Blood brain barrier disruption and edema formation: Regulative mechanisms and effects of cortical speading depression (CSD) triggered matrix metalloproteinase (MMP) activation

点击翻译按钮获取中文摘要

Cortical spreading depression (CSD) is discussed as pathophysiological mechanism in migraine, cerebrovascular diseases, head injury and epilepsy. Recently, matrix metalloproteases (MMP) have been suggested to be involved in the integrity of the neurovascular unit by degrading matrix proteins, enhancing blood brain barrier (BBB) permeability and brain edema. It has been shown that intense neuronal and glial depolarisation during CSD activates MMP-9 for at least 72 hrs. Preliminary data suggest that this MMP activation promotes perivascular plasma protein leakage. The two key objectives of the intended research will explore the novel hypothesis that the MMP activation during CSD is caused in part by neuronal and glial activation and contributes to the development of edema in ischemia and BBB disruption. Aim 1 will examine upstream mechanisms triggering MMP activation during CSD by exploring pathways in the transcriptional regulation of MMP-9. Aim 2 will determine the consequences of CSD-induced MMP activation during ischemia and explore the contributions of MMPs to vascular permeability changes. By doing so, the intention is to explore ways in which neuronal activity during cerebral ischemia modulates the extracellular matrix and neurovascular unit and contributes to tissue injury.