HSP70 protects rats and hippocampal neurons from central nervous system oxygen toxicity by suppression of NO production and NF-κB activation

Abstract

During diving, central nervous system oxygen toxicity may cause drowning or barotrauma, which has dramatically limited the working benefits of hyperbaric oxygen in underwater operations and clinical applications. The aim of this study is to understand the effects and the underlying mechanism of heat shock protein 70 on central nervous system oxygen toxicity and its mechanisms in vivo and in vitro. Rats were given geranylgeranylacetone (800 mg/kg) orally to induce hippocampal expression of heat shock protein 70 and then treated with hyperbaric oxygen. The time course of hippocampal heat shock protein 70 expression after geranylgeranylacetone administration was measured. Seizure latency and first electrical discharge were recorded to evaluate the effects of HSP70 on central nervous system oxygen toxicity. Effects of inhibitors of nitric oxide synthase and nuclear factor-κB on the seizure latencies and changes in nitric oxide, nitric oxide synthase, and nuclear factor-κB levels in the hippocampus tissues were examined. In cell experiments, hippocampal neurons were transfected with a virus vector carrying the heat shock protein 70 gene (H3445) before hyperbaric oxygen treatment. Cell viability, heat shock protein 70 expression, nitric oxide, nitric oxide synthase, and NF-κB levels in neurons were measured. The results showed that heat shock protein 70 expression significantly increased and peaked at 48 h after geranylgeranylacetone was given. Geranylgeranylacetone prolonged the first electrical discharge and seizure latencies, which was reversed by neuronal nitric oxide synthase, inducible nitric oxide synthase and NF-κB inhibitors. Nitric oxide, nitric oxide synthase, and inducible nitric oxide synthase levels in the hippocampus were significantly increased after hyperbaric oxygen exposure, but reversed by geranylgeranylacetone, while heat shock protein 70 inhibitor quercetin could inhibit this effect of geranylgeranylacetone. In the in vitro study, heat shock protein 70-overexpression decreased the nitric oxide, nitric oxide synthase, and inducible nitric oxide synthase levels as well as the cytoplasm/nucleus ratio of nuclear factor-κB and protected neurons from hyperbaric oxygen-induced cell injury. In conclusion, overexpression of heat shock protein 70 in hippocampal neurons may protect rats from central nervous system oxygen toxicity by suppression of neuronal nitric oxide synthase and inducible nitric oxide synthase-mediated nitric oxide production and translocation of nuclear factor-κB to nucleus. Impact statement Because the pathogenesis of central nervous system oxygen toxicity (CNS-OT) remains unclear, there are few interventions available. To develop an efficient strategy against CNS-OT, it is necessary to understand its pathogenesis and in particular, the relevant key factors involved. This study examined the protective effects of heat shock protein 70 (HSP70) on CNS-OT via in vivo and in vitro experiments. Our results indicated that overexpression of HSP70 in hippocampal neurons may protect rats from CNS...

Moringa oleiferaseed oil or virgin coconut oil supplementation abrogates cerebral neurotoxicity induced by antineoplastic agent methotrexate by suppression of oxidative stress and neuro‐inflammation in rats

“…We suggest that the consequence of MTX‐induced oxidative stress‐mediated pro‐inflammation is the prominent increases in TNF‐α, IL‐6 and NO levels. Nitric oxide may react with ROS or superoxide anion to produce peroxynitrite which has strong oxidizing and nitrification abilities to cause cerebral damage (Yi, Huang, Zhang, Liu, & Xu, ). Our findings are consistent with the literature that MTX provokes sciatic nerve and hepatorenal pro‐inflammation evident by markedly increased levels of TNF‐α, IL‐1β, IL‐6, NF‐кB and iNOS (Kandemir et al, ; Khafaga & El‐Sayed, ).…”

Hsc70-4 aggravates PolyQ-mediated neurodegeneration by modulating NF-κB mediated immune response in Drosophila

“…Studies have shown that hyperactivated immune response is one of the critical hallmarks of polyQ -mediated neurodegeneration ( Ellwardt and Zipp, 2014 ; McManus and Heneka, 2017 ; Gelders et al, 2018 ). Hsp70 regulates NF-κB activation by inhibiting IκB-α phosphorylation ( Huang et al, 2013 ; Chang et al, 2014 ; Wang et al, 2017 ; Yi et al, 2018 ). However, Hsc70 is involved in the activation of NF-κB via promoting phosphorylation of IκB-α and maintaining the NF-κB/IκB-α/IKKβ complex, thus playing a crucial role in the cleavage of inhibitor domain at the time of NF-κB activation ( Sheppard et al, 2014 ; Kumada et al, 2019 ).…”

The correlation between the granulocyte colony-stimulating factor and the Notch signaling pathway in ischemic brain injury

“…NF-κB and the hypoxia-inducing factor-1 alpha (HIF-1 alpha), which can be specifically activated in the ischemic CNS, are closely related to cerebral ischemia and reperfusion injury. [16] NF-κB is a multi-directional transcription factor that is commonly found in various human tissue, with its homologous or heterologous dimer protein belonging to the nf-tcB/Rel family. [17] By regulating gene expression, NF-κB participates in various biologic processes such as immunity, inflammation, and apoptosis.…”