1400 W ameliorates acute hypobaric hypoxia/reoxygenation-induced cognitive deficits by suppressing the induction of inducible nitric oxide synthase in rat cerebral cortex microglia

Shi, Qinghai; Liu, Xin; Wang, Ning; Zheng, Xinchuan; Ran, Juntao; Liu, Zhengxiang; Fu, Jianfeng; Zheng, Jie

doi:10.1016/j.bbr.2016.11.039

Cited by 11 publications

(8 citation statements)

References 62 publications

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“…On the other hand, iNOS expression appears to increase after 24 h of reoxygenation, [57]. The NO • can generate peroxynitrite (ONOO – ), thus increasing damage due to oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain

et al. 2017

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Acute hypoxia increases the formation of reactive oxygen species (ROS) in the brain. However, the effect of reoxygenation, unavoidable to achieve full recovery of the hypoxic organ, has not been clearly established. The aim of the present study was to evaluate the effects of exposition to acute severe respiratory hypoxia followed by reoxygenation on the evolution of oxidative stress and apoptosis in the brain. We investigated the effect of in vivo acute severe normobaric hypoxia (rats exposed to 7% O2 for 6 h) and reoxygenation in normoxia (21% O2 for 24 h or 48 h) on oxidative stress markers, the antioxidant system and apoptosis in the brain. After respiratory hypoxia we found increased levels of HIF-1α expression, lipid peroxidation, protein oxidation and nitric oxide in brain extracts. Antioxidant defence systems such as superoxide dismutase (SOD), reduced glutathione (GSH) and glutathione peroxidase (GPx) and the reduced/oxidized glutathione (GSH/GSSG) ratio were significantly decreased in the brain. After 24 h of reoxygenation, oxidative stress parameters and the anti-oxidant system returned to control values. Regarding the apoptosis parameters, acute hypoxia increased cytochrome c, AIF and caspase 3 activity in the brain. The apoptotic effect is greatest after 24 h of reoxygenation. Immunohistochemistry suggests that CA3 and dentate gyrus in the hippocampus seem more susceptible to hypoxia than the cortex. Severe acute hypoxia increases oxidative damage, which in turn could activate apoptotic mechanisms. Our work is the first to demonstrate that after 24 h of reoxygenation oxidative stress is attenuated, while apoptosis is maintained mainly in the hippocampus, which may, in fact, be the cause of impaired brain function.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain

et al. 2017

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“…Additionally, NO induces neuronal modifications, for example, microglial activation, neuronal cell apoptosis, and oxidative stress, and high concentrations of NO are harmful to cognitive performance. The bioavailability of NO is recognized as a predictive risk marker for AD and early POCD [17][18][19]. Therefore, the surgery-induced inflammatory response, which induces high levels of iNOS expression in the hippocampus, then causes NO overproduction in the hippocampus followed by the promotion of oxidative stress, microglial activation, neuronal cell apoptosis, and hippocampal lesions eventually induce the development of POCD.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, NO is involved in cellular modifications such as microglial activation, neuronal cell apoptosis, and oxidative stress, and overproduction of NO impairs cognitive function. The bioavailability of NO is recognized as a predictive risk factor for Alzheimer's disease (AD) and early POCD [17][18][19]. NO is synthetized by nitric oxide synthases (NOS), which are grouped into three classes: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS).…”

Section: Introductionmentioning

confidence: 99%

“…The production of iNOS is not restricted to specific cells but is expressed following different stimuli such as inflammation, and is a major pro-inflammatory and destructive mediator in inflammatory disease [20]. 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].…”

Section: Introductionmentioning

confidence: 99%

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

Yin

Shun-li

2020

BMC Anesthesiol

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Background: To investigate the effect and mechanisms of exogenous hydrogen sulfide in surgery-induced neuroinflammatory cognitive dysfunction. Methods: C57BL/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. Results: We 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 H 2 S 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. Conclusion: The 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 H 2 S may be a promising therapy for POCD.

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“…THP-1 cells were seeded into 6-well plates and induced with phorbol 12-myristate 13-acetate. After incubation for 12 h and observation of adherent growth, the THP-1 cells were randomized into 4 groups treated as follows: blank control, 4 Gy radiation, 1400W treatment (60 μM), 4 Gy radiation combined with 1400W treatment (60 μM) [24]. After incubation for 12 h and 24 h, the supernatant was collected and applied to Jurkat cells cultured in 6-well plates.…”

Section: T Cell Proliferation Assaymentioning

confidence: 99%

Downregulation of Nitric Oxide Collaborated with Radiotherapy to Promote Anti-Tumor Immune Response via Inducing CD8+ T Cell Infiltration

Xu¹,

Luo²,

Yuan³

et al. 2020

Int. J. Biol. Sci.

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The production of nitric oxide (NO) is a key feature of immunosuppressive myeloid cells, which impair T cell activation and proliferation via reversibly blocking interleukin-2 receptor signaling. NO is mainly produced from L-arginine by inducible NO synthase (iNOS). Moreover, L-arginine is an essential element for T cell proliferation and behaviors. Impaired T cell function further inhibits anti-tumor immunity and promotes tumor progression. Previous studies indicated that radiotherapy activated anti-tumor immune responses in multiple tumors. However, myeloid-derived cells in the tumor microenvironment may neutralize these responses. We hypothesized that iNOS, as an important regulator of the immunosuppressive effects in myeloid-derived cells, mediated radiation resistance of cancer cells. In this study, we used 1400W dihydrochloride, a potent small-molecule inhibitor of iNOS, to explore the regulatory roles of NO in anti-tumor immunity. Radiotherapy and iNOS inhibition by 1400W collaboratively suppressed tumor growth and increased survival time, as well as increased tumor-infiltrating CD8 + T cells and specific inflammatory cytokine levels, in both lung and breast cancer cells in vivo. Our results also suggested that myeloid cell-mediated inhibition of T cell proliferation was effectively counteracted by radiation and 1400W-mediated NO blockade in vitro. Thus, these results demonstrated that iNOS was an important regulator of radiotherapy-induced antitumor immune responses. The combination of radiotherapy with iNOS blockade might be an effective therapy to improve the response of tumors to clinical radiation.

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1400 W ameliorates acute hypobaric hypoxia/reoxygenation-induced cognitive deficits by suppressing the induction of inducible nitric oxide synthase in rat cerebral cortex microglia

Cited by 11 publications

References 62 publications

Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain

Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain

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

Downregulation of Nitric Oxide Collaborated with Radiotherapy to Promote Anti-Tumor Immune Response via Inducing CD8+ T Cell Infiltration

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