Ischemic strokes account for approximately 80% of all strokes and are caused by obstructed arteries that deprive the brain of oxygen and nutrients. Ischemic strokes damage brain tissue primarily through excitotoxicity, a term used to describe cell death induced by high levels of Glutamate in the synaptic cleft. Excess Glutamate over-activates NMDA receptors (NMDA R) on postsynaptic cells which induces cell death by a number of mechanisms. These include generation of reactive oxygen species and activation of proteases such as Calpain which proteolytically cleave structural proteins in the cell. Upregulation of matrix metalloproteinases (MMPs) exacerbates tissue damage by disrupting the blood-brain barrier (BBB). Strategies to limit neuronal death following an ischemic stroke include restoring blood flow to the affected area using t-Plasminogen Activator (tPA), a thrombolytic agent.
In contrast, hemorrhagic strokes stem from ruptured blood vessels that increase intracranial pressure and reduce blood flow to surrounding brain tissue. Following the initial tissue damage induced by intracerebral bleeding, hemorrhagic strokes promote further cell death by Thrombin which is stimulated by the presence of extravascular blood in the brain. High Thrombin levels activate MMPs which compromise BBB integrity and activate Protease-Activated Receptors (PARs). PARs contribute to cell death by recruiting microglia and potentiating NMDA receptor activation.