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Permissive hypercapnia and hypercapnic hypoxia inhibit signaling pathways of neuronal apoptosis in ischemic/hypoxic rats

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Abstract

Introduction

In the present study, we aimed to test the hypothesis that hypercapnia, independently and/or in combination with hypoxia, can activate signaling pathways related to the inhibition of proapoptotic (caspase-dependent and caspase-independent) factors and the induction of antiapoptotic factors in facilitating adaptation to hypoxia/ischemia.

Materials and methods

Following exposure to permissive hypercapnia and/or normobaric hypoxia, the degree of apoptosis was evaluated in experimental ischemia models in vivo and in vitro. The percentages of caspase-3, apoptosis-inducing factor (AIF), Bax, and Bcl-2 in astrocytes and neurons derived from male Wistar rats were also calculated. In vitro, cells were subjected to various types of respiratory exposure (hypoxia and/or hypercapnia for 24 or 12 h) as well as further sublethal chemical hypoxia. The percentages of these molecules in nerve cells in the ischemic penumbra of the brain after photothrombotic injury were also calculated.

Results

The degree of apoptosis was found to decrease in ischemic penumbra, mostly due to the hypercapnic component. It was also discovered that the levels of caspase-3, AIF, and Bax decreased in this region, whereas the Bcl-2 levels increased following exposure to hypercapnia and hypercapnic hypoxia.

Conclusions

This integrative assessment of the rate of apoptosis/necrosis in astrocyte and neuron cultures shows that the combination of hypercapnia and hypoxia resulted in the maximum neuroprotective effect. The levels of apoptosis mediators in astrocyte and neuron cultures were calculated after modeling chemical hypoxia in vitro. These results show that the exposure models where permissive hypercapnia and normobaric hypoxia were combined also had the most pronounced inhibitory effects on apoptotic signaling pathways.

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Acknowledgements

The study was supported by a grant from the Russian Science Foundation (Project No. 18-75-00016). We wish to thank Prof. Alla Salmina and Dr. Elizaveta Boytsova for great help in the work on this study. The work was done using the resource base Shared Core Facilities Molecular and Cell Technologies Krasnoyarsk State Medical University.

Funding

Funding was provided by Russian Science Foundation (Grant no. 18-75-00016).

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Authors and Affiliations

  1. Krasnoyarsk State Medical University Named After Prof. V.F. Voino-Yasenetsky, Krasnoyarsk, Russia, 660022

    Pavel Tregub, Natalia Malinovskaya, Elena Hilazheva & Andrey Morgun

  2. Altai Medical Institute of Postgraduate Education, Barnaul, Russia, 656000

    Vladimir Kulikov

  3. Federal State Budgetary Scientific Institution Research Center of Neurology, Volokolamsk Highway, 80, Moscow, Russia, 125367

    Pavel Tregub

  4. Altay State Medial University, Barnaul, Russia, 656000

    Vladimir Kulikov

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  1. Pavel Tregub
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Corresponding author

Correspondence to Pavel Tregub.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the local Ethics Committee of Krasnoyarsk State Medical University (protocol code No. 81/2018, date of approval—22.02.2018). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed (EU Directive 2010/63/EU for animal experiments).

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Tregub, P., Malinovskaya, N., Hilazheva, E. et al. Permissive hypercapnia and hypercapnic hypoxia inhibit signaling pathways of neuronal apoptosis in ischemic/hypoxic rats. Mol Biol Rep 50, 2317–2333 (2023). https://doi.org/10.1007/s11033-022-08212-4

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