Cellular Mechanism Involved in Hemorrhagic Progression of Contusion Following Traumatic Brain Injury

Introduction: Cerebral contusion, a severe outcome of head trauma, leads to tissue damage that can spread into new hemorrhages—a process called hemorrhagic progression of a contusion (HPC). Glibenclamide, a SUR1 antagonist, reduces HPC after traumatic brain injury (TBI) by inhibiting SUR1-TRPM4 channel activity, which is upregulated in brain microvessels before hemorrhagic breakdown. This study used a mouse TBI model to investigate HPC lesion volume and assess neurofunctional outcomes, including cognition, memory, motor coordination, and balance.

Methods: Genetically modified mice with cell-specific deletion of the Abcc8/SUR1 gene were used to study the role of SUR1 in TBI. A controlled cortical impact (CCI) model was used to induce contusion-TBI, followed by three series of experiments: (1) glibenclamide administered zero hours post-injury, (2) glibenclamide given zero and ten hours post-injury, and (3) NN414 administration to assess maximal SUR1 activation. Neurofunctional tests were conducted before and 24 hours post-CCI to evaluate motor coordination, balance, cognition, and memory. Brains were harvested post-euthanasia, and lesion areas were scanned to quantify tissue damage.

Results: Preliminary results validated the model, suggesting that glibenclamide has a therapeutic effect in a TBI model. The first group improved in cognition and memory but not in sensorimotor coordination. The second group saw improved cognition and memory as well as gait function; however, it had no significant effect on neuromuscular coordination. Image analysis of coronal brain sections post-contusion aligned with neurofunctional outcomes.

Conclusion : Authenticating the mouse TBI model with HPC allows for future histological and neurobehavioral evaluation of cell-specific deletion of Abcc8/SUR1 in transgenic mouse strains. Future studies on Abcc8/SUR1 gene suppression in endothelial and astrocytic cells will elucidate the individual effect of glibenclamide on each microvessel layer. Identifying the cell-specific targets of glibenclamide may aid in future drug discovery and provide a therapeutic benefit for TBI patients.