The neurovascular/gliovascular unit has recently gained increased attention in cerebral ischemic research, especially regarding the cellular and molecular changes that occur in astrocytes and endothelial cells. In this paper we summarize the recent knowledge of these changes in association with edema formation, interactions with the basal lamina, and blood-brain barrier dysfunctions. We also review the involvement of astrocytes and endothelial cells with recombinant tissue plasminogen activator, which is the only FDA-approved thrombolytic drug after stroke. However, it has a narrow therapeutic time window and serious clinical side effects. Lastly, we provide alternative therapeutic targets for future ischemia drug developments such as peroxisome proliferator- activated receptors and inhibitors of the c-Jun N-terminal kinase pathway. Targeting the neurovascular unit to protect the blood-brain barrier instead of a classical neuron-centric approach in the development of neuroprotective drugs may result in improved clinical outcomes after stroke. 1. Introduction: Current Clinical Overview of Stroke In the United States, stroke is the number one cause of chronic disability and the fourth leading cause of death, with approximately 7 million adults affected [1]. Annually there are approximately 800,000 strokes in the US, of which 87% are ischemic strokes, 10% are primary hemorrhages, and 3% are subarachnoid hemorrhages [1]. Together they cause the country a financial burden of approximately 62.7 billion dollars [2]. Cerebral ischemic stroke is caused by an occlusion of a cerebral blood vessel, typically by a thrombus, which causes a decrease in cerebral blood flow and thus limits the supply of oxygen and nutrients globally (in global ischemia) or to certain regions of the brain (in focal brain ischemia). This absence of blood flow in a brain region causes neuronal death in addition to damaging the vascular tree; the vascular tree is usually made more fragile during the ischemic period and damaged during reperfusion. Time is an important parameter in the evolution of brain injury. In 2006, Saver et al. have estimated the impact of stroke on the brain tissue [3] to be immense; the brain may lose up to 120 million neurons, 830 billion synapses and 714？km of myelinated fibers for each hour after stroke onset [3]. Ischemic stroke seems to accelerate aging of the brain at a rate of 3.6 years each time when the symptoms are not treated [3]. Therefore, the clinical goal of acute stroke treatment is to reduce brain damage by limiting the time of ischemia through
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