Profile of intravenous glyburide for the prevention of cerebral edema following large hemispheric infarction: evidence to date

Abstract

Glyburide (also known as glibenclamide) is a second-generation sulfonylurea drug that inhibits sulfonylurea receptor 1 (Sur1) at nanomolar concentrations. Long used to target K_ATP (Sur1-Kir6.2) channels for the treatment of diabetes mellitus type 2, glyburide was recently repurposed to target Sur1-transient receptor potential melastatin 4 (Trpm4) channels in acute central nervous system injury. Discovered nearly two decades ago, SUR1-TRPM4 has emerged as a critical target in stroke, specifically in large hemispheric infarction, which is characterized by edema formation and life-threatening brain swelling. Following ischemia, SUR1-TRPM4 channels are transcriptionally upregulated in all cells of the neurovascular unit, including neurons, astrocytes, microglia, oligodendrocytes and microvascular endothelial cells. Work by several independent laboratories has linked SUR1-TRPM4 to edema formation, with blockade by glyburide reducing brain swelling and death in preclinical models. Recent work showed that, following ischemia, SUR1-TRPM4 co-assembles with aquaporin-4 to mediate cellular swelling of astrocytes, which contributes to brain swelling. Additionally, recent work linked SUR1-TRPM4 to secretion of matrix metalloproteinase-9 (MMP-9) induced by recombinant tissue plasminogen activator in activated brain endothelial cells, with blockade of SUR1-TRPM4 by glyburide reducing MMP-9 and hemorrhagic transformation in preclinical models with recombinant tissue plasminogen activator. The recently completed GAMES (Glyburide Advantage in Malignant Edema and Stroke) clinical trials on patients with large hemispheric infarctions treated with intravenous glyburide (RP-1127) revealed promising findings with regard to brain swelling (midline shift), MMP-9, functional outcomes and mortality. Here, we review key elements of the basic science, preclinical experiments and clinical studies, both retrospective and prospective, on glyburide in focal cerebral ischemia and stroke.

Keywords: brain swelling; cerebral ischemia; glyburide; malignant edema; matrix metalloproteinase-9; stroke; sulfonylurea receptor 1.

Figure 1

Depictions of the K_ATP (Sur1–Kir6.2) and the SUR1–TRPM4 channels. Notes: (A, B) The hetero-octameric structure comprising four Sur1 subunits and four Kir6.2 subunits depicted for K_ATP is known. The structure depicted for the SUR1–TRPM4 channel is hypothesized by analogy. Also shown are the principal physiological actions of the two channels when they are activated by ATP depletion: 1) outward flux of K⁺ via the K⁺-selective pore-forming subunit, Kir6.2, resulting in hyperpolarization with the K_ATP channel and 2) inward flux of Na⁺ via the nonselective monovalent cation pore-forming subunit, Trpm4, resulting in depolarization with the SUR1–TRPM4 channel. Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V. Sulfonylurea receptor 1 in central nervous system injury: a focused review. J Cereb Blood Flow Metab. 32(9):1699–1717. Copyright © [2012] (SAGE Journals). Reprinted by permission of SAGE Publications. (C, left) Putative model of SUR1–TRPM4–AQP4 complex, showing AQP4 tetramers (blue) intercalated between SUR1 monomers (pink) and interacting with the central tetrameric TRPM4 (green); protein profiles and relative protein sizes are based upon previously published structures for AQP4, SUR1 and TRP channels; overall channel topology is based on the structure of the K_ATP channel. (C, right) Model of SUR1–TRPM4–AQP4 water flux showing that raised intracellular Ca²⁺ triggers SUR1–TRPM4 channel activation and Na⁺ influx, resulting in raised osmotic pressure (π) which, in turn, drives water influx (blue arrows) through AQP4. Copyright © 2018. John Wiley and Sons. Adapted from Stokum JA, Kwon MS, Woo SK, et al. SUR1–TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling. Glia. 2018;66(1):108–125. Abbreviations: AQP4, aquaporin-4; SUR1, sulfonylurea receptor 1; TRPM4, transient receptor potential melastatin 4.

Figure 2

Glyburide extends the therapeutic window for hypothermia and enhances its ability to attenuate cerebral edema and decrease infarct volume. Notes: Rats were subjected to hypothermia or not at 6 or 8 hours after ischemia onset and rewarmed slowly at 0.5°C/h. (A) Representative triphenyltetrazolium chloride-stained coronal sections of rat brains at 24 hours after MCAo with treatments begun at 6 hours, as indicated, for vehicle only, vehicle combined with hypothermia at 6 hours after ischemia onset (V+D6HT), glyburide only, or glyburide with hypothermia at 6 hours after ischemia onset (G+D6HT). (B, C) Hemispheric swelling was compared among animals treated at 6 hours (B) or 8 hours (C). (D, E) Infarct volume was compared among animals treated at 6 hours (D) or 8 hours (E); **P<0.01. Copyright © 2003. Europe PMC. Adapted from Wu Z, Zhu SZ, Hu YF, et al. Glibenclamide enhances the effects of delayed hypothermia after experimental stroke in rats. Brain Res. 2016;1643:113–122. Abbreviations: MCAo, middle cerebral artery occlusion; ns, no significance.

Figure 3

Vasogenic edema on T2 FLAIR is attenuated by glyburide treatment in human stroke. Notes: (A) Representative examples of DWI (left) and FLAIR sequences (right) from a control subject (top panels) and an RP-1127-treated subject (bottom panels); MRI scans were obtained at day 2 from the onset of stroke. (B) Quantitative analysis of the FLAIR ratio in control and GAMES-Pilot subjects shows a reduced FLAIR ratio with RP-1127 treatment; ***P<0.005 by repeated measures MANOVA. (C) Segmentation of the stroke lesions demonstrates an equivalent effect of RP-1127 on both gray and white matter regions; **P<0.01. (D) The plasma concentration of glyburide correlates with FLAIR ratio intensity in the GAMES-Pilot subjects; *P<0.01. Reprinted by permission from Springer Nature: Neurocrit Care. Glyburide is associated with attenuated vasogenic edema in stroke patients. Kimberly WT, Battey TW, Pham L, et al. 2014;20(2):193–201. Abbreviations: DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; MANOVA, multivariate analysis of variance; MRI, magnetic resonance imaging.

Figure 4

Secondary clinical outcomes in the glyburide and placebo groups in GAMES-RP. Notes: (A) Distribution of mRS scores in the per-protocol sample at 90 days. (B) Kaplan–Meier survival curve for each treatment group. Reprinted from The Lancet, 15(11), Sheth KN, Elm JJ, Molyneaux BJ, et al. Safety and efficacy of intra venous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial, Pages No. 1160–1169, Copyright (2016), with permission from Elsevier. Abbreviation: mRS, modified Rankin score.