Endogenous and exogenous protection of the BBB in stroke

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DESCRIPTION (provided by applicant): Endogenous and exogenous protection of the BBB in stroke. Blood-brain barrier (BBB) dysfunction occurs in a wide variety of neurological diseases and injuries (e.g. stroke). Such dysfunction may participate in those states by enhancing the influx of leukocytes into the brain, allowing the entry of potentially neurotoxic blood components and causing vasogenic edema. In addition, it may affect disease treatment (e.g. hemorrhagic transformation is a major limiting factor for the use of tissue plasminogen activator-induced reperfusion therapy for ischemic stroke). There is, therefore, a great need for methods to protect the BBB. Therapeutic targets may potentially be identified by examining which endogenous mechanisms are altered in disease states. We have shown that preconditioning stimuli can protect the BBB and cerebral endothelial cells in vivo and in vitro. We have also shown that stroke-related factors cause a marked increase in the expression of the cystine/glutamate exchanger (system xc-), a regulator of intracellular glutathione, in cerebral endothelial cells. This exchanger is regulated by nrf2 (an anti-oxidant transcription factor) and xc- can be markedly upregulated by exposure to sulforaphane, an activator of Nrf2 and a component of cruciferous vegetables. These results have led us to hypothesize that: Nrf2 and the proteins it regulates (e.g. xCT, heme oxygenase 1 and ferritin) may be a target for protecting the BBB. As Nrf2 regulation of these proteins requires protein synthesis, we also hypothesize that the function of this system is to protect against delayed BBB disruption, particularly due to migrating leukocytes in ischemia. These hypotheses will be examined in five specific aims: 1+2) Determine whether upregulation of system xc- by stroke-related factors, inflammatory mediators or sulforaphane is protective. 3+4) Determine whether Nrf2 is activated in the cerebral endothelium after stroke or inflammation and whether its activation and the upregulation of downstream proteins will protect the cerebral endothelium. 5) Examines whether treatment with sulforaphane can protect the BBB in vivo. These specific aims will be examined in vitro, to allow elucidation of molecular mechanisms, and in vivo, to determine pathophysiological relevance. The results should highlight endogenous BBB protective mechanisms and the potential exogenous compounds to activate or inhibit those mechanisms. PUBLIC HEALTH RELEVANCE: Brain blood vessels have very specialized functions, forming a blood-brain barrier. Disuption of that barrier occurs in many neurological disorders and injuries, contributing to brain dysfunction. This proposal examines natural defense mechanisms that may protect the blood-brain barrier, how to activate those mechanisms or prevent their inactivation therapeutically.