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      Transport of brain-derived neurotrophic factor across the blood–brain barrier

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      Neuropharmacology

      Elsevier BV

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          Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data.

          A theoretical model of blood-brain exchange is developed and a procedure is derived that can be used for graphing multiple-time tissue uptake data and determining whether a unidirectional transfer process was dominant during part or all of the experimental period. If the graph indicates unidirectionality of uptake, then an influx constant (Ki) can be calculated. The model is general, assumes linear transfer kinetics, and consists of a blood-plasma compartment, a reversible tissue region with an arbitrary number of compartments, and one or more irreversible tissue regions. The solution of the equations for this model shows that a graph of the ratio of the total tissue solute concentration at the times of sampling to the plasma concentration at the respective times (Cp) versus the ratio of the arterial plasma concentration-time integral to Cp should be drawn. If the data are consistent with this model, then this graph will yield a curve that eventually becomes linear, with a slope of Ki and an ordinate intercept less than or equal to the vascular plus steady-state space of the reversible tissue region.
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            Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF.

            A comparison was made of the permeabilities of different neurotrophic factors at the blood-brain barrier (BBB) and blood-nerve barrier (BNB) in normal adult rats by quantifying the permeability coefficient-surface area (PS) product after correction for the residual plasma volume (Vp) occupied by the protein in the capillary bed of the nerve endoneurium or different brain regions. The i.v. bolus injection technique was used in the cannulated brachial vein and artery using the same protein radioiodinated with a second isotope of iodine (125I vs. 131I) to separately determine the PS and Vp values. The plasma washout showed a decreasing plasma half-life in the order of brain-derived neurotrophic factor (BDNF) < neurotrophin-3 (NT-3) < ciliary neurotrophic factor (CNTF) < nerve growth factor (NGF). The PS at the BNB for NGF was 1.40 +/- 0.15 x 10(-6) ml/g/s (mean +/- SEM). The other neurotrophic proteins were all significantly higher than NGF (CNTF: 9.5 x ; NT-3: 20.8 x ; BDNF: 18.9 x ). The Vp for NGF at the BNB was 1.92 +/- 0.12 microliters/g and was not significantly different from the other proteins except for NGF vs. BDNF (P < 0.05). The PS for NGF at the BBB ranged from 1.5 to 2.7 x 10(-6) ml/g/s for six different brain regions. The PS for CNTF ranged from 6.0 to 8.0-fold higher than NGF; NT-3: 10.6 to 15.2-fold higher; and BDNF: 11.3 to 16.4-fold higher. The Vp values were not significantly different except for CNTF in the hippocampus and cortex (P < 0.05). SDS-PAGE analyses of all the radioiodinated neurotrophic proteins after 60 min of uptake revealed intact protein in the endoneurium and in the six different brain regions with exposure times of 2-42 days. The quantification of the permeability of these neurotrophic proteins provides baseline values for comparison of different protein modifications that enhance the PS while still preserving the neurotrophic activity (e.g., protein glycation; Poduslo and Curran, Mol. Brain Res., 23 (1994) 157). Enhanced permeability following modification might allow the use of systematic delivery of these proteins for practical therapeutic treatment of various neurodegenerative disorders.
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              Murine tumor necrosis factor alpha is transported from blood to brain in the mouse.

              The cytokines are important components of the brain-immune axis. Recent work has shown that [125I]IL-1 alpha and [125I]IL-1 beta are transported from the blood into the brain by a saturable system. Here we show that murine tumor necrosis factor alpha (mTNF alpha) labeled with 125I (I-mTNF alpha) crosses the blood-brain barrier (BBB) after i.v. injection by a transport system different from that for the interleukins. Self inhibition with mTNF alpha showed that this transport system was saturable, and lack of inhibition by IL-1 alpha, IL-1 beta, IL-6, or MIP-1 alpha showed selectivity of the system. High performance liquid chromatography (HPLC) of the radioactivity recovered from brain and from cerebrospinal fluid after the i.v. injection of I-mTNF alpha showed that the cytokine crossed the BBB largely in intact form. Capillary depletion showed that the accumulation of I-mTNF alpha in the cerebral cortex was due to passage across the BBB rather than to sequestration by capillaries. Transport rate was not changed by acute treatment with the neurotoxin aluminium or by acute and chronic treatment with the cationic chelator deferoxamine, but it was more than three times faster in neonatal rats. Efflux of I-mTNF alpha from the brain was slower than would have been predicted based on reabsorption of cerebrospinal fluid, suggesting that TNF alpha is sequestered by the brain. The BBB was not disrupted by up to 50 micrograms kg-1 of mTNF alpha i.v. in either adult mice or neonatal rats as assessed by the BBB's impermeability to radioactively labeled albumin.(ABSTRACT TRUNCATED AT 250 WORDS)
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                Author and article information

                Journal
                Neuropharmacology
                Neuropharmacology
                Elsevier BV
                00283908
                December 1998
                December 1998
                : 37
                : 12
                : 1553-1561
                Article
                10.1016/S0028-3908(98)00141-5
                9886678
                © 1998

                http://www.elsevier.com/tdm/userlicense/1.0/

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