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Recombinant human brain natriuretic peptide attenuates ischemic brain injury in mice by inhibiting oxidative stress and cell apoptosis via activation of PI3K/AKT/Nrf2/HO-1 pathway

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Abstract

Ischemic stroke followed by cerebral artery occlusion is a main cause of chronic disability worldwide. Recombinant human brain natriuretic peptide (rhBNP) has been reported to alleviate sepsis-induced cognitive dysfunction and brain I/R injury. However, the function and molecular mechanisms of rhBNP in ischemic brain injury have not been clarified. For establishment of an animal model of ischemic brain injury, C57BL/6 mice were treated with middle cerebral artery occlusion (MCAO) surgery for 1 h and reperfusion for 24 h. After subcutaneous injection of rhBNP into model mice, neurologic deficits were assessed by evaluating behavior of mice according to Longa scoring system, and TTC staining was utilized to determine the brain infarct size of mice. The levels of oxidative stress markers, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA), were detected in hippocampal tissues of mice by corresponding kits. Cell apoptosis in hippocampus tissues was examined by TUNEL staining. Protein levels of antioxidant enzymes (HO-1 and NQO1) in cerebral cortex, apoptotic markers (Bax, Bcl-2, and cleaved caspase), and PI3K/AKT pathway-associated factors in hippocampus were tested by western blot analysis. The results revealed that injection of rhBNP decreased neurologic deficit scores, the percent of brain water content, and infarct volume. Additionally, rhBNP downregulated MDA level, upregulated the levels of SOD, CAT, and GSH in hippocampus of mice, and increased protein levels of HO-1 and NQO1 in the cortex. Cell apoptosis in hippocampus tissues of model mice was inhibited by rhBNP which was shown as the reduced TUNEL-positive cells, the decreased Bax, cleaved caspase-3, and cleaved caspase-9 protein levels, and the enhanced Bcl-2 protein level. In addition, rhBNP treatment activated the PI3K/AKT signaling pathway and upregulated the protein levels of HO-1 and NRF2. Overall, rhBNP activates the PI3K/AKT/HO-1/NRF2 pathway to attenuate ischemic brain injury in mice after MCAO by suppression of cell apoptosis and oxidative stress.

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All data generated or analyzed during this study are included either in this article or in the supplementary information files.

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Acknowledgements

The authors appreciate all the participants providing supports for this study.

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  1. Tong Li and DaJing Su have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Nanning Second People’s Hospital, Nanning, 530031, China

    Tong Li, DaJing Su, HuaWen Lu, YunQing Gao, ShaoHua Wang, YuTing Hou, KeMin Qin, XianTing Que, XiaoPing Chen, BaiLing Qin & ZiJun Wang

  2. Department of Urology Surgery, Nanning Second People’s Hospital, Nanning, 530031, China

    YongGang Liu

  3. Department of Medical Records, Nanning Second People’s Hospital, No. 13, Dancun Road, Jiangnan District, Nanning, 530031, Guangxi, China

    Yan Deng

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  1. Tong Li
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Contributions

TL and DJS were the main designers of this study. TL, DJS, HWL, YQG, YGL, SHW, YTH, KMQ, XTQ and YD performed the experiments and analyzed the data. TL, DJS, XPC, BLQ, ZJW and YD drafted the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yan Deng.

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The authors declare no conflicts of interest.

Ethical approval

All the experiments associated with animals were in line the Care and Use of Laboratory Animals and had been approved by the Ethics Committee of Nanning Second People’s Hospital.

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Communicated by Sreedharan Sajikumar.

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Li, T., Su, D., Lu, H. et al. Recombinant human brain natriuretic peptide attenuates ischemic brain injury in mice by inhibiting oxidative stress and cell apoptosis via activation of PI3K/AKT/Nrf2/HO-1 pathway. Exp Brain Res 241, 2751–2763 (2023). https://doi.org/10.1007/s00221-023-06716-4

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