Journal Article

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

Seifi, Behjat, Kianian, Farzaneh, Heidari, Fatemeh, Ranjbaran, Mina, Hamidizad, Zeinab, Kadkhodaee, Mehri

2025

Overview

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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Acetic acid / Animals / Biomedical and Life Sciences / Biomedicine / Cognition / Cognition Disorders - drug therapy / Cognition Disorders - etiology / Cognition Disorders - prevention & control / Cognitive Dysfunction - drug therapy / Cognitive Dysfunction - etiology / Cognitive Dysfunction - prevention & control / Creatinine / Cystathionine b-synthase / Cystathionine beta-Synthase - metabolism / Dementia disorders / Heme oxygenase (decyclizing) / Heme Oxygenase (Decyclizing) - biosynthesis / Heme Oxygenase (Decyclizing) - metabolism / Heme Oxygenase-1 - biosynthesis / Heme Oxygenase-1 - metabolism / Hippocampus / Hippocampus - drug effects / Hippocampus - metabolism / Hydrogen sulfide / Internal Medicine / Intracellular signalling / Kidney diseases / Latency / Male / Maze Learning - drug effects / Memory / Nephrectomy / Neurology / Neuroprotection / Neuroprotective Agents - pharmacology / Neuroprotective Agents - therapeutic use / Neurosciences / NF-E2-Related Factor 2 - metabolism / Nitric oxide / Nitric Oxide - metabolism / Nitric Oxide Donors - pharmacology / Nitric Oxide Donors - therapeutic use / Nitroprusside - pharmacology / Nitroprusside - therapeutic use / Oxidative stress / Pattern recognition / Prefrontal cortex / Prefrontal Cortex - drug effects / Prefrontal Cortex - metabolism / Rats / Rats, Sprague-Dawley / Renal Insufficiency, Chronic - complications / Renal Insufficiency, Chronic - drug therapy / Renal Insufficiency, Chronic - etiology / Risk factors / Signal transduction / Signal Transduction - drug effects / Sodium nitroprusside / Toxicity