Emerging therapeutic targets for cerebral edema

Abstract

Introduction: Cerebral edema is a key contributor to death and disability in several forms of brain injury. Current treatment options are limited, reactive, and associated with significant morbidity. Targeted therapies are emerging based on a growing understanding of the molecular underpinnings of cerebral edema.

Areas covered: We review the pathophysiology and relationships between different cerebral edema subtypes to provide a foundation for emerging therapies. Mechanisms for promising molecular targets are discussed, with an emphasis on those advancing in clinical trials, including ion and water channels (AQP4, SUR1-TRPM4) and other proteins/lipids involved in edema signaling pathways (AVP, COX2, VEGF, and S1P). Research on novel treatment modalities for cerebral edema [including recombinant proteins and gene therapies] is presented and finally, insights on reducing secondary injury and improving clinical outcome are offered.

Expert opinion: Targeted molecular strategies to minimize or prevent cerebral edema are promising. Inhibition of SUR1-TRPM4 (glyburide/glibenclamide) and VEGF (bevacizumab) are currently closest to translation based on advances in clinical trials. However, the latter, tested in glioblastoma multiforme, has not demonstrated survival benefit. Research on recombinant proteins and gene therapies for cerebral edema is in its infancy, but early results are encouraging. These newer modalities may facilitate our understanding of the pathobiology underlying cerebral edema.

Keywords: AQP4 (Aquaporin4); AVP (Arginine Vasopressin); COX2 (Cyclooxygenase-2); Celecoxib; Cerebral edema; Conivaptan; Fingolimod; Glyburide / Glibenclamide; S1P (sphingosine 1 phosphate); SUR1-TRPM4 (sulfonylurea receptor 1- transient receptor potential cation channel subfamily M member 4); VEGF (Vascular Endothelial Growth Factor); bevacizumab.

Figure 1.. Emerging Therapeutic Strategies for Cerebral Edema.

Schematic showing advances in diagnostics and discovery technologies (shaded pink) that have the potential to inform and identify key molecular contributors to cerebral edema. These include biomarker analysis (for risk stratification, theragnostics, and monitoring the therapeutic response), transcriptomics and proteomics (for unbiased identification of novel RNA and protein-based biomarkers and therapeutic targets), NextGen sequencing (to identify important variants that may alter host response to injury and inform individualized targets), advanced imaging (for edema endophenotyping), mass cytometry (immune cell atlas to determine cellular properties), and 3D printing (to facilitate experimental modeling). The bottom panel highlights some novel anti-cerebral edema therapies under development including recombinant proteins (rhFGF21, rhFGF20, rCCL17, rmVEGF), nanoparticles (loaded with glyburide/glibenclamide), gene therapies (including CRISPR/Cas9 gene editing, microRNA, shRNA and lncRNA targets, AAV and lentiviral vectors), and current promising molecular targets with therapeutic agents in clinical trials (AQP4, AVP, COX2, S1P, SUR1-TRPM4 and VEGF). The inset rectangle depicts various contributors to cerebral edema (ion channels, inflammasome, BBB dysfunction, and cytokine storms) as well as potential detrimental after- effects (apoptosis). Figure created with the assistance of BioRender. Abbreviations: AAV = adeno associated virus; ABCC8 = ATP Binding Cassette Subfamily C Member 8; AQP4 = aquaporin4; AVP = arginine vasopressin; BBB = blood–brain barrier; COX2 = cyclooxygenase 2; CRISPR = clustered regularly interspaced short palindromic repeats; rhFGF = recombinant human fibroblast growth factor; lncRNA = long non-coding RNA; MALAT1 = Metastasis Associated Lung Adenocarcinoma Transcript 1; MST1 =mammalian-sterile 20 like kinase 1; NDRG2 = N-myc downstream regulated gene 2; rCCL17 = recombinant CC chemokine ligand 17; rmVEGF = recombinant mouse vascular endothelial growth factor; RNA = ribonucleic acid; shRNA = short hairpin RNA; S1P = sphingosine 1 phosphate; SUR1 = sulfonylurea receptor 1; TRPM4 = transient receptor potential cation channel subfamily M member 4; VEGF = vascular endothelial growth factor

Figure 2.. Promising Molecular Targets and Pathophysiologic Evolution of Cerebral Edema.

(A) One side of the capillary endothelium is used to demonstrate the molecularly related spectrum of cerebral edema as it progresses from cellular/ionic to vasogenic to hemorrhage progression. Key mediators for each step are listed under the edema subtype, with evidence of molecular overlap. Mediators involved with ionic and cytotoxic edema are listed under the respective subheadings with the direction of water movement shown with light blue arrows. Cellular edema affects neurons (purple) astrocytes (blue-green), microglia (yellow), and endothelial capillary cells (red). Ionic edema results in transcapillary flux of water (light blue open head arrows) due to ion channels present on the luminal and abluminal surfaces, whereas cellular/cytotoxic edema results in water influx into the cell without equivalent efflux (light blue closed head arrows). Vasogenic edema, results in paracellular protein extravasation along with water (dark blue arrow) into the interstitial space due to mechanisms that result in blood–brain barrier disruption (e.g. disruption of tight junctions, inflammation, endothelial cell retraction, mechanisms that cause cellular swelling and oncotic cell death in endothelial cells or astrocyte podocytes such as via SUR1-TRPM4). Ultimately, complete breakdown of the blood–brain barrier (phase-3) results in red blood cell extravasation along with water and plasma proteins, resulting in hemorrhagic progression. The relatively more recent contribution of the glymphatic system to cerebral edema (purple arrow) involves CSF contribution to water and ions entering the interstitium and perivascular spaces, possibly mediated by AQP4.(B) Schematic showing key molecular targets that contribute to cerebral edema and the corresponding pharmacological agents being evaluated in clinical trials. These targets are distributed on multiple cell types and include ion channels (SUR1-TRPM4, yellow; AQP4, blue), G-protein receptors for S1P (S1P1-R, red) and AVP (V1a-R, purple), tyrosine kinase receptors for VEGF (VEGF-R, green), and COX2 (enzyme that catalyzes conversion of arachidonic acid to prostaglandins).

Figure 2.. Promising Molecular Targets and Pathophysiologic Evolution of Cerebral Edema.

(A) One side of the capillary endothelium is used to demonstrate the molecularly related spectrum of cerebral edema as it progresses from cellular/ionic to vasogenic to hemorrhage progression. Key mediators for each step are listed under the edema subtype, with evidence of molecular overlap. Mediators involved with ionic and cytotoxic edema are listed under the respective subheadings with the direction of water movement shown with light blue arrows. Cellular edema affects neurons (purple) astrocytes (blue-green), microglia (yellow), and endothelial capillary cells (red). Ionic edema results in transcapillary flux of water (light blue open head arrows) due to ion channels present on the luminal and abluminal surfaces, whereas cellular/cytotoxic edema results in water influx into the cell without equivalent efflux (light blue closed head arrows). Vasogenic edema, results in paracellular protein extravasation along with water (dark blue arrow) into the interstitial space due to mechanisms that result in blood–brain barrier disruption (e.g. disruption of tight junctions, inflammation, endothelial cell retraction, mechanisms that cause cellular swelling and oncotic cell death in endothelial cells or astrocyte podocytes such as via SUR1-TRPM4). Ultimately, complete breakdown of the blood–brain barrier (phase-3) results in red blood cell extravasation along with water and plasma proteins, resulting in hemorrhagic progression. The relatively more recent contribution of the glymphatic system to cerebral edema (purple arrow) involves CSF contribution to water and ions entering the interstitium and perivascular spaces, possibly mediated by AQP4.(B) Schematic showing key molecular targets that contribute to cerebral edema and the corresponding pharmacological agents being evaluated in clinical trials. These targets are distributed on multiple cell types and include ion channels (SUR1-TRPM4, yellow; AQP4, blue), G-protein receptors for S1P (S1P1-R, red) and AVP (V1a-R, purple), tyrosine kinase receptors for VEGF (VEGF-R, green), and COX2 (enzyme that catalyzes conversion of arachidonic acid to prostaglandins).

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