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Cerebroprotective actions of hydrogen sulfide in the epileptic brain in newborn pigs

Pediatric Research volume 94, pages 495–502 (2023)Cite this article

Abstract

Background

Neonatal epileptic seizures cause postictal dysregulation of cerebral blood flow. Hydrogen sulfide (H2S), a mediator with vasodilator and antioxidant properties, is produced in the brain by astrocyte cystathionine β-synthase (CBS). This study investigated whether H2S improves the cerebral vascular outcome of seizures.

Methods

Epileptic seizures were induced in newborn pigs using bicuculline. The effects of the CBS inhibitor aminooxyacetate (AOA) and the H2S donor NaHS on cerebral vascular outcome of seizures were examined in live pigs, cerebral endothelial cells, and cortical astrocytes.

Results

Brain H2S was elevated during seizures. AOA blocked H2S and reduced functional hyperemia in the epileptic brain. The endothelium- and astrocyte-dependent vasodilation of pial arterioles was impaired 48 h after seizures suggesting cerebral vascular dysfunction. Systemic NaHS elevated brain H2S and blocked reactive oxygen species in the epileptic brain and in primary endothelial cells and astrocytes during inflammatory and excitotoxic conditions. Postictal cerebrovascular dysfunction was exaggerated in H2S-inhibited pigs and minimized in NaHS-treated pigs.

Conclusions

H2S elevation in the epileptic brain via activation of CBS contributes to functional hyperemia and exhibits cerebroprotective properties. The H2S donor NaHS enhances brain antioxidant defense and provides a therapeutic approach for preventing adverse cerebral vascular outcome of neonatal epileptic seizures.

Impact

  • Epileptic seizures in neonates lead to prolonged postictal cerebral vascular dysregulation.

  • The role of hydrogen sulfide (H2S), a mediator with vasodilator and antioxidant properties, in the epileptic brain has been explored.

  • Astrocytes are major sites of enzymatic H2S production in the epileptic brain.

  • Postictal cerebral vascular dysfunction is exaggerated when astrocyte H2S production is pharmacologically inhibited during seizures.

  • Postictal cerebral vascular dysfunction is minimized when the brain H2S is elevated by systemic administration of NaHS during seizures.

  • NaHS provides a therapeutic approach for improving cerebrovascular outcome of epileptic seizures via a mechanism that involves the antioxidant potential of H2S.

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Fig. 1: CBS contributes to brain H2S production and pial arteriolar dilation during seizures.
Fig. 2: CBS inhibition aggravates long-term impairment of postictal cerebral vasodilator functions.
Fig. 3: Systemic administration of NaHS increases H2S in the brain and dilates pial arterioles.
Fig. 4: Antioxidant effects of NaHS in the epileptic brain and in cultured neurovascular cells exposed to seizure-related pro-oxidants.
Fig. 5: NaHS improves long-term cerebral vascular outcome of neonatal seizures.
Fig. 6: NaHS prevents apoptosis caused by oxidative stress in cerebral microvascular endothelial cells and cortical astrocytes.

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Data availability

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. All data generated or analyzed during this study are included in this published article.

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Funding

The works were supported by awards NS101717 (to H.P.) and NS105655 (to H.P.) from the National Institutes of Health.

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Authors and Affiliations

  1. Departments of Physiology and Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA

    Jianxiong Liu, Massroor Pourcyrous, Alexander L. Fedinec & Helena Parfenova

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  1. Jianxiong Liu
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  2. Massroor Pourcyrous
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  3. Alexander L. Fedinec
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  4. Helena Parfenova
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Contributions

H.P., M.P., and J.L. conceived and designed research; J.L. and A.F. performed experiments; H.P., J.L., and A.F. analyzed data; H.P., M.P., and J.L. interpreted results of experiments; H.P., M.P., and J.L. drafted, edited, and revised manuscript; all authors approved the final version of the manuscript.

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Correspondence to Helena Parfenova.

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Liu, J., Pourcyrous, M., Fedinec, A.L. et al. Cerebroprotective actions of hydrogen sulfide in the epileptic brain in newborn pigs. Pediatr Res 94, 495–502 (2023). https://doi.org/10.1038/s41390-023-02486-5

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