In addition, hyperglycemia can induce early extracellular HMGB1 secretion from ischemic brain tissue, increasing the accumulation of several excitatory mediators that play critical roles in neuronal death such as glutamate, which strongly increases infarct volume, enhance neurological deficits, and cerebral edema, and promotes blood–brain barrier disruption, which is a central step in the growth of cerebral edema during early stages of ischemic brain injury [75,76]. This evidence concerns the gene HMGB1 and brain edema.