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  • Title: Protein kinase C family members as a target for regulation of blood-brain barrier Na,K,2Cl-cotransporter during in vitro stroke conditions and nicotine exposure.
    Author: Yang T, Roder KE, Bhat GJ, Thekkumkara TJ, Abbruscato TJ.
    Journal: Pharm Res; 2006 Feb; 23(2):291-302. PubMed ID: 16450214.
    Abstract:
    PURPOSE: The aim of the study is to identify specific protein kinase C (PKC) isoforms involvement in K(+) transport mediated at altered blood-brain barrier (BBB) response to stroke conditions with prior nicotine exposure, which provides ways to intervene pharmacologically in PKC-mediated molecular pathways that could lead to effective treatment for smoking stroke patients. METHODS: Changes in PKC isoform levels were studied in the cytosolic and membrane fractions of bovine brain microvessel endothelial cells subjected to stroke conditions as well as nicotine/cotinine exposure. Furthermore, abluminal Na,K,2Cl-cotransporter (NKCC) activity regulated by specific conventional PKC isoform activators and inhibitors was investigated using rubidium ((86)Rb) uptake studies. RESULTS: Membrane-bound PKCalpha, PKCbetaI, and PKCepsilon levels were increased after 6 h hypoxia/aglycemia, and this was attenuated by 24-h nicotine/cotinine exposure. Interestingly, membrane-bound PKCgamma protein level was decreased after 6 h hypoxia/aglycemia and increased by 24-h nicotine/cotinine exposure. (86)Rb uptake studies showed that basolateral NKCC activity was down-regulated by both a conventional PKC inhibitor and specific inhibitors for PKCalpha, PKCbeta, and PKCvarepsilon and was up-regulated by an activator of conventional PKCs during 6-h hypoxia/aglycemia treatment. CONCLUSION: Specific PKC inhibitors or activators might be designed to individualize stroke therapies and improve health outcome for smokers by rebalancing ion transport into and out of the brain.
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