Glibenclamide Reduces Hippocampal Injury and Preserves Rapid Spatial Learning in a Model of Traumatic Brain Injury

Abstract

Cognitive disturbances after traumatic brain injury (TBI) are frequent, even when neuroimaging shows no overt hemorrhagic or other abnormality. Sulfonylurea receptor 1 (SUR1) plays a key role in various forms of CNS injury, but its role in hippocampal dysfunction after mild to moderate TBI is unknown. To assess the hypothesis that postinjury SUR1 upregulation in the hippocampus is associated with a later disturbance in learning, we studied a rat model of cortical impact TBI calibrated to avoid primary and secondary hemorrhage in the underlying hippocampus. The transcription factor, specificity protein 1, which regulates expression of SUR1 and caspase-3, was activated in the hippocampus 15 minutes after injury. Upregulation of SUR1 protein and of Abcc8 (which encodes SUR1) messenger RNA was evident by 6 hours. To assess the role of SUR1, injured rats were administered vehicle or a low dose of the specific sulfonylurea inhibitor glibenclamide for 1 week. At 2 weeks, the increase in activated caspase-3 in the hilus of glibenclamide-treated rats was half of that in vehicle-treated rats. Testing for rapid learning in a Morris water maze at 4 weeks showed significantly better performance in glibenclamide-treated rats; performance inversely correlated with Fluoro-Jade staining for degenerated neurons in the hilus. We conclude that glibenclamide may have long-term protective effects on the hippocampus after mild-to-moderate TBI.

On Potential Interactions between Non-selective Cation Channel TRPM4 and Sulfonylurea Receptor SUR1

“…Accordingly, expression of SUR1 is up-regulated in reactive astrocytes, neurons, and capillaries of rodent models for ischemia, traumatic brain injury, and spinal cord injury (11,12,(43)(44)(45). The effects of trauma appear to be reduced by administration of glibenclamide (46,47); clinical trials to test the potential of this antidiabetic drug as a treatment for brain edema are under way (48), but the subject remains controversial (49,50). On the other hand, fragmentation and hemorrhaging in capillaries correlate with an increase in TRPM4 expression in rats after spinal cord injury and are significantly mitigated in TRPM4-null mice (17).…”

Patients with brain contusions: predictors of outcome and relationship between radiological and clinical evolution

“…Recent findings suggest that the latter scenario prevails. 23,29 Severe cerebral contusion is often associated with nonhemorrhagic mass effects that progress rapidly within 12-48 hours after trauma. The mechanisms underlying such a rapid progression of mass effect cannot be fully explained by classic concepts of vasogenic and cytotoxic brain edema.…”

Sulfonylurea Receptor 1 in Humans with Post-Traumatic Brain Contusions

“…19,[47][48][49] Mechanical absorption of kinetic energy by the endothelium of pericontusional tissue, and the hypoxic environment created in that tissue by reduced cerebral blood flow and microvascular dysfunction, triggers a set of molecular mechanisms that increase the permeability pore of the BBB in the traumatic penumbra, promoting ionic and water flux through it. 48 In the case of SUR1-TRPM4, it is likely that both hypoxia and mechanical stress cause up-regulation of this channel that predisposes to edema and hemorrhagic progression. 19 An increase in the permeability pore facilitates brain edema (cytoxic, ionic, and vasogenic) and, in Simard's concept, progression to end-stage edema: hemorrragic conversion.…”