Investigations into hydrogen sulfide-induced suppression of neuronal activity in vivo and calcium dysregulation in vitro

Dong-Suk Kim; Isaac N Pessah; Cristina M Santana; Benton Purnell; Rui Li; Gordon F Buchanan; Wilson K Rumbeiha

doi:10.1093/toxsci/kfad022

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Investigations into hydrogen sulfide-induced suppression of neuronal activity in vivo and calcium dysregulation in vitro

Journal article

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Investigations into hydrogen sulfide-induced suppression of neuronal activity in vivo and calcium dysregulation in vitro

Dong-Suk Kim, Isaac N Pessah, Cristina M Santana, Benton Purnell, Rui Li, Gordon F Buchanan and Wilson K Rumbeiha

Toxicological sciences, Vol.192(2), pp.247-264

04/2023

DOI: 10.1093/toxsci/kfad022

PMCID: PMC10109532

PMID: 36882182

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Abstract

Acute exposure to high concentrations of hydrogen sulfide (H2S) leads to sudden death and, if survived, lingering neurological disorders. Clinical signs include seizures, loss of consciousness, and dyspnea. The proximate mechanisms underlying H2S-induced acute toxicity and death have not been clearly elucidated. We investigated electrocerebral, cardiac and respiratory activity during H2S exposure using electroencephalogram (EEG), electrocardiogram (EKG) and plethysmography. H2S suppressed electrocerebral activity and disrupted breathing. Cardiac activity was comparatively less affected. To test whether Ca2+ dysregulation contributes to H2S-induced EEG suppression, we developed an in vitro real-time rapid throughput assay measuring patterns of spontaneous synchronized Ca2+ oscillations in cultured primary cortical neuronal networks loaded with the indicator Fluo-4 using the fluorescent imaging plate reader (FLIPR-Tetra®). Sulfide >5 ppm dysregulated synchronous calcium oscillation (SCO) patterns in a dose-dependent manner. Inhibitors of NMDA and AMPA receptors magnified H2S-induced SCO suppression. Inhibitors of L-type voltage gated Ca2+ channels and transient receptor potential channels prevented H2S-induced SCO suppression. Inhibitors of T-type voltage gated Ca2+ channels, ryanodine receptors, and sodium channels had no measurable influence on H2S-induced SCO suppression. Exposures to > 5 ppm sulfide also suppressed neuronal electrical activity in primary cortical neurons measured by multi-electrode array (MEA), an effect alleviated by pretreatment with the nonselective transient receptor potential channel inhibitor, 2-APB. 2-APB also reduced primary cortical neuronal cell death from sulfide exposure. These results improve our understanding of the role of different Ca2+ channels in acute H2S-induced neurotoxicity and identify transient receptor potential channel modulators as novel structures with potential therapeutic benefits.

neurotoxicity

hydrogen sulfide

L-type calcium channel

calcium dysregulation

in vitro models

transient receptor potential

Details

Title: Subtitle: Investigations into hydrogen sulfide-induced suppression of neuronal activity in vivo and calcium dysregulation in vitro
Creators: Dong-Suk Kim - University of California, Davis
Isaac N Pessah - University of California, Davis
Cristina M Santana - MRIGlobal
Benton Purnell - University of Iowa
Rui Li - University of Iowa
Gordon F Buchanan - University of Iowa
Wilson K Rumbeiha - University of California, Davis
Resource Type: Journal article
Publication Details: Toxicological sciences, Vol.192(2), pp.247-264
DOI: 10.1093/toxsci/kfad022
PMID: 36882182
PMCID: PMC10109532
NLM abbreviation: Toxicol Sci
eISSN: 1096-0929
Grant note: name: UC Davis and Iowa State University for Wilson Rumbeiha
Language: English
Electronic publication date: 03/06/2023
Date published: 04/2023
Academic Unit: Neurology; Iowa Neuroscience Institute
Record Identifier: 9984378111102771

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