Sulfonylurea Receptor 1 in Humans with Post-Traumatic Brain Contusions

Abstract

Post-traumatic brain contusions (PTBCs) are traditionally considered primary injuries and can increase in size, generate perilesional edema, cause mass effect, induce neurological deterioration, and cause death. Most patients experience a progressive increase in pericontusional edema, and nearly half, an increase in the hemorrhagic component itself. The underlying molecular pathophysiology of contusion-induced brain edema and hemorrhagic progression remains poorly understood. The aim of this study was to investigate sulfonylurea 1/transient receptor potential melastatin 4 (SUR1-TRPM4) ion channel SUR1 expression in various cell types (neurons, astrocytes, endothelial cells, microglia, macrophages, and neutrophils) of human brain contusions and whether SUR1 up-regulation was related to time postinjury. Double immunolabeling of SUR1 and cell-type-specific proteins was performed in 26 specimens from traumatic brain injury patients whose lesions were surgically evacuated. Three samples from limited brain resections performed for accessing extra-axial skull-base tumors or intraventricular lesions were controls. We found SUR1 was significantly overexpresed in all cell types and was especially prominent in neurons and endothelial cells (ECs). The temporal pattern depended on cell type: 1) In neurons, SUR1 increased within 48 h of injury and stabilized thereafter; 2) in ECs, there was no trend; 3) in glial cells and microglia/macrophages, a moderate increase was observed over time; and 4) in neutrophils, it decreased with time. Our results suggest that up-regulation of SUR1 in humans point to this channel as one of the important molecular players in the pathophysiology of PTBCs. Our findings reveal opportunities to act therapeutically on the mechanisms of growth of traumatic contusions and therefore reduce the number of patients with neurological deterioration and poor neurological outcomes.

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

“…Sur1 is a key regulatory protein involved in CE generation in multiple CNS disorders including TBI and ischemic stroke[7–9,15]. Sur1 expression has been demonstrated in human contusional tissue[28]. We have exciting preliminary data suggesting human CSF Sur1 levels are undetectable in non-injured controls, elevated in patients with sTBI, and trajectories may correlate with CE and outcomes ( In Press , Critical Care Medicine, abstract presented at American Academy of Neurology, 2016[29]).…”

Sulfonylurea Receptor-1: A Novel Biomarker for Cerebral Edema in Severe Traumatic Brain Injury

“…Supportive data from imaging, neurological-examinations, and biomarkers are valuable adjuncts. Sur1 is a promising and novel target: it has a pathophysiologic basis-its role in a specific pathway of CE is established in animal models(29–31), its upregulation is specific to CNS injury and is seen in human contusions(29, 32, 42), and inhibition of this receptor by Glibenclamide in animal models and early clinical trials in ischemic stroke has reduced the development of edema and improved outcomes(29–31, 41). …”

“…Glibenclamide) had reduced mortality (14% vs 36%, p=0.03) and decreased evidence of cerebral edema determined by midline shift between 72–96 hours (4.4±3.6 mm vs 8.8±4.9 mm, p=0.0006)(41). Sur1 upregulation has also been demonstrated in multiple cell types in human cerebral contusions(42). However, to our knowledge, quantification of human Sur1 in cerebrospinal fluid(CSF) from patients with any CNS injury remains undefined.…”

HIV-1 Vpr-induced Proinflammatory Response and Apoptosis are Mediated through the Sur1-Trpm4 Channel in Astrocytes

“…Trpm4 forms heterodimers and a functional Sur1-Trpm4 channel that antagonizes calcium influx mediated by receptor operated calcium entry (ROCE) cation channels 35 . This ion channel is not expressed constitutively but is transcriptionally upregulated in microglia and astrocytes 36 in responsive to various neuroinflammatory brain conditions including traumatic brain injury (TBI) 37 , subarachnoid hemorrhage (SAH) [38][39][40] , and neuroinflammatory conditions such as multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE) 21,41 . Thus, the Sur1-Trpm4 channel is a key neuro-regulator involved in various neurological disorders including brain injuries and neurodegeneration 5,20 .…”

“…Therefore, it is possible that Sur1-Trpm4 channel-induced neuropathological effects are responsible for the Vpr effects or are part of the collective induction of Vpr-induced HAND. If this is true, this finding might be clinically significant because the Sur1-Trpm4 channel has shown to be a key drug target of various neuroinflammatory conditions 21,[37][38][39][40][41] , and pharmacologic inhibition of this channel by the repurposed and FDA-approved drug glibenclamide significantly improved clinical outcomes of those neurologic disorders 21,[42][43][44][45] . Indeed, the Sur1 inhibitor glibenclamide suppresses Vpr-induced apoptosis in a concentration-dependent manner (Fig.…”