Injury to the brain caused by cerebral ischemia is a major public health concern. System xc (Sxc) is a cystine- glutamate antiporter, which functions to import cystine while simultaneously exporting glutamate. Using in vitro models, we previously demonstrated that alterations in Sxc function contribute to the development and - progression of hypoxia- and hypoglycemia-induced neuronal injury. This led us to hypothesize that Sxc could play a role in acute stroke injury. In keeping with idea, we have determined that mice deficient in Sxc are less susceptible to transient cerebral ischemic injury than control mice in vivo. However, the well-characterized ability of system xc to import cystine to support synthesis of the antioxidant molecule, glutathione (GSH), has - also led us to speculate that system xc activation could also be potentially important for stroke recovery. Indeed, the same enhancement of Sxc in astrocytes, sans energy deprivation, protects astrocytes alone and both neurons and astrocytes in co-culture against oxidative injury in a GSH-dependent manner. Whether this translates into a benefit in stroke recovery in vivo remains unknown. Hence, studies in this proposal, are designed to analyze the biphasic role of Sxc with respect to its potential contribution to acute cerebral ischemic damage (Aim 1) as well as to recovery/ repair following cerebral ischemia in vivo (Aim 2). Utilization of newly developed pharmacological drugs as well as state-of-the-art tools to test the underlying hypothesis will allow us to obtain both preclinical information as well as to enhance our mechanistic understanding of the injury process, respectively.
Morbidity associated with stroke remains a huge emotional and economic burden due in large part to a void in treatment options. Many clinical trials for the treatment of stroke have been initiated and have failed. An intriguing idea has recently been put forth suggesting that failure may be due to the fact that many molecular targets that had been considered for stroke therapy have a biphasic role following stroke, meaning they may mediate injury in the acute phase but also may also be important for remodeling/repair during the recovery phase. Our studies on the cystine/glutamate antiporter System xc (Sxc )-a heteromeric amino acid transport -- system that imports of L-cystine (CysS) while exporting L-glutamate (Glu) - suggest it may fit into this bimodal paradigm. Hence, it is our contention that successful completion of the goals will aid in our understanding of the potential biphasic nature of Sxc so that we may use this information to devise strategies to harness its beneficial effects and when appropriate, to employ strategies to reduce its deleterious activity.
