Potential of glyburide to reduce intracerebral edema in brain metastases

Abstract

Metastatic disease to the brain results in significant morbidity because of edema in the central nervous system. Current anti-edema therapies are either expensive or result in unwanted long-term side effects. Sulfonylurea receptor 1 (Sur1) is a transmembrane protein that, when activated in the central nervous system, allows for unregulated sodium influx into cells, a process that has been linked to cytotoxic edema formation in ischemic stroke, subarachnoid hemorrhage, spinal cord injury, traumatic brain injury, and, most recently, brain metastases. In this focused review, we explore preclinical data linking Sur1 channel formation to development of edema and reference evidence suggesting that the antidiabetic sulfonylurea drug glyburide (a Sur1 inhibitor) is an inexpensive and well-tolerated agent that can be clinically tested to reduce or prevent malignancy and/or treatment-associated edema.

Keywords::

• brain metastases
• edema
• glyburide
• radiosurgery
• Sur1 receptor

Financial & competing interests disclosure

JM Simard holds a US patent (#7,285,574), “A novel non-selective cation channel in neural cells and methods for treating brain swelling”, and is a member of the scientific advisory board and holds shares in Remedy Pharmaceuticals. No support was provided to JM Simard for this paper. MP Mehta has served in the following capacities, none of which are directly related to this grant: Consultant for Abbott, Bristol-Meyers-Squibb, Celldex, Elekta, Novelos, Novocure, Phillips, Roche and has stock options with Accuray and Pharmacyclics. MP Mehta also serves on the Board of Directors for Pharmacyclics and has received research funding from Novocure. N Knight, University of Maryland, provided editorial assistance for this paper. The authors have no other 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.

Key issues

• Cerebral edema is a major cause of morbidity in patients with brain metastases, and current therapeutic options are expensive (bevacizumab) or have a high side-effect profile (dexamethasone).

• The sulfonylurea receptor 1 (Sur1)-Trpm4 channel is upregulated in the brain under ischemic and hypoxic conditions.

• Lack of ATP causes the Sur1-Trpm4 channel to be permanently opened, resulting in unregulated sodium influx into the cell, causing cytotoxic edema.

• Glyburide, a sulfonylurea, inhibits opening of the Sur1 channel in the central nervous system and decreases cerebral edema in stroke, traumatic brain injury, subarachnoid hemorrhage and animal models of brain metastases.

• Infusional glyburide (RP-1127) is being tested in stroke patients to reduce vasogenic edema.

• Oral glyburide has not been approved for use in nondiabetic patients. Trials utilizing oral glyburide to decrease edema should be undertaken in diabetic patients. Alternatively, studies utilizing oral glyburide in nondiabetic patients can utilize concurrent dexamethasone (which increases blood glucose levels).

• Predictors of development of cerebral edema in patients with brain metastases receiving radiosurgery include melanoma/renal histology, extended smoking history, large pretreatment edema/tumor ratio and prior whole-brain radiation therapy.

• Glyburide is an inexpensive and relatively well-tolerated investigative agent that may help to prophylactically decrease brain metastases–induced edema in select high-risk populations.

Notes