Abstract
BackgroundTo investigate the effect and mechanisms of exogenous hydrogen sulfide in surgery-induced neuroinflammatory cognitive dysfunction.MethodsC57BL/6 J male mice (n = 140) were used and randomly divided into seven groups: the sham group, surgery group, GYY4137 group, L-NAME group, surgery+GYY4137 group, surgery +L-NAME group, and surgery+GYY4137 + L-NAME group. After the interventions, open field tests (OFT) and the Morris water maze (MWM) test were conducted to evaluate learning and memory abilities in the mice. ELISAs, nitrate reductase assays, and Western blots (WB) were conducted to evaluate interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and antioxidant enzyme superoxide dismutase (SOD) levels. Furthermore, the expression level of microglial marker ionized calcium binding adaptor molecule 1 (IBA) in the hippocampal CA1 and CA3 areas was detected by an immunohistochemical (IHC) assay and apoptotic cells were observed using terminal deoxynucleotidyl transferase dUTP end-labeling (TUNEL) staining kits.ResultsWe found that surgery induced neuroinflammatory cognitive dysfunction, oxidative stress, microglial activation, and cell apoptosis in the hippocampus. Moreover, following surgery, NO and iNOS levels were elevated in the hippocampus. Notably, all the effects caused by surgery were reversed by the H2S donor GYY4137 or the iNOS inhibitor N(gamma)-nitro-L-arginine methyl ester (L-NAME). However, the combined application of GYY4137 and L-NAME was not superior to treatment with either agent alone and the effect of GYY4137 was similar to that of L-NAME.ConclusionThe long-acting hydrogen sulfide donor GYY4137 had an ability to reversed the cognitive deficits and inflammation caused by carotid artery exposure surgery. This implies that NO signaling pathways might participate in this process. These results indicate that exogenous H2S may be a promising therapy for POCD.
Highlights
To investigate the effect and mechanisms of exogenous hydrogen sulfide in surgery-induced neuroinflammatory cognitive dysfunction
Exogenous Hydrogen sulfide (H2S) reverses impaired cognitive function without altering the locomotor dysfunction caused by surgical injury, and is similar to L-nitro-arginine methyl ester (L-NAME) In our study, cognitive performance was assessed using the open field tests (OFT) and Morris water maze (MWM)
Compared with the sham group, the exogenous H2S donor GYY4137 significantly improved spatial learning and memory capacity, and, compared with the surgery group, GYY4137 could partially reverse the effects of surgical injury
Summary
To investigate the effect and mechanisms of exogenous hydrogen sulfide in surgery-induced neuroinflammatory cognitive dysfunction. Post-operative cognitive dysfunction (POCD) is characterized by cognitive impairments, including learning and memory deficits in patients after anesthesia and surgery, and affects about 30% of young and elderly patients after hospital discharge [1,2,3]. Structural and biochemical alterations, such as reduced neurogenesis and the induction of neuroinflammation in the hippocampus, an area of the brain mainly responsible for cognition that is highly vulnerable to aging, are most likely the mechanisms underlying POCD [10,11,12,13]. Animal studies suggest that neuroinflammation may be a major cause of anesthesia and surgery-induced cognitive impairment [14, 15]. The causes and pathogenesis of POCD are yet to be fully investigated
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