| Title: |
Sexually Dimorphic Responses Reveal Multifaceted Benefits of Glibenclamide in Traumatic Brain Injury |
| Authors: |
Rani, Anupama; Raikwar, Sudhanshu P; Yoo, Wonsuk; Ahmad, Saif; Vagni, Vincent A; Janesko-Feldman, Keri L; Carlson, Shaun W; Eberle, Adam; Miller, Margaux; Helm, John; Catapano, Joshua; Zusman, Benjamin E; Desai, Shashvat; Javelosa, Raemier Anne; Afework, Semeon; McNally, Erin Audrey; Kohanbash, Gary; Rajasundaram, Dhivyaa; Waters, Michael F; Ducruet, Andrew; Jadhav, Ashutosh; Kumar, Aditya; Phuah, Chia-Ling; Kochanek, Patrick M; Jha, Ruchira M |
| Source: |
Translational Neuroscience |
| Publisher Information: |
Barrow - St. Joseph's Scholarly Commons |
| Publication Year: |
2025 |
| Subject Terms: |
cerebral blood flow; cognitive outcome; neurodegeneration; neurogenesis; sex differences; Animals; Brain Injuries; Traumatic (drug therapy); Mice; Male; Female; Sex Characteristics; Glyburide (pharmacology; therapeutic use); Inbred C57BL; Neuroprotective Agents (pharmacology) |
| Description: |
Sex disparities in traumatic brain injury (TBI) remain poorly understood. Previous data suggest that males are more susceptible to acute secondary injury processes and cell death, whereas females are more vulnerable chronically. Additional sex-based differences have been reported depending on injury model/severity and post-traumatic neurodegeneration. This gap in understanding limits therapy translation. We previously demonstrated sex-based differences in genetic modulation of a key pathway of secondary injury in TBI, sulfonylurea-receptor 1 (SUR1). Glibenclamide (GLI, SUR1-inhibitor) has shown promise in pre-clinical and early clinical studies of TBI and stroke. Here, we evaluated GLI's modulation of multifaceted TBI outcomes across sex for the first time. In total, 120 mice were randomized to controlled cortical impact (CCI) ± GLI or vehicle (dimethyl sulfoxide, DMSO). Either vehicle or GLI treatment was administered post-CCI using an intraperitoneal (IP) loading dose (10 µg/mouse, 10 min post-TBI), followed by a 7-day subcutaneous maintenance infusion at 0.5 µL/h using ALZET mini-osmotic pumps (1007D, Durect Corp.). Mice were tested for cognitive function (Morris water maze, MWM), motor function (rotarod), anxiety (elevated plus maze, EPM), immunofluorescence markers of neurodegeneration (TAU, TDP43), neurogenesis (SOX2, Ki67), angiogenesis (VEGFA), and cerebral blood flow (CBF) to interrogate behavioral, molecular, and physiological effects of TBI and therapy. Different measures within behavioral, immunofluorescence, and CBF outcomes varied across sex, either post-CCI and/or in response to GLI. Motor impairment had baseline differences across sex post-CCI. In both sexes, behavioral deficits were improved by GLI. The effect of GLI on behavior was moderated by sex, with greater benefit in males versus females, including improved MWM latency (p < 0.0001) and rotarod latency (p = 0.016, revolutions per minute, p = 0.03). Males had increased anxiety post-CCI (EPM); GLI was beneficial across sexes. TDP43 and ... |
| Document Type: |
text |
| Language: |
unknown |
| Relation: |
https://scholar.barrowneuro.org/neurobiology/2482; https://doi.org/10.1089/neu.2024.0232 |
| DOI: |
10.1089/neu.2024.0232 |
| Availability: |
https://scholar.barrowneuro.org/neurobiology/2482; https://doi.org/10.1089/neu.2024.0232 |
| Accession Number: |
edsbas.1CD0C847 |
| Database: |
BASE |