Hamidizad Zeinab, Kadkhodaee Mehri, Kianian Farzaneh, Ranjbaran Mina, Heidari Fatemeh, Seifi Behjat
Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Department of Physiology, Faculty of Medicine, Qom University of Medical Sciences, Qom, Iran.
Neuromolecular Med. 2025 Jan 7;27(1):8. doi: 10.1007/s12017-024-08828-8.
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.
慢性肾脏病（CKD）是认知障碍和痴呆症一个可能的新风险因素。尿毒症毒性、氧化应激和外周 - 中枢炎症被认为是CKD诱导神经障碍的重要介质。一氧化氮（NO）是突触中的逆行神经递质，在神经元的细胞内信号传导中起重要作用。本研究旨在通过考虑核因子 - 红细胞2相关因子2（Nrf2）/血红素加氧酶 - 1（HO - 1）信号通路以及胱硫醚β合酶（CBS，硫化氢产生酶）的重要作用，来确定NO对CKD诱导的认知缺陷的有效性。将40只大鼠分为四个实验组：假手术组、五分之六肾切除组（5/6Nx，CKD组）、CKD + NO供体组（硝普钠，SNP）、CKD + SNP及CBS抑制剂组（氨基氧乙酸，AOAA）。为评估神经认知能力，在5/6Nx术后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）。在5/6Nx术后第12周，评估血尿素氮（BUN）和血清肌酐（sCr）水平，以及核因子 - 红细胞2相关因子2（Nrf2）、血红素加氧酶 - 1（HO - 1）的表达水平，和海马体及前额叶皮质中的神经元损伤情况。如预期的那样，CKD大鼠的BUN和sCr水平（均P < 0.001）以及海马体（CA1、CA3、齿状回，P < 0.001）和前额叶皮质（P < 0.001）中的神经元损伤增加，并且5/6Nx诱导CKD大鼠海马体和前额叶皮质中Nrf2（均P < 0.001）/HO - 1（分别为P < 0.001、P < 0.01）信号通路活性降低。此外，CKD导致认知障碍和记忆丧失（新物体识别测试（NOR）（P < 0.001）、被动回避测试（PA）（P < 0.001）和巴恩斯迷宫测试（逃避潜伏期（P < 0.001）；错误次数（P < 0.001））。SNP治疗显著改善了CKD大鼠海马体和前额叶皮质中的Nrf2（均P < 0.001）/HO - 1（分别为P < 0.001、P < 0.05）信号通路以及神经元损伤（CA1、CA3、齿状回，P < 0.001），并增强了CKD大鼠的学习和记忆能力。然而，CBS抑制剂和硫化氢减少使SNP对认知障碍（NOR（P < 0.05）、PA（P < 0.001）和巴恩斯迷宫测试（逃避潜伏期（P < 0.05）；错误次数（P < 0.001））以及Nrf2（海马体和前额叶皮质分别为P < 0.01、P < 0.001）/HO - 1（两者均为P < 0.05）信号通路活性的改善作用无效。总之，本研究表明NO改善了CKD诱导的认知障碍和神经元死亡，这可能依赖于CBS活性和内源性硫化氢水平。
