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Novel neurosteroid pregnanolone pyroglutamate suppresses neurotoxicity syndrome induced by tetramethylenedisulfotetramine but is ineffective in a rodent model of infantile spasms

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Abstract

Background

Neurosteroids are investigated as effective antidotes for the poisoning induced by tetramethylenedisulfotetramine (TMDT) as well as treatments for epileptic spasms during infancy. Both these conditions are quite resistant to pharmacotherapy; thus, a search for new treatments is warranted.

Methods

In this study, we determined the efficacy of two novel neurosteroids, pregnanolone glutamate (PAG) and pregnanolone pyroglutamate (PPG), and tested these drugs in doses of 1–10 mg/kg (ip) against the TMDT syndrome and in our rodent model of infantile spasms.

Results

Only PPG in doses 5 and 10 mg/kg suppressed the severity of the TMDT syndrome and TMDT-induced lethality, while the 1 mg/kg dose was without an effect. Interestingly, the 1 mg/kg dose of PPG in combination with 1 mg/kg of diazepam was also effective against TMDT poisoning. Neither PAG nor PPG were effective against experimental spasms in the N-methyl-D-aspartate (NMDA)-triggered model of infantile spasms.

Conclusions

While evidence suggests that PAG can act through multiple actions which include allosteric inhibition of NMDA-induced and glycine receptor-evoked currents as well as augmentation of ɣ-aminobutyric acid subtype A (GABAA) receptor-induced currents, the agent appears to neither have the appropriate mechanistic signature for activity in the infantile spasm model, nor the adequate potency, relative to PPG, for ameliorating the TMDT syndrome. The full mechanisms of action of PPG, which may become a potent TMDT antidote either alone or in combination with diazepam are yet unknown and thus require further investigation.

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Data availability

All data generated or analysed during this study are included as supplementary information files.

Abbreviations

ACTH:

Adrenocorticotropic hormone

ANOVA:

Analysis of variance

CDX:

Cyclodextrin

DMSO:

Dimethylsulfoxide

DZP:

Diazepam

EEG:

Electroencephalography

G:

Gestational day

GABA:

ɣ-Aminobutyric acid

GABAAR:

ɣ-Aminobutyric acid receptor subtype A

IACUC:

Institutional animal use and care committee

ip :

Intraperitoneal

IS:

Infantile spasms

NIH:

National Institutes of Health

NMDA:

N-methyl-D-aspartate

P:

Postnatal day

PAG:

Pregnanolone glutamate

PPG:

Pregnanolone pyroglutamate

sc :

Subcutaneous

TBPS:

Tert-butylbicyclophosphorothionate

TMDT:

Tetramethylenedisulfotetramine, also TETS

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Funding

This study was supported by the Institute of Organic Chemistry and Biochemistry Grant and NIH-NINDS award R21NS118337-01 to LV. MPS was supported by the NIH-CounterACT Program (R21NS084900). JV was supported by R01NS092786 from NIH-NINDS.

Author information

Authors and Affiliations

  1. Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA

    Chian-Ru Chern, Marcela Lauková, Antonia Schonwald, Chian-Jiang Chern, Michael P. Shakarjian, Jana Velíšková & Libor Velíšek

  2. Institute of Experimental Endocrinology, Biomedical Research Center of the Slovak Academy of Science, Bratislava, Slovakia

    Marcela Lauková

  3. Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic

    Eva Kudová & Hana Chodounská

  4. Department of Public Health, Environmental Health Science Program, New York Medical College, Valhalla, NY, USA

    Michael P. Shakarjian

  5. Department of Obstetrics and Gynecology, New York Medical College, Valhalla, NY, USA

    Jana Velíšková

  6. Department of Neurology, New York Medical College, Valhalla, NY, USA

    Jana Velíšková & Libor Velíšek

  7. Department of Pediatrics, New York Medical College, Valhalla, NY, USA

    Libor Velíšek

  8. Department of Medicine, Division of Pulmonary and Critical Care Medicine, Rutgers-Robert Wood Johnson Medical School, 675 Hoes Ln W, Piscataway, NJ, 08854, USA

    Michael P. Shakarjian

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  1. Chian-Ru Chern
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  2. Marcela Lauková
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Contributions

EK, MPS, JV and LV conceptualized the work, analyzed and interpreted the data. C-RC, C-JC, AS, ML, HC, EK performed the experiments. All authors participated on drafting the manuscript and approved the final version.

Corresponding author

Correspondence to Libor Velíšek.

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Conflict of interest

LV is a consultant for Angelini Pharma on topics unrelated to this project. Other co-authors have no conflicts to report besides the funding statement.

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Chern, CR., Lauková, M., Schonwald, A. et al. Novel neurosteroid pregnanolone pyroglutamate suppresses neurotoxicity syndrome induced by tetramethylenedisulfotetramine but is ineffective in a rodent model of infantile spasms. Pharmacol. Rep 75, 177–188 (2023). https://doi.org/10.1007/s43440-022-00437-1

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