(Sulfonylurea Receptor-1) Impact on Brain Atrophy after Traumatic Brain Injury Varies by Sex

Authors

Swathi Tata, Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Benjamin E. Zusman, Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Patrick M. Kochanek, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Volodymyr Gerzanich, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Min Seong Kwon, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Seung Kyoon Woo, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Robert S. Clark, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Keri Janesko-Feldman, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Vincent A. Vagni, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Marc Simard, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Ruchira M. Jha, Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.Follow

Document Type

Article

Abstract

Females have been understudied in pre-clinical and clinical traumatic brain injury (TBI), despite distinct biology and worse clinical outcomes versus males. Sulfonylurea receptor 1 (SUR1) inhibition has shown promising results in predominantly male TBI. A phase II trial is ongoing. We investigated whether SUR1 inhibition effects on contusional TBI differ by sex given that this may inform clinical trial design and/or interpretation. We studied the moderating effects of sex on post-injury brain tissue loss in 142 male and female ATP-binding cassette transporter subfamily C member 8 () wild-type, heterozygote, and knockout mice (12-15 weeks). Monkey fibroblast-like cells and mouse brain endothelium-derived cells were used for studies. Mice were injured with controlled cortical impact and euthanized 21 days post-injury to assess contusion, brain, and hemisphere volumes (vs. genotype- and sex-matched naïves). knockout mice had smaller contusion volumes ( = 0.012) and larger normalized contralateral (right) hemisphere volumes (nRHV;  = 0.03) after injury versus wild type. This was moderated by sex: Contusions were smaller ( = 0.020), nRHV was higher ( = 0.001), and there was less global atrophy ( = 0.003) in male, but not female, knockout versus wild-type mice after TBI. Less atrophy occurred in males for each copy of lost ( = 0.023-0.002, all outcomes). , sex-determining region Y (SRY) stimulated promoter activity and increased expression. Loss of strongly protected against post-traumatic cerebral atrophy in male, but not female, mice. This may partly be mediated by SRY on the Y-chromosome. Sex differences may have important implications for ongoing and future trials of SUR1 blockade.

Medical Subject Headings

Animals; Atrophy; Brain Injuries, Traumatic (etiology, metabolism, pathology); Cell Culture Techniques; Disease Models, Animal; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Sex Factors; Sex-Determining Region Y Protein (physiology); Sulfonylurea Receptors (physiology)

Publication Date

9-1-2021

Publication Title

Journal of neurotrauma

E-ISSN

1557-9042

Volume

38

Issue

17

First Page

2473

Last Page

2485

PubMed ID

33940936

Digital Object Identifier (DOI)

10.1089/neu.2021.0105

Recommended Citation

Tata, Swathi; Zusman, Benjamin E.; Kochanek, Patrick M.; Gerzanich, Volodymyr; Kwon, Min Seong; Woo, Seung Kyoon; Clark, Robert S.; Janesko-Feldman, Keri; Vagni, Vincent A.; Simard, J Marc; and Jha, Ruchira M., "(Sulfonylurea Receptor-1) Impact on Brain Atrophy after Traumatic Brain Injury Varies by Sex" (2021). Neurology. 1316.
https://scholar.barrowneuro.org/neurology/1316