Peggy Nguyen, MD

Hafez S, Abdelsaid M, El-Shafey S, Johnson MH, Fagan SC, Ergul A. Matrix Metalloprotease 3 Exacerbates Hemorrhagic Transformation and Worsens Functional Outcomes in Hyperglycemic Stroke. Stroke. 2016

Hyperglycemia in the setting of acute ischemic stroke has been associated with worsened outcomes, with an association seen with worsened vascular injury, increased infarct size, and hemorrhagic transformation; however, the mechanisms through which this occurs is not well elucidated. Here, matrix metalloprotease 3 (MMP3), which has previously been shown to contribute to tPA induced hemorrhagic transformation, was identified as a possible mediator of injury in hyperglycemic stroke.

Using animal models, researchers identified increased MMP3 activity n the cerebral vasculature with induced hyperglycemia, and found that the use of MMP3 inhibitor at reperfusion reduced MMP3 activity in the brain. When MMP3 was inhibited in the hyperglycemic animal stroke model, hemorrhagic transformation and edema, albeit not infarct size, were reduced. Early inhibition did not lead to a mortality benefit, but did reduce hyperglycemic induced neurobehavioral deficits and improved functional outcomes at days 3 and 7 after stroke. A similar association was seen in MMP3 knockdown mice in terms of reduced brain edema, without effect on infarct size, as well as increase in neurobehavioral composite score and grip strength.

Within this animal model, then, MMP3 does seem to be a mediator of injury in hyperglycemic stroke and may, at least partially, account for some of the poorer outcomes seen in hyperglycemic stroke. More importantly, the model is suggestive of MMP3 as a potential target for neuroprotection, not only in acute ischemic stroke, but possibly in hemorrhagic stroke, given its protective effect in hemorrhagic transformation, which is hugely important for hyperacute clinical research of neuroportection in the pre-emergency room setting.