Research Assistant Department of Neurosurgery, University of Maryland School of Medicine College Park, Maryland
Abstract Text: Background: Hemorrhagic progression of contusion (HPC) refers to the expansion of a hemorrhagic contusion that develops shortly after a traumatic brain injury (TBI). Previous research indicated that sulfonylurea receptor 1 (SUR1) levels are upregulated in cerebral microvessels post-TBI, and that the SUR1 antagonist, glibenclamide, ameliorates capillary fragmentation and HPC. However, the specific cellular target of glibenclamide is unknown. Here, we report on initial experiments to determine which of the 3 cellular elements of the blood-brain barrier – endothelium, pericytes and astrocyte endfeet – may be the target of glibenclamide.
Methods: We used a mouse controlled cortical impact TBI model, measured neurofunctional outcomes (motor coordination, balance, cognition, and memory), and assessed brains for hemorrhagic lesion volumes. Subjects included wild-type mice administered vehicle or glibenclamide (10 g at t=0 hours, without or with a second dose at t=10 hours), mice with astrocyte-specific knockout of Abcc8/SUR1, mice with endothelium-specific knockout of Abcc8/SUR1, and littermate controls.
Results: Mice treated with a single dose of glibenclamide showed improvement in cognition and memory, but no improvement in motor coordination or balance. Mice treated with 2 doses showed improvement in cognition, memory, and motor function. Coronal brain sections at the epicenter of the impact showed smaller contusions in mice that received two doses of glibenclamide compared to mice that received a single dose. Mice with astrocyte-specific or endothelium-specific knockout of Abcc8/SUR1 showed no evidence of protection.
Conclusion: Targeting SUR1 with the appropriate dose/dose timing protects against HPC and improves neurological function. Evidence to date suggests that astrocytes and endothelium may not be critical for HPC.
Keywords: glibenclamide, hemorrhagic progression of contusion (HPC), Abcc8/SUR1
