Inflammatory cascade leading to secondary brain inflammation and cell death after ischemic injury. Cerebral ischemia alone leads to both an initial cell necrosis and generation of reactive oxygen species (ROS) and proinflammatory molecules like interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) from injured neurons as well as inducing blood–brain barrier (BBB) dysfunction with loosening of cell-to-cell tight junctions between endothelial cells and upregulation of endothelial cell expression of various cell adhesion molecules (e.g., vascular cell adhesion molecules (VCAM), intracellular adhesions molecule-1 (ICAM-1)). This increase causes adherence, migration, and extravasation of circulating leukocytes into the brain parenchyma. When in the brain, leukocytes and activated microglia generate a variety of proinflammatory molecules like inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), IL-1β and TNF-α, and continue to generate ROS. These events lead to secondary brain injury, increased inflammation, and ultimately cell death. ECM, extracellular matrix; NO, nitric oxide.