Ambroxol alleviates hippocampus injury after BRIR through suppression of the IRE1α/TRAF2 signaling pathway

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-07-19 DOI:10.1016/j.lfs.2025.123875

Noha F. Elshazly , Marwa E. Elsherbiny , Azza S. Awad , Ahmed F. Mohamed , Nesrine S. El Sayed , Yasmin S. Mohamed

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Abstract

Acute kidney injury(AKI) is commonly linked to cognitive and neurological impairments. The study aims to investigate the relationship between bilateral renal ischemia reperfusion (BRIR) and hippocampal damage and evaluates the effects of ambroxol against BRIR-induced hippocampal injury and neuroinflammation.

Thirty adult male rats were randomly assigned to three groups: control (laparotomy without renal occlusion), BRIR model (bilateral renal ischemia was induced by clamping both renal pedicles for 60 min, followed by 3 days of reperfusion), and ambroxol treatment (70 mg/kg, I.P., once daily during reperfusion). Hippocampal injury was assessed through biochemical (ELISA, Western blot, and PCR), histopathological, and behavioral analysis.

Compared to the control group, BRIR significantly increased serum Cr, BUN, and renal injury markers (MDA, MCP-1, KIM-1) (p < 0.0001), along with notable renal tubular degeneration and necrosis. In the hippocampus, BRIR elevated inflammatory markers (NF-κB, TNF-α, MCP-1, IL-1β, G-CSF), reduced antioxidants (SOD, GSH), and altered apoptotic markers (increased Bax, decreased Bcl-2) (all p < 0.0001). Behavioral tests revealed impairments in learning, memory, and locomotor activity. Histology showed degeneration of pyramidal neurons in the CA1 region.

Ambroxol treatment significantly ameliorated these effects, preserving CA1 neuronal structure, restoring blood-brain barrier (BBB) integrity (via Occludin and Claudin-5), enhancing BDNF and IBA-1 expression, and modulating MAPK/NF-κB and IRE1α/TRAF2 signaling pathways.

Finally, BRIR induces both renal and hippocampal injury. Ambroxol mitigates this damage by reducing oxidative stress and inflammation, repairing BBB components, and regulating endoplasmic reticulum stress pathways (ERS).

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氨溴索通过抑制IRE1α/TRAF2信号通路减轻brr后海马损伤

急性肾损伤（AKI）通常与认知和神经损伤有关。本研究旨在探讨双侧肾缺血再灌注（BRIR）与海马损伤的关系，并评价氨溴索对BRIR诱导的海马损伤和神经炎症的影响。将30只成年雄性大鼠随机分为3组：对照组（开腹无肾闭塞）、BRIR模型组（夹闭双肾蒂诱导双侧肾缺血60 min，再灌注3 d）和氨溴索治疗组（70 mg/kg，再灌注时ig，每日1次）。通过生化（ELISA、Western blot和PCR）、组织病理学和行为分析评估海马损伤。与对照组相比，brr显著提高了血清Cr、BUN和肾损伤标志物（MDA、MCP-1、KIM-1） (p <；0.0001)，并伴有明显的肾小管变性和坏死。在海马中，BRIR升高炎症标志物（NF-κB、TNF-α、MCP-1、IL-1β、G-CSF），降低抗氧化剂（SOD、GSH），改变凋亡标志物（Bax升高，Bcl-2降低）(均p <；0.0001)。行为测试显示学习、记忆和运动活动受损。组织学显示CA1区锥体神经元变性。氨溴索治疗可显著改善这些作用，保留CA1神经元结构，恢复血脑屏障（BBB）完整性（通过Occludin和Claudin-5），增强BDNF和IBA-1表达，调节MAPK/NF-κB和IRE1α/TRAF2信号通路。最后，BRIR诱导肾脏和海马损伤。氨溴索通过减少氧化应激和炎症、修复血脑屏障成分和调节内质网应激途径（ERS）来减轻这种损伤。

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来源期刊

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.