New drugs on the horizon for cerebral edema: what’s in the clinical development pipeline?

ABSTRACT

Introduction

Research has advanced our understanding of the molecular and cellular mechanisms of cerebral edema and has propelled the development of novel antiedema therapeutics. Current evidence supports aberrant neuro-glial ion transport as a central mechanism that underlies pathological fluid accumulation after central nervous system injury.

Areas covered

Novel agents in clinical development show potential in altering the natural history and treatment of cerebral edema. Using the PubMed and Google Scholar databases, we review recent advances in our understanding of cerebral edema and describe agents under active investigation, their mechanism, and their application in recent and ongoing clinical trials.

Expert opinion

Pharmacotherapies that target molecular mechanisms underlying the compensatory post-injury response of ion channels and transporters that lead to pathological alteration of osmotic gradients are the most promising therapeutic strategies. Repurposing of drugs such as glyburide that inhibit the aberrant upregulation of ion channels such as SUR1-TRPM4, and novel agents, such as ZT-1a, which reestablish physiological regulation of ion channels such as NKCC1/KCC, could be useful adjuvants to prevent and even reverse fluid accumulation in the brain parenchyma.

KEYWORDS:

• Cerebral edema
• ion transport
• blood brain barrier
• anti-edema agents

Article highlights

• Cerebral edema is the pathological accumulation of fluid in the brain and a potentially life-threatening complication of many central nervous system insults, including traumatic brain injury, stroke, infection, tumor, and inflammatory disease.

• Due to the constraints of a rigid skull, cerebral edema often leads to increased intracranial pressure (ICP) and compromised cerebral blood flow, resulting in cell death and neurological dysfunction. Current strategies to reduce cerebral edema and ICPs have been used for over a century and rely on osmotic agents and surgery.

• Historically, cerebral edema has been classified as either cytotoxic, vasogenic, or ionic, depending on location of water accumulation and blood brain barrier integrity. As our understanding of the underlying pathological mechanisms of cerebral edema expands, these classifications are being redefined to reflect the molecular mediators involved and allow development of more specific treatment targets.

• Cerebral edema is dynamic and time dependent, factors that must be considered when developing and administering targeted therapies. Ongoing research is exploring the temporal expression and regulation of proteins and transporters and their role in cerebral protection and development of cerebral edema. This will guide timing and indications for newly developed targeted therapies.

• Development of new drugs, and repurposing of currently used drugs, to target recently discovered pathways, such as cation-chloride cotransporters and SUR1-TRPM4, will provide more effective treatment, and potentially prevention, of cerebral edema resulting from multiple intracranial pathologies.

• Given the heterogenous presentation, progression, and etiology of cerebral edema, a standardized mechanism to assessment of efficacy of treatment is needed to guide clinical implementation and further treatment development.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The work in the laboratory of the authors has been funded by U.S. Department of Health and Human Services, National Institutes of Health R01 NS109358,R01 NS111029-01A1 and Yale-National Institutes of Health (NIH) Center for Mendelian Genomics 5U54HG006504