Abcc8 (Sulfonylurea Receptor-1) Impact on Brain Atrophy after Traumatic Brain Injury Varies by Sex
| العنوان: | Abcc8 (Sulfonylurea Receptor-1) Impact on Brain Atrophy after Traumatic Brain Injury Varies by Sex |
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| المؤلفون: | Volodymyr Gerzanich, Min Seong Kwon, Ruchira M. Jha, J. Marc Simard, Robert B. Clark, Keri Janesko-Feldman, Vincent Vagni, Swathi Tata, Seung Kyoon Woo, Patrick M. Kochanek, Benjamin E Zusman |
| المصدر: | J Neurotrauma |
| بيانات النشر: | Mary Ann Liebert Inc, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | endocrine system, 030506 rehabilitation, biology, business.industry, Traumatic brain injury, Central nervous system, Original Articles, medicine.disease, Bioinformatics, ABCC8, 03 medical and health sciences, 0302 clinical medicine, Atrophy, medicine.anatomical_structure, biology.protein, Medicine, Sulfonylurea receptor, Neurology (clinical), 0305 other medical science, business, 030217 neurology & neurosurgery |
| الوصف: | 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 (Abcc8) wild-type, heterozygote, and knockout mice (12–15 weeks). Monkey fibroblast-like cells and mouse brain endothelium-derived cells were used for in vitro 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). Abcc8 knockout mice had smaller contusion volumes (p = 0.012) and larger normalized contralateral (right) hemisphere volumes (nRHV; p = 0.03) after injury versus wild type. This was moderated by sex: Contusions were smaller (p = 0.020), nRHV was higher (p = 0.001), and there was less global atrophy (p = 0.003) in male, but not female, knockout versus wild-type mice after TBI. Less atrophy occurred in males for each copy of Abcc8 lost (p = 0.023–0.002, all outcomes). In vitro, sex-determining region Y (SRY) stimulated Abcc8 promoter activity and increased Abcc8 expression. Loss of Abcc8 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. |
| تدمد: | 1557-9042 0897-7151 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e52c82e77d628911894a726da68a1dd3 https://doi.org/10.1089/neu.2021.0105 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e52c82e77d628911894a726da68a1dd3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15579042 08977151 |
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