Ischemic stroke is a leading cause of death and disability. The incidence of hyperglycemia (HG) in acute ischemic stroke (AIS) patients exacerbates the cerebral hemorrhage and worsens the functional outcomes. It has been shown that patients with acute HG experience 5patients. Tissue plasminogen activator (tPA) is the only FDA approved thrombolytic therapy for AIS patients. However, its use in the clinical setting is limited due to its narrow therapeutic window and increased risk of intracerebral hemorrhage (ICH). Moreover, HG was shown to exacerbate the tPA induced hemorrhagic transformation (HT). The underlying mechanisms through which hyperglycemia exacerbates HT and worsens the clinical outcomes after stroke, especially with the administration of tPA are not fully understood. Matrix metalloproteinase 3 (MMP3) is an endopeptidase with broad substrate specificity that can target and degrade all the components of the neurovascular unit. It was previously shown that MMP3 is the critical mediator of the tPA induced ICH after stroke. However, the role of MMP3 in mediating HT in hyperglycemic stroke was not previously studied. Accordingly, we aimed in our work to investigate the impact of the interaction between HG and tPA on HT and stroke outcomes, elucidating the deleterious role of MMP3. We showed that the degree of the neurovascular injury after stroke is dependent on the severity of HG and that the interaction between tPA and acute HG exacerbates the HT and worsens the functional outcomes independent of the method of reperfusion. Furthermore, we are the first to point out the role of MMP3 in exacerbating the vascular injury and HT in hyperglycemic stroke. We showed that the pharmacological inhibition and focal knockdown of MMP3 in the brain significantly reduced the HT and improved the outcomes. Our findings provide a better understanding of the mechanisms involved in mediating the HG induced HT after stroke and points out MMP3 as a novel and potential therapeutic target in hyperglycemic stroke and that its inhibition can reduce the HG induced HT and provide a potential clinical solution for safer administration of tPA.
