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

Overview

Journal Neuromolecular Med

Specialty Biochemistry

Date 2025 Jan 8

PMID 39775152

Authors

Zeinab Hamidizad

Mehri Kadkhodaee

Farzaneh Kianian

Mina Ranjbaran

Fatemeh Heidari

Behjat Seifi

Affiliations

Soon will be listed here.

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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