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Premium Upregulation of efflux transport at blood‐central nervous system barriers in diabetes
Hawkins Brian T,
Ocheltree Scott M,
Norwood Kristi M,
Egleton Richard D
Publication year2006
Publication title
the faseb journal
Resource typeJournals
PublisherFederation of American Societies for Experimental Biology
The blood‐brain and blood‐cerebrospinal fluid barriers (BBB/BCSFB) regulate the passage of substances to and from the central nervous system (CNS). Using in situ brain perfusion, we have demonstrated that BBB permeability to sucrose, a marker for paracellular permeability of the BBB, is increased in streptozotocin (STZ)‐induced diabetic rats with the unidirectional transport coefficient (K in ) increased from 0.76 ± 0.18 μl g ‐1 min ‐1 to 1.90 ± 0.39 μl g ‐1 min ‐1 . While paracellular permeability is limited by tight junctions, the BBB/BCSFB also express efflux proteins including multidrug resistance proteins (MRP) and organic anion transporters (OAT). Sodium fluorescein (NF), though used as a paracellular marker, is also a substrate for MRP‐1/2 and OAT‐1/3, and MRP‐mediated efflux of NF can be stimulated by glucose. In this study, we assessed BBB permeability to NF in STZ‐treated rats. K in for NF were determined by linear least‐squares regression. K in in saline controls was 0.81 ± 0.12 μl g ‐1 min ‐1 (R 2 = 0.9779), comparable to sucrose. In STZ‐treated animals, K in for NF was reduced to 0.35 ± 0.07 μl g ‐1 min ‐1 when fit to a linear model (R 2 = 0.9007). When fit to a nonlinear model, K in was higher but not significantly different (0.95 ± 0.44 μl g ‐1 min ‐1 ) with an efflux constant (k out ) of 0.43 ± 0.18min ‐1 and a better least‐squares fit (R 2 = 0.9679). We conclude that in addition to compromising the paracellular permeability of the BBB diabetes may lead to an upregulation of efflux transport at the BBB/BCSFB, potentially affecting the CNS distribution of therapeutics in diabetic patients. Support: NIDDK R01‐DK065003 and NIH T32 HL07249
Subject(s)biochemistry , biology , biophysics , blood–brain barrier , central nervous system , chemistry , diabetes mellitus , efflux , endocrinology , glucose transporter , insulin , medicine , membrane , paracellular transport , permeability (electromagnetism) , pharmacology , streptozotocin
SCImago Journal Rank1.709

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