处理可消除热巴的神经保护作用。意义:热巴具有重要的神经保护作用,通过激活SIRT1和抑制相关的氧化、神经炎症和铁下沉途径。
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来源期刊
Life sciences
Life sciences 医学-药学
CiteScore
12.20
自引率
1.60%
发文量
841
审稿时长
6 months
期刊介绍: Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.
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