Astrocyte‐derived glutathione attenuates hemin‐induced cytotoxicity in murine cerebral microvessel

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Intracerebral hemorrhage (ICH) induces neurovascular injury following the rupture of a blood vessel within the brain via poorly defined mechanisms. The aim of the present study was to determine whether glio‐vascular communication may restrict hemorrhagic vascular injury. Hemin concentration‐ and time‐dependently increased oxidative cytotoxicity in mouse bEND.3 microvessel cells. Cell death was preceded by a NFκB‐mediated increase in inflammatory gene expression, including up‐regulation of inducible nitric oxide synthase (iNOS) expression and activity. The inhibition of iNOS or the addition of a peroxynitrite decomposition catalyst reduced cell death. Interestingly, co‐treatment with astrocyte conditioned media (ACM) reversed hemin‐induced NF ?ÛB activation, nitrotyrosine formation, and apoptotic cell death via the release of the endogenous antioxidant, reduced glutathione (GSH). Prior treatment of astrocytes with the glutathione‐depleting agent, DL‐buthionine (S,R)‐sulfoximine (BSO) or direct addition of diethyl maleate, a thiol depleting agent, to ACM reversed the observed protection. In contrast, the addition of exogenous GSH or the GSH precursor, N‐acetylcysteine, were protective in bEND.3 cells. These data identify a previously unrecognized vasculoprotective role for astrocyte‐derived GSH and indicate therapeutic targeting of GSH may reduce neurovascular injury following ICH.