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Plasma Hypoxanthine Is a Biomarker of Brain Edema After Ischemic Stroke

Key findings

  • This study investigated potential mechanisms of malignant brain edema after ischemic stroke by examining which metabolites were associated with brain edema and were also modified by intravenous glibenclamide treatment
  • Plasma hypoxanthine was the only metabolite significantly associated with two markers of brain edema: midline shift (β, 1.83) and the plasma level of matrix metalloproteinase-9 (MMP-9) (β, 0.32)
  • Glibenclamide significantly reduced hypoxanthine at all time points studied through 72 hours (β, -0.62), and hypoxanthine level mediated the effect of glibenclamide on midline shift and MMP-9
  • Higher pre-treatment hypoxanthine level significantly predicted midline shift by day 4 (OR, 3.35) and worse functional outcome at 90 days, based on the modified Rankin Scale score (OR, 1.69)
  • These findings support the use of hypoxanthine as a serial biomarker of treatment response to glibenclamide after a large ischemic stroke

Malignant brain edema—rapid clinical decline in the first 24 to 72 hours after ischemic stroke due to mass-occupying tissue swelling—is a leading cause of poor functional outcomes and death.

The randomized, controlled GAMES-RP trial published in The Lancet Neurology showed that glibenclamide, long used to treat type 2 diabetes, reduced two measures of brain edema in patients suffering large hemispheric infarction: midline shift and the plasma level of matrix metalloproteinase-9 (MMP-9). Increased MMP-9 in the blood or brain tissue is believed to promote the breakdown of the blood–brain barrier.

W. Taylor Kimberly, MD, PhD, chief of the Division of Neurocritical Care in the Department of Neurology at Massachusetts General Hospital, and colleagues recently provided insight into how glibenclamide attenuates brain edema. In Cell Reports Medicine, they report evidence that glibenclamide reduces midline shift and MMP-9 by reducing the level of hypoxanthine.

Study Population

Plasma samples were stored for 83 of the 86 patients in the GAMES-RP trial: 44 patients were randomly assigned to intravenous glibenclamide (also known as glyburide) and 39 were assigned to placebo. In each sample, the researchers quantified 152 metabolites that are sentinel markers for a broad array of biochemical pathways.

Hypoxanthine and Markers of Brain Edema

Hypoxanthine was the only metabolite significantly associated with midline shift and MMP-9 levels. Previous research has suggested elevated hypoxanthine is a marker of hypoxia in several disease states, has a role in forming free radicals and reactive oxygen species, and is implicated in ischemia–reperfusion injury.

In multivariable analysis, hypoxanthine remained an independent predictor of:

  • Midline shift—β, 1.83 (P=2.99 x 10−5)
  • MMP-9—β, 0.32 (P=1.56 x 10−5)

Predicting Brain Edema

A higher baseline hypoxanthine level (pre-treatment, within nine hours of stroke onset) predicted:

  • Midline shift by day 4—OR, 3.35 (P=0.013)
  • Worse 90-day score on the modified Rankin Scale—OR, 1.69 (P=0.013)

Glibenclamide and Hypoxanthine

Hypoxanthine was the only metabolite studied that was reduced by glibenclamide therapy (mean reduction, 23%; P=0.0031). Relative to placebo, glibenclamide reduced the hypoxanthine level at all time points studied through 72 hours (β, −0.62; P=2.69 x 10−3).

According to mediation analysis, hypoxanthine was responsible for 32% of the effect of glibenclamide on midline shift and 52% of its effect on MMP-9.

Looking Ahead

Only an in vitro study can determine whether a causal mechanism underlies the associations between hypoxanthine, brain edema, and glibenclamide. Still, the current analysis suggests hypoxanthine is a candidate serial biomarker for brain edema after a large ischemic stroke.

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