Abstract:

Brain ischemic stroke is the leading cause of long-lasting neurological disability and death in adults. Although the brain represents only about 2% of the total body mass, it consumes almost 20% of the body's oxygen. For this reason, brain neurons are extremely sensitive to hypoxia. In an ischemic stroke, blood supply to part of the brain is loss that triggers a series of intracellular stress events eventually leading to cell death. Depending on the nature of the ischemic insult, the affected tissue can be classified into two major zones of injury. In the core zone, which is an area with the most severe reduction in blood flow, and within which brain cells undergo rapid cell dies regardless of subsequent reperfusion. In contrast, adjacent to the central core zone is defined as the penumbra zone, characterized by levels of blood flow slightly greater than the core zone itself. Therefore, cell death in the core zone is rapid, whereas cells in the penumbra zone may remain viable for several hours. This indicates prompt restoration of blood flow to an ischemic area may allow threatened tissue to be salvaged. To restore blood flow before major damage occurred, rapidly administration of thrombolytic agents such as tissue-type plasminogen activator (tPA), has now generally be accepted in carefully selected patients with ischemic stroke. However, if blood flow is restored in the penumbra before significant cell death occurs, the process of reperfusion can also causes additional hypoxia-reoxygenation (H/R) damages. It is known H/R can induce significant neuronal death through triggering overproduction of reactive oxygen species (ROS) accompanied with mitochondrial dysfunction and subsequent cell death. In particular, glycogen synthase kinase 3β (GSK3β) has been linked to mitochondrial dysfunction after H/R-induced oxidative stress. GSK3β is a serine-threonine kinase that was first discovered to phosphorylate and inactivate glycogen synthase, an enzyme in the glycogen synthesis pathway. Normally, GSK3βis suppressed by prosurvival signals such as insulin/insulin-like growth factor (IGF) as well as Akt. However, GSK3βis activated by ischemic injury, which promotes the mitochondrial dysfunction and induces apoptosis. Thus, inhibition of GSK3β is proposed as a putative therapeutic strategy after an acute ischemic insult. Although GSK3β inhibition is a rational strategy to combat ischemic stroke, its therapeutic success is limited by the adverse events and a rather small therapeutic window.