Ameliorative effects of hydrogen sulfide (NaHS) on chronic kidney disease-induced brain dysfunction in rats: implication on role of nitric oxide (NO) signaling

Abstract

Chronic kidney disease (CKD) is a major public health problem worldwide and is associated with spatial learning deficits. The aim of the present study was to evaluate the protective effects of hydrogen sulfide (H2S) on CKD-mediated behavioral deficits with emphasis to the role of nitric oxide (NO) in these effects. Fifty rats were randomly allocated to five experimental groups including: sham, Five-sixth (5/6) nephrectomy (Nx), 5/6Nx + NaHS, 5/6Nx + NaHS+L-nitroarginine methyl ester (L-NAME), and 5/6Nx + NaHS+aminoguanidine (AMG). Twelve weeks after 5/6Nx, we evaluated proteinuria, creatinine clearance (CrCl), oxidative/antioxidant status, and hippocampus neuro-inflammation and NO synthase genes in all groups. Furthermore, training trials of all animals were conducted in the Morris water maze (MWM) task one day before animal euthanizing. As predicted, 5/6Nx induced several injuries, including enhancement of proteinuria and reduction of CCr, oxidant/antioxidant imbalance and up-regulation of TNF-α and IL-1β gene expressions in the hippocampus tissues. As predicted, 5/6Nx resulted in learning and memory impairments, and increased escape latency during acquisition trials in the MWM task. Interestingly, NaHS (H2S donor) improved behavioral deficits, renal dysfunction, accelerated anti-oxidant/anti-inflammatory responses and increased eNOS and decreased iNOS. Moreover, these effects of NaHS were prevented by L-NAME but not AMG co-administration. In conclusion, H2S ameliorates CKD-mediated brain dysfunctions, through interaction with NO signaling in the hippocampus.

Behavioral Changes During Development of Chronic Kidney Disease in Rats

“…It has been shown that mild CKD may lead to activation of limbic system, central sympathetic, stress-and pain-related brain areas (31). Some CKD-related neurological complications have been attributed to impaired permeability of the blood-brain barrier (22,32,33), neuroinflammation, and oxidative stress (21)(22)(23). Neurotoxicity induced by numerous substances, such as urea, accumulated in blood during kidney disease (34)(35)(36) might also play a role (33).…”

“…Individual's quality of life can be further decreased by sexual dysfunction (7), neurological and mental disorders including anxiety and depression (7)(8)(9)(10)(11), as well as cognitive impairment (12)(13)(14)(15)(16)(17) or epileptic seizures (18), all of which lead to increased socio-economic burden of affected people (19). Although, the exact pathophysiological mechanisms underlying the neurological complications of CKD remain unclear, there are several factors that might play a role, e.g., uremic encephalopathy (20), oxidative stress (21)(22)(23) and inflammation (21,22).…”

Exogenous hydrogen sulfide alleviates surgery-induced neuroinflammatory cognitive impairment in adult mice by inhibiting NO signaling

“…Exogenous H 2 S also been demonstrated to have neuroprotective effects against brain edema, neurobehavioral function, including learning and memory, and neuronal cell death following subarachnoid hemorrhage [36]. Furthermore, H 2 S can regulate the release of NO, and its interaction with NO in the hippocampus can alleviate brain dysfunction [22][23][24]. Here, we are the first to demonstrate that exogenous H 2 S ameliorates spatial learning and memory deficits in a surgery-induced POCD mouse model by inhibiting NO and reducing iNOS levels in the hippocampus.…”

“…iNOS also promotes synaptic plasticity and brain function deficits, such as cognitive deficits [17,21]. L-nitro-arginine methyl ester (L-NAME), an inhibitor of NOS that can inhibit NO biosynthesis, can attenuate brain dysfunction [22]. Therefore, NO may represent a pathogenic signal for POCD.…”

“…Hydrogen sulfide (H 2 S), the third gaseous transmitter alongside NO, can regulate the release of NO and its interaction with NO in the hippocampus can alleviate brain dysfunction [22][23][24]. In addition, H 2 S exerts both pro-and anti-inflammatory effects [24].…”