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Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome

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Abstract

Early brain injury (EBI), highlighted with inflammation and apoptosis, occurring within 72 h after subarachnoid hemorrhage (SAH), is associated with the prognosis of SAH. Recent studies have revealed that hydrogen-rich saline (HS) exerted multiple neuroprotective properties in many neurological diseases including SAH, involved to anti-oxidative and anti-apoptotic effect. We have previously reported that HS could attenuate neuronal apoptosis as well as vasospasm. However, the underlying mechanism of HS on inflammation in SAH-induced EBI remains unclear. In this study, we explored the influence of HS on nuclear factor-κB (NF-κB) pathway and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome at early stage after SAH, by injecting HS intraperitoneally to SAH rats. One hundred and twenty-nine SD rats were randomly divided into four groups: sham group, SAH group, SAH+vehicle group, and SAH+HS group. SAH model was conducted using endovascular perforation method; all rats were sacrificed at 24 h after SAH. Protein level of pIκBα, cytosolic and nuclear p65, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, interleukin-1β (IL-1β), and cleaved caspase-3 were measured by western blot. mRNA level of IL-1β, interleukin-6 (IL-6), tumor necrosis factor-c (TNF-α) were evaluated by RT-PCR. Cellular injury and death was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Nissl staining, respectively. Our results showed that pIκBα, nuclear p65, NLRP3, ASC, caspase-1, IL-1β, cleaved caspase-3 proteins, as well as the mRNA of IL-1β, IL-6, and TNF-ɑ increased at 24 h after SAH, while cytosolic p65 decreased. TUNEL and Nissl staining presented severe cellular injury at 24 h post-SAH. However, after HS administration, the changes mentioned above were reversed. In conclusion, HS may inhibit inflammation in EBI and improve neurobehavioral outcome after SAH, partially via inactivation of NF-κB pathway and NLRP3 inflammasome.

Schematic representation of the mechanism of HS-mediated anti-inflammatory effect in EBI after SAH. The NF-κB inflammatory pathway and NLRP3 inflammasome are involved in the anti-neuroinflammatory effect of HS post-SAH. SAH-induced oxidative stress enhances the activation of NF-κB, thus promoting the translocation of p65 subunit into nucleus and increasing the mRNA level of its downstream proinflammatory cytokines (IL-1β, IN-6, TNF-α) and NLRP3. Elevated expression of NLRP3 mRNA increases the assembly of NLRP3 inflammasome. In addition, oxidative stress after SAH stimulates the activation of NLRP3 inflammasome, therefore, promoting caspase-1 activation and the cleavage of pro-IL-1β into mature IL-1β. Finally, activation of NF-κB pathway and NLRP3 inflammasome contribute to the inflammation response and cellular injury in EBI after SAH. HS treatment reversed the detrimental effect mentioned above via inactivation of NF-κB pathway and NLRP3 inflammasome. NF-κB nuclear factor-κB, IκB inhibitor of NF-κB, IKK Iκ kinase, NLRP3 nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3, ASC apoptosis-associated speck-like protein containing a caspase recruitment domain

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Abbreviations

SAH:

Subarachnoid hemorrhage

EBI:

Early brain injury

ROS:

Reactive oxygen species

HS:

Hydrogen-rich saline

NF-κB:

Nuclear factor-κB

IκB:

Inhibitor of NF-κB

IKK:

Iκ kinase

NLRP3:

Nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3

ASC:

Apoptosis-associated speck-like protein containing a caspase recruitment domain

MDA:

Malondialdehyde

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

DIND:

Delayed ischemic neurological deficit

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Acknowledgments

This study was supported by Zhenni Guo from the First Norman Bethune Hospital of Jilin University and Lusha Tong from the Second Affiliated Hospital, School of Medicine, Zhejiang University. This work was supported by grant 81171096, 81371369, and 81371433 from the National Natural Science Foundation of China. This study was also supported by Grant 2011KYA49 from Health department of Zhejiang province (Zhao Qiong).

Compliance with Ethical Standards

All experimental protocols involving animals (including all surgical procedure) were approved by the Institutional Animal Care and Use Committee (IACUC) of Zhejiang University. All rat experimental procedures were performed in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals approved by the State Council of People’s Republic of China.

Conflict of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

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    Authors and Affiliations

    1. Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China

      Anwen Shao, Haijian Wu, Yuan Hong, Qun Wu & Jianmin Zhang

    2. Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China

      Sheng Tu & Qiong Zhao

    3. Department of Diving Medicine, The Second Military Medical University, Shanghai, 200433, China

      Xuejun Sun

    4. Brain Research Institute, Zhejiang University, Hangzhou, 310009, China

      Jianmin Zhang

    5. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China

      Jifang Sheng

    6. Department of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China

      Jifang Sheng

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    1. Anwen Shao
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    Correspondence to Qiong Zhao or Jianmin Zhang.

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    Anwen Shao and Haijian Wu contributed equally to this work.

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    Shao, A., Wu, H., Hong, Y. et al. Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome. Mol Neurobiol 53, 3462–3476 (2016). https://doi.org/10.1007/s12035-015-9242-y

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