Glyburide is associated with attenuated vasogenic edema in stroke patients

Abstract

Background: Brain edema is a serious complication of ischemic stroke that can lead to secondary neurological deterioration and death. Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 and transient receptor potential cation channel subfamily M member 4. However, the relevance of this pathway to the development of cerebral edema in stroke patients is not known.

Methods: Using a case-control design, we retrospectively assessed neuroimaging and blood markers of cytotoxic and vasogenic edema in subjects who were enrolled in the glyburide advantage in malignant edema and stroke-pilot (GAMES-Pilot) trial. We compared serial brain magnetic resonance images (MRIs) to a cohort with similar large volume infarctions. We also compared matrix metalloproteinase-9 (MMP-9) plasma level in large hemispheric stroke.

Results: We report that IV glyburide was associated with T2 fluid-attenuated inversion recovery signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood MMP-9 level.

Conclusions: Several surrogate markers of vasogenic edema appear to be reduced in the setting of IV glyburide treatment in human stroke. Verification of these potential imaging and blood biomarkers is warranted in the context of a randomized, placebo-controlled trial.

Figures

Figure 1. Cytotoxic edema is not altered by glyburide treatment in human stroke

A) Representative examples of apparent diffusion coefficient (ADC) maps in a control subject (top panels) and a glyburide-treated subject (bottom panels). The initial baseline ADC maps were obtained at approximately 7 hours after onset of the stroke symptoms (lefthand panels), and the follow-up ADC maps were obtained at about 32 hours after stroke onset. B) Quantitative analysis of the control and glyburide (GAMES) cohorts show a similar decrease in relative ADC values from the Baseline to Day 1 MRI scan, but no difference between the two groups at either time point. Box plots show the median and interquartile range, and whiskers show the range.

Figure 2. Vasogenic edema on T2 FLAIR is attenuated by glyburide treatment in human stroke

A) Representative examples of DWI (lefthand panels) and FLAIR sequences (righthand panels) from a control subject (top panels) and a glyburide-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 subjects shows a reduced FLAIR ratio with glyburide treatment. Dots represent median, whiskers are the interquartile range. ***, p<0.005 by repeated measures MANOVA. C) Segmentation of the stroke lesions demonstrate an equivalent effect of glyburide on both gray and white matter regions. Box plots show the median and interquartile range, and whiskers show the range. **, p<0.01. D) The pharmacokinetic concentration of glyburide correlates with FLAIR ratio intensity in the GAMES-Pilot subjects. Glyburide concentration was dichotomized at 25 ng/mL (see text). The FLAIR ratio values were higher at the low glyburide concentration group compared to the high concentration group. Box plots show the median and interquartile range, and whiskers show the range. *, p=0.01.

Figure 3. Vasogenic edema measured by ADC pseudonormalization is attenuated by glyburide treatment in human stroke

A) Representative example of ADC maps showing an increase in value between day 1 and day 2, which corresponds to increasing water diffusivity from edema formation. The top panels show a control subject and the bottom panels show a subject treated with IV glyburide. B) Water diffusivity is increased in controls subjects compared to GAMES subjects between days 1 and 2. There is less change in the ADC values within the stroke lesion in GAMES subjects (*, p=0.028). Box plots show the median and interquartile range, and whiskers show the range.

Figure 4. MMP-9 level is reduced by glyburide treatment in human stroke

A) Time course of total MMP-9 level in the GAMES subjects, measured by ELISA. The baseline MMP-9 prior to infusion is shown at time 0, and the timing of IV glyburide is indicated by the bar. B) Total MMP-9 at approximately 36 hours after stroke onset in the SPOTRIAS control and GAMES cohorts. Bars represent the mean, whiskers represent the standard deviation. **, p<0.01. C) Representative gelatin zymography analysis of MMP-9 in the control and GAMES cohorts. The pro-enzyme migrates slightly higher that the active form of MMP-9. MMP-2 is also detectable using this method. D) Band intensity quantitation of gelatin zymography shows that glyburide reduces the level of the pro-MMP-9 enzyme but not the active form (p=0.68). Bars represent the mean, whiskers represent the standard deviation. ***, p<0.005, ** p<0.01.