In the United States, stroke is the fifth leading cause of death and stroke survivors often face long-term disability. After ischemic stroke, the ischemic territory can expand and recruit previously viable tissues into the lesioned area. During this critical period, there is an unsettling lack of interventions that prevent or treat secondary neuronal loss and cognitive decline. Clinical subdural recordings have revealed a close link between infarct progression and waves of spreading depolarizations (SD) in the acutely injured brain. SD is a slowly progressing wave of near-complete neuroglia depolarization that is extremely energetically demanding and this additional metabolic ‘hit’ of SD in vulnerable tissues (i.e. penumbra) could underlie secondary lesion progression. While deleterious to metabolically impaired neurons, SD may theoretically promote recovery and repair processes in otherwise healthy cortex, distant from the initial injury site. This dissertation work characterized the impact of tissue metabolic status on deleterious consequences of SD in order to test interventions that reduce neuronal injury without preventing SD outright. From this work, we now know that SD consequences can be targeted to limit deterioration of vulnerable tissues without preventing any theoretical benefits in remote brain regions that may play a role in cortical reorganization and recovery after focal ischemia.