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Alda-1, an Activator of ALDH2, Improves Postresuscitation Cardiac and Neurological Outcomes by Inhibiting Pyroptosis in Swine

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Abstract

Aldehyde dehydrogenase 2 (ALDH2) has been proven to protect the heart and brain against regional ischemia/reperfusion injury, in which the protective role is related to the inhibition of pyroptosis. In the present study, we investigated whether an ALDH2 activator N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichloro-benzamide (Alda-1) would improve postresuscitation cardiac and neurological outcomes in a clinically relevant swine model of cardiac arrest (CA) and resuscitation. The animal model was established by 8 min of untreated ventricular fibrillation and then 8 min of cardiopulmonary resuscitation (CPR). After restoring spontaneous circulation, the animals were randomly divided to receive either Alda-1 (0.88 mg/kg, n = 6) or saline (n = 5). Postresuscitation hemodynamic parameters, cardiac function, and cardiac and cerebral injuries were periodically measured for a total of 24 h. At 24 h postresuscitation, neurological function was evaluated, and then the animals were sacrificed, and cardiac and cerebral tissue samples were obtained for the measurements of oxidative stress, inflammation and pyroptosis. Consequently, postresuscitation cardiac and neurological dysfunction were significantly improved accompanied with significantly milder cardiac and cerebral injuries in the Alda-1 group compared with the CPR group. In addition, the increase in NLR family pyrin domain-containing 3 inflammasome expression and proinflammatory cytokine production, which indicated the occurrence of inflammatory response, were significantly less in the Alda1 group than in the CPR group. The expression level of gasdermin D used as a protein marker of pyroptosis was also significantly reduced in all resuscitated animals receiving Alda1 treatment. Moreover, the severity of oxidative stress indicated by the changes of 4-hydroxy-2-nonenal and malondialdehyde was significantly decreased in the heart and brain in all animals treated with Alda-1 compared to the CPR group. Thus, Alda-1 mitigated postresuscitation cardiac and neurological dysfunction and injuries possibly by inhibiting oxidative stress-mediated NLRP3 inflammasome activation and pyroptosis in a swine model of CA and resuscitation.

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Data Availability

The data that support the findings of this study are included in electronic Supplementary Material.

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Acknowledgements

We thank AJE (www.aje.com) for its linguistic assistance during the preparation of this manuscript.

Funding

This study was funded by research Grants from the National Natural Science Foundation of China (Nos. 82002008 and 82072126), and Zhejiang Provincial Public Welfare Research Project (No. LGD20H150002).

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Author notes

  1. Mengyuan Diao, Jiefeng Xu and Jiangang Wang have contributed equally to this work.

Authors and Affiliations

  1. Department of Critical Care Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, No. 261 Huansha Road, Hangzhou, 310006, China

    Mengyuan Diao, Chenghao Wu, Ying Zhu & Wei Hu

  2. Department of Emergency Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, China

    Jiefeng Xu, Minhai Zhang & Mao Zhang

  3. Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, No. 88 Jiefang Road, Hangzhou, 310009, China

    Jiefeng Xu, Minhai Zhang & Mao Zhang

  4. Hangzhou Emergency Medical Center of Zhejiang Province, No. 568 Mingshi Road, Hangzhou, 310021, China

    Jiangang Wang

  5. Department of Anesthesiology, First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, China

    Xin Hu

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  1. Mengyuan Diao
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Contributions

MD, JX, MZ and WH conceived, designed and supervised the study. MD, JX, JW, MZ, FL, LS, ZK, CW and YZ performed the experiments. MD, JX, and MZ analyzed the data. MD wrote the manuscript. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Mao Zhang or Wei Hu.

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The authors declare that they have no conflict of interest.

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All the animal experiments in this study were approved by the Institutional Animal Care and Use Committee of Second Affiliated Hospital, Zhejiang University School of Medicine.

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Supplementary Information

Below is the link to the electronic supplementary material.

11064_2021_3511_MOESM1_ESM.eps

Supplementary file1 Fig S1. Immunofluorescence staining of Cleaved Caspase-1, and GSDMD in the myocardium at 24 hours after resuscitation in different groups. (A) Representative images of Cleaved Caspase-1. (B) Representative images of GSDMD (EPS 107 KB)

11064_2021_3511_MOESM2_ESM.eps

Supplementary file2 Fig S2. Immunofluorescence staining of Cleaved Caspase-1, and GSDMD in the hippocampus at 24 hours after resuscitation in different groups. (A) Representative images of Cleaved Caspase-1. (B) Representative images of GSDMD (EPS 79 KB)

11064_2021_3511_MOESM3_ESM.eps

Supplementary file3 Fig S3. Immunofluorescence staining of Cleaved Caspase-1, and GSDMD in the cortex at 24 hours after resuscitation in different groups. (A) Representative images of Cleaved Caspase-1. (B) Representative images of GSDMD (EPS 75 KB)

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Diao, M., Xu, J., Wang, J. et al. Alda-1, an Activator of ALDH2, Improves Postresuscitation Cardiac and Neurological Outcomes by Inhibiting Pyroptosis in Swine. Neurochem Res 47, 1097–1109 (2022). https://doi.org/10.1007/s11064-021-03511-x

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