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Abstract and Introduction
Abstract
Currently available modalities for the treatment of acute ischemic stroke are aimed at preserving or augmenting cerebral blood flow. Experimental evidence suggests that statins, which show 25-30% reduction of stroke incidence in clinical trials, confer stroke protection by upregulation of eNOS and increasing cerebral blood flow. The upregulation of eNOS by statins is mediated by inhibition of small GTP-binding protein RhoA. Our recent study uncovered a unique role for a Rho-family member Rac1 in stroke protection. Rac1 in endothelium does not affect cerebral blood flow. Instead, inhibition of endothelial Rac1 leads to broad upregulation of the genes relevant to neurovascular protection. Intriguingly, inhibition of endothelial Rac1 enhances neuronal cell survival through endothelium-derived neurotrophic factors, including artemin. This review discusses the emerging therapeutic opportunities to target neurovascular signaling beyond the BBB, with special emphasis on the novel role of endothelial Rac1 in stroke protection.
Introduction
Ischemic stroke is the third leading cause of death in developed countries. To date, nearly 300 clinical trials concerned with acute treatment of ischemic stroke have been registered; However, most of the completed trials, have been disappointing, except for the modest benefit seen with the use of tissue plasminogen activator (tPA). In addition, although some agents, such as statins, show proven efficacy in stroke prevention, the magnitude of this effect is unsatisfactory. Therefore, a critical need exists for a deeper understanding of stroke pathophysiology for new therapeutic paradigms.
The disease process of stroke is multifactorial. It is noteworthy, however, that all modalities currently available for the treatment or prophylaxis of ischemic stroke, such as antiplatelet, antithrombotic and thrombolytic drugs, are aimed at preserving or restoring cerebral blood flow (CBF); this clearly underscores the importance of vascular function in the treatment of stroke. On the other hand, the limited efficacy of therapies targeting CBF has necessitated additional approaches for direct neuroprotection. Energy depletion in ischemia initiates a cascade of events: excitotoxicity, oxidative stress, proteolysis and inflammation, which ultimately lead to cell demise. Many promising experimental treatments targeting these processes have shown little effect in clinical trials. There are several sources for this failure, including the poor penetration of the agents across the BBB. Remarkable advances have been made recently that may ultimately lead to circumventing the BBB and facilitate direct neuroprotection. In this review, we will discuss recent progress in the neuroprotective modalities that target vascular endothelium to prevent or treat ischemic stroke, with special emphasis on the emerging heterogeneic roles of the Rho proteins, RhoA and Rac1, in these processes.
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