Sulfonylurea Receptor 1 in Central Nervous System Injury: An Updated Review

Abstract

Sulfonylurea receptor 1 (SUR1) is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily, encoded by Abcc8, and is recognized as a key mediator of central nervous system (CNS) cellular swelling via the transient receptor potential melastatin 4 (TRPM4) channel. Discovered approximately 20 years ago, this channel is normally absent in the CNS but is transcriptionally upregulated after CNS injury. A comprehensive review on the pathophysiology and role of SUR1 in the CNS was published in 2012. Since then, the breadth and depth of understanding of the involvement of this channel in secondary injury has undergone exponential growth: SUR1-TRPM4 inhibition has been shown to decrease cerebral edema and hemorrhage progression in multiple preclinical models as well as in early clinical studies across a range of CNS diseases including ischemic stroke, traumatic brain injury, cardiac arrest, subarachnoid hemorrhage, spinal cord injury, intracerebral hemorrhage, multiple sclerosis, encephalitis, neuromalignancies, pain, liver failure, status epilepticus, retinopathies and HIV-associated neurocognitive disorder. Given these substantial developments, combined with the timeliness of ongoing clinical trials of SUR1 inhibition, now, another decade later, we review advances pertaining to SUR1-TRPM4 pathobiology in this spectrum of CNS disease-providing an overview of the journey from patch-clamp experiments to phase III trials.

Keywords: SUR 1; TRPM4; cellular swelling; clinical trials; edema; stroke; sulfonylurea receptor; traumatic brain injury.

Figure 1

Schematic depiction of SUR1, TRPM4, and Kir6.2 topology. TRPM4 monomers consist of six transmembrane helices with a pore region (P). SUR1 is composed of two interacting six-helix trans-membrane domains (TMD1 and TMD2), each containing a nucleotide binding domain NBD1 and NBD2. TMD0 interacts directly with Kir6.2. Four TRPM4 subunits oligomerize with four SUR1 subunits to form the functional SUR1-TRPM4 octameric channel. Influx of Na⁺ via the nonselective monovalent cation pore-forming subunit TRPM4 leads to depolarization. Figure created with BioRender.com (2021).

Figure 2

(A) Sodium azide induced ATP depletion, resulting in cellular depolarization. Current clamp recording demonstrating cellular resting potential (~60 mV). After exposure to 1 mM oubain (downward arrow), cell depolarization was <5 mV with rapid recovery after washout. Conversely, 3 min exposure to 1 mM sodium azide induced ATP depletion and resulted in a depolarizing inward current with cell depolarization to almost 0 mV. Scanning electron micrograph of a freshly isolated reactive astrocyte under control conditions (B), 5 min after exposure to 1 mM sodium azide (C) and 25 min after exposure to 1 mM sodium azide (D). Scale bar is 12 μm. Adapted with permission from Ref. [7].

Figure 3

(A) Schematic depiction of upregulated pathways after CNS injury related to SUR1-TRPM4. Hypoxia/ischemia results in upregulation of HIF1α, which is transported to the nucleus where it binds with the HIF-binding site, leading to the upregulation of SP1—which in turn leads to the upregulated transcription of Abcc8 (SUR1). Mechanical stimuli after traumatic brain injury or spinal cord injury results in increased levels of TNFα, which is an upstream regulator of Abcc8 (SUR1). Increased levels of TNFα lead to upregulation of IKK and NF-κB, ultimately resulting in transcriptional activation of Abcc8 (SUR1). Upregulation of SUR1 leads to increased association of SUR1-TRPM4 on the plasma membrane. An open SUR1-TRPM4 channel results in Na⁺ influx, leading to depolarization and an oncotic gradient. Association of the SUR1-TRPM4-AQP4 complex results in increased influx of water into the cell (following the oncotic gradient), ultimately leading to cell swelling. Increased SUR1 may contribute to neuroinflammation (by activating NOS2, INFγ, IL-17, BAFF, CCL2, GFAP), disruption of the blood brain barrier (by activating IgG, MMP-9 and ZO-1), and cell death (via upregulation of caspase 3 and BAX). (B) Schematic representation of the signaling effects of SUR1 inhibition via genetic Abcc8 knockout or pharmacological inhibition by glibenclamide. Edema is reduced via channel blockade. Neuroinflammation is decreased (lower levels of TNFα, NOS2, INFγ, IL-17, BAFF, CCL2, GFAP); the blood–brain barrier disruption is minimized (downregulated ZO-1, MMP-9), and cell death reduced (upregulation BCL-2, downregulation of BAX and caspase 3). Figure created with BioRender.com (2021).

Figure 3

(A) Schematic depiction of upregulated pathways after CNS injury related to SUR1-TRPM4. Hypoxia/ischemia results in upregulation of HIF1α, which is transported to the nucleus where it binds with the HIF-binding site, leading to the upregulation of SP1—which in turn leads to the upregulated transcription of Abcc8 (SUR1). Mechanical stimuli after traumatic brain injury or spinal cord injury results in increased levels of TNFα, which is an upstream regulator of Abcc8 (SUR1). Increased levels of TNFα lead to upregulation of IKK and NF-κB, ultimately resulting in transcriptional activation of Abcc8 (SUR1). Upregulation of SUR1 leads to increased association of SUR1-TRPM4 on the plasma membrane. An open SUR1-TRPM4 channel results in Na⁺ influx, leading to depolarization and an oncotic gradient. Association of the SUR1-TRPM4-AQP4 complex results in increased influx of water into the cell (following the oncotic gradient), ultimately leading to cell swelling. Increased SUR1 may contribute to neuroinflammation (by activating NOS2, INFγ, IL-17, BAFF, CCL2, GFAP), disruption of the blood brain barrier (by activating IgG, MMP-9 and ZO-1), and cell death (via upregulation of caspase 3 and BAX). (B) Schematic representation of the signaling effects of SUR1 inhibition via genetic Abcc8 knockout or pharmacological inhibition by glibenclamide. Edema is reduced via channel blockade. Neuroinflammation is decreased (lower levels of TNFα, NOS2, INFγ, IL-17, BAFF, CCL2, GFAP); the blood–brain barrier disruption is minimized (downregulated ZO-1, MMP-9), and cell death reduced (upregulation BCL-2, downregulation of BAX and caspase 3). Figure created with BioRender.com (2021).

Figure 4

(A) Graph showing percent survival of rats over 7 days after middle cerebral artery occlusion (MCAO, malignant cerebral edema model) when treated by saline (open squares) vs. glibenclamide (filled black squares). At 7 days, mortality was significantly different in the glibenclamide group (24%) vs. vehicle group (65%, p < 0.002). Representative TTC-stained coronal sections 2 days after MCAO (thromboembolic model) in a rat treated with saline (B) vs. glibenclamide (C) showing cortical sparing in the latter. Adapted with permission from Ref. [65].

Figure 5

Figures from the GAMES-RP clinical trial demonstrating the effect of glyburide on midline shift (A,C,D) and plasma MMP-9 levels (B). (A) Boxplot showing the median midline shift (horizontal line, box = interquartile range, whiskers = 10–90 percentile) in each treatment group in the per-protocol sample. (B) Temporal profile of mean total plasma MMP9 levels for the per-protocol sample (error bars are 95% confidence intervals at the specific timepoint shown). (C,D) Representative examples of median extent of midline shift on follow-up brain MRI with a patient treated with intravenous glyburide (5 mm) vs a placebo-treated patient (9 mm). The redline is a reference showing the brain midline. Adapted with permission from Ref. [47].

Figure 6

Schematic representation of SUR1, TRPM4, and KIR6.2 expression and timelines in neuron, microglia, astrocytes, and microvessels after TBI in rodents and humans. Figure created with BioRender.com (2021).

Figure 7

Hypothetical schematic example of precision medicine using genotype-based risk stratification of hemorrhage progression. Patients with high-risk genotypes of ABCC8 or TRPM4 variants (red) may have higher levels of channel mRNA and/or protein expression and in turn be at higher risk of hemorrhage progression after traumatic brain injury. Genotype-based stratification could inform clinician prognostication, enrich patient selection/decrease sample size and cost of clinical trials, guide subgroup analyses, and also be valuable for discovery of novel therapeutic targets based on gene expression/regulation/post translational modifications in this pathway.