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Cerebral ischemia, most notably in the form of stroke, is a leading cause of morbidity and mortality resulting in long-term disability in the United States (U.S.). Investigating therapies that could be preemptively administered to individuals with a risk factor for stroke could improve prognosis following this devastating condition. One such prophylactic therapy could be represented by ischemic preconditioning (IPC). IPC is the intrinsic neuroprotective response from a brief sub-lethal ischemic event which increases the tolerance towards a future lethal ischemic event. However, previous preconditioning studies in the brain have been studied mainly from the perspective of neurons; as a result, the role of astrocytes in mediating IPC-induced neuroprotection is poorly understood. Two functions ascribed to astrocytes are antioxidant production and lactate production. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in upregulating endogenous antioxidant production, and may help ameliorate oxidative stress following cerebral ischemia. In addition, astrocyte-derived lactate has been implicated in maintaining neuronal metabolism, particularly under ischemic conditions. As oxidative stress and bioenergetic failure act cooperatively to contribute to the pathogenesis of stroke, the central hypothesis of my thesis work was that IPC treatment modulates astrocyte function, leading to neuroprotection in the context of cerebral ischemia. My findings suggest that Nrf2 is significantly enriched in rodent astrocytes compared to neurons. Subsequent work demonstrates that IPC and resveratrol preconditioning (RPC), an IPC-mimetic treatment, had reduced neuroprotective effects in Nrf2-/-mice compared to WT mice. These studies suggest that Nrf2 contributes to preconditioned-induced protection of astrocytes and neurons. To investigate the effects of IPC-treatment of astrocytes on neuroprotection, we developed a modified astrocyte-neuronal co-culture system that allows us to precondition astrocytes independent of neurons. IPC-treatment of astrocytes alone induced protection of neurons against lethal oxygen-glucose deprivation (OGD), an in vitro model of cerebral ischemia. In addition, we found that astrocytes increased lactate production following IPC treatment. Finally, exogenous lactate administration to neurons for 48 hours induces neuroprotection against lethal OGD. These findings suggest that IPC-treatment of astrocytes can induce ischemic tolerance to neurons. In addition, exogenous administration of lactate may represent a neuroprotective agent to be used in the context of cerebral ischemia. From my current thesis work, our results suggest that the astrocyte-enriched transcription factor Nrf2 contributes to IPC and RPC-induced neuroprotection. Furthermore, IPC-treatment of astrocytes alone transferred ischemic tolerance to neurons through soluble mediators. One of these mediators may be lactate, as exogenous lactate administration induced neuroprotection to neurons in vitro. As oxidative stress and bioenergetic failure are hallmarks of stroke, the ability of astrocytes to produce antioxidants and lactate in the context of cerebral ischemia could represent viable targets for future stroke therapy.
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