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Treatment of Stroke at a Delayed Timepoint with a Repurposed Drug Targeting Sigma 1 Receptors

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Abstract

Sigma 1 receptors are intracellular chaperone proteins that have been explored as a subacute treatment to enhance post-stroke recovery. We recently identified the antitussive oxeladin as a selective sigma 1 receptor agonist with the ability to stimulate the release of brain-derived neurotrophic factor from neurons in vitro. In this study, we hypothesized that oral oxeladin citrate would stimulate BDNF secretion and improve stroke outcomes when administered to male rats starting 48 h after transient middle cerebral artery occlusion. Oxeladin did not alter blood clotting and crossed the blood brain barrier within 30 min of oral administration. Rats underwent 90 min of transient middle cerebral artery occlusion. Forty-eight hours later rats began receiving daily oxeladin (135 mg/kg) for 11 days. Oxeladin significantly improved neurological function on days 3, 7, and 14 following MCAO. Infarct size was not altered by a single dose, but the final extent of infarct after 14 days was decreased. However, there was no significant reduction in astrogliosis or microgliosis compared to vehicle-treated control rats. In agreement with in vitro studies, oxeladin increased the amount of mature BDNF in the cerebral cortex 2, 6, and 24 h after single oral dose. However, the increase in BDNF did not result in increases in cellular proliferation in the subventricular zone or dentate gyrus when compared to vehicle-treated controls. These results suggest that oxeladin may reduce the extent of infarct expansion in the subacute phase of stroke, although this action does not appear to involve a reduction in inflammation or increased cell proliferation.

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Data Availability

The corresponding author will make data available upon request.

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Acknowledgements

The authors thank Dr. Fen Sun for help in performance of these experiments.

Funding

This work was supported by the National Institutes of Health NIH 1R21NS095271-01A1 to D.A.S. and J.A.S.

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Authors and Affiliations

  1. Department of Pharmacology and Neuroscience, University of North Texas Helath Science Center, Fort Worth, Texas, 76107, USA

    Derek A. Schreihofer, Daniel Metzger, Anthony Oppong-Gyebi & John A. Schetz

  2. Capsigen, 1010 Washington Street, Vancouver, WA, 98660, USA

    Dhwanil Dalwadi

  3. Department of Cellular and Molecular Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, 60153, USA

    Seongcheol Kim

  4. Cognizant Technology Solutions, 300 Frank W. Burr Blvd, Teaneck, NJ, 07666, USA

    Anthony Oppong-Gyebi

  5. Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas, 76107, USA

    Paromita Das-Earl

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  1. Derek A. Schreihofer
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Contributions

Derek A. Schreihofer: Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Visualization; Writing—original draft; Writing—review & editing. Dhwanil Dilwadi: Investigation. Seongcheol Kim: Investigation, Formal analysis. Daniel Metzger: Investigation, Formal analysis. Anthony Oppong-Gyebi: Investigation, Formal analysis. Paromita Das-Earl: Investigation, Methodology. John A. Schetz: Conceptualization; Data curation; Formal analysis; Funding acquisition; Methodology; Project administration; Resources; Supervision; Validation.

Corresponding author

Correspondence to Derek A. Schreihofer.

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Ethical Approval

All procedures were approved by the UNTHSC Institutional Animal Care and Use Committee in accordance with the Guide for the Care and Use of Laboratory Animals.

Competing Interests

Derek A. Schreihofer wishes to declare on behalf of himself and John A. Schetz (deceased).

U.S. Provisional Patent Application.

Title: Drug Repurposing For Delayed Treatment of Ischemic Stroke.

Serial NO.: 63/308,259.

Filing data: February 9, 2022.

Inventors: D. Schreihofer and J. Schetz.

HSC Ref. No.: 2021–016-01.PRO.

Attorney File No.: UNTH.P0008US.P1.

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John A. Schetz is deceased. This paper is dedicated to his memory.

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Schreihofer, D.A., Dalwadi, D., Kim, S. et al. Treatment of Stroke at a Delayed Timepoint with a Repurposed Drug Targeting Sigma 1 Receptors. Transl. Stroke Res. (2023). https://doi.org/10.1007/s12975-023-01193-x

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