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-surf ace area (PS) product after correction for the residual plasma volume (V-p) occupied by the protein in the capillary bed of the nerve endone urium or different brain regions. The i.v. bolus injection technique w as used in the cannulated brachial vein and artery using the same prot ein radioiodinated with a second isotope of iodine (I-125 vs. I-131) t o separately determine the PS and V-p values. The plasma washout showe d a decreasing plasma half-life in the order of brain-derived neurotro phic factor (BDNF) < neurotrophin-3 (NT-3) < ciliary neurotrophic fact or (CNTF)< nerve growth factor (NGF). The PS at the BNB for NGF was 1. 40 +/- 0.15 X 10(-6) ml/g/s ((x) over bar +/- SEM). The other neurotro phic proteins were all significantly higher than NGF (CNTF: 9.5 X; NT- 3: 20.8 X; BDNF: 18.9 X). The V-p for NGF at the BNB was 1.92 +/- 0.12 mu l/g and was not significantly different from the other proteins ex cept for NGF vs. BDNF (P < 0.05). The PS for NGF at the BBB ranged fro m 1.5 to 2.7 X 10(-6) ml/g/s for six different brain regions. The PS f or 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 V-p values were not significantly different except for CNTF in the hippocampus and co rtex (P < 0.05). SDS-PAGE analyses of all the radioiodinated neurotrop hic proteins after 60 min of uptake revealed intact protein in the end oneurium and in the six different brain regions with exposure times of 2-42 days. The quantification of the permeability of these neurotroph ic proteins provides baseline values for comparison of different prote in modifications that enhance the PS while still preserving the neurot rophic activity (e.g., protein glycation; Poduslo and Curran, Mol. Bra in Res., 23 (1994) 157). Enhanced permeability following modification might allow the use of systemic delivery of these proteins for practic al therapeutic treatment of various neurodegenerative disorders.