Neuroprotective Effects of Sodium Nitroprusside on CKD-Induced Cognitive Dysfunction in Rats: Role of CBS and Nrf2/HO-1 Pathway.

IF 3.3 4区 医学 Q2 NEUROSCIENCES NeuroMolecular Medicine Pub Date : 2025-01-07 DOI:10.1007/s12017-024-08828-8
Zeinab Hamidizad, Mehri Kadkhodaee, Farzaneh Kianian, Mina Ranjbaran, Fatemeh Heidari, Behjat Seifi
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Abstract

Chronic kidney disease (CKD) is a conceivable new risk factor for cognitive disorder and dementia. Uremic toxicity, oxidative stress, and peripheral-central inflammation have been considered important mediators of CKD-induced nervous disorders. Nitric oxide (NO) is a retrograde neurotransmitter in synapses, and has vital roles in intracellular signaling in neurons. This research aims to determine the effectiveness of NO in CKD-induced cognitive deficits by considering the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling pathway and the important roles of cystathionine beta-synthase (CBS, H2S producing enzyme). Forty rats were divided into four experimental groups: sham, five-sixth (5/6) nephrectomy (5/6Nx, CKD), CKD + NO donor (Sodium nitroprusside, SNP), CKD + SNP and a CBS inhibitor (amino-oxy acetic acid, AOAA). To assess the neurocognitive abilities, eleven weeks after 5/6Nx, behavioral tests (Novel object recognition test, Passive avoidance test, and Barnes maze test) were done. Twelfth week after 5/6Nx, blood urea nitrogen (BUN) and serum creatinine (sCr) levels, as well as the nuclear factor-erythroid factor 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) expression levels and neuronal injury in the hippocampus and prefrontal cortex were assessed. As predicted, the levels of BUN and sCr (both P < 0.001) and neuronal injury in the hippocampus (P < 0.001 for CA1; CA3; DG) and prefrontal cortex (P < 0.001) increased in CKD rats as well as 5/6Nx induced reduction of Nrf2 (both P < 0.001) /HO-1(P < 0.001; P < 0.01 respectively) pathway activity in the hippocampus and prefrontal cortex in CKD rats. Moreover, CKD leads to cognitive disorder and memory loss (Novel object recognition test (NOR) (P < 0.001), Passive avoidance test (PA) (P < 0.001) and Barnes maze (BA) (Escape latency (P < 0.001); Error (P < 0.001)). SNP treatment significantly improved Nrf2 (both P < 0.001) /HO-1 (P < 0.001; P < 0.05 respectively) pathways and neuronal injury (P < 0.001 for CA1; CA3; DG) in the hippocampus and prefrontal cortex in CKD rats as well as enhanced learning and memory ability in CKD rats. However, ameliorating effects of SNP on cognitive disorder (NOR (P < 0.05), PA (P < 0.001) and BA (Escape latency (P < 0.05); Error (P < 0.001)) and Nrf2 (P < 0.01; P < 0.001 in the hippocampus and prefrontal cortex respectively) /HO-1 (P < 0.05 in both) signaling pathway activity were nullified by CBS inhibitor and H2S reduction. In conclusion, this study demonstrated that NO improved CKD-induced cognitive impairment and neuronal death which is may be depended to CBS activity and endogenous H2S levels.

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硝普钠对ckd诱导的大鼠认知功能障碍的神经保护作用:CBS和Nrf2/HO-1通路的作用
慢性肾脏疾病(CKD)是认知障碍和痴呆的一个可能的新危险因素。尿毒症毒性、氧化应激和外周-中枢炎症被认为是ckd诱导的神经紊乱的重要介质。一氧化氮(NO)是突触中的逆行神经递质,在神经元细胞内信号传导中起着重要作用。本研究旨在通过考虑核因子-红细胞因子2相关因子2 (Nrf2)/血红素加氧酶-1 (HO-1)信号通路和胱硫氨酸β -合成酶(CBS, H2S生成酶)的重要作用,确定NO在ckd诱导的认知缺陷中的有效性。40只大鼠分为4个实验组:假手术组、五/六(5/6)肾切除术组(5/6Nx, CKD)、CKD + NO供体组(硝普钠,SNP)、CKD + SNP和CBS抑制剂组(氨基氧乙酸,AOAA)。5/6Nx后11周进行行为测试(新物体识别测试、被动回避测试和巴恩斯迷宫测试)评估神经认知能力。5/6Nx后第12周,检测大鼠血尿素氮(BUN)、血清肌酐(sCr)水平,以及核因子-红细胞因子2相关因子2 (Nrf2)、血红素加氧酶-1 (HO-1)表达水平和海马、前额叶皮层神经元损伤情况。正如预测的那样,BUN和sCr (P
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来源期刊
NeuroMolecular Medicine
NeuroMolecular Medicine 医学-神经科学
CiteScore
7.10
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: NeuroMolecular Medicine publishes cutting-edge original research articles and critical reviews on the molecular and biochemical basis of neurological disorders. Studies range from genetic analyses of human populations to animal and cell culture models of neurological disorders. Emerging findings concerning the identification of genetic aberrancies and their pathogenic mechanisms at the molecular and cellular levels will be included. Also covered are experimental analyses of molecular cascades involved in the development and adult plasticity of the nervous system, in neurological dysfunction, and in neuronal degeneration and repair. NeuroMolecular Medicine encompasses basic research in the fields of molecular genetics, signal transduction, plasticity, and cell death. The information published in NEMM will provide a window into the future of molecular medicine for the nervous system.
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