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 (V-p) 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 (I-125 vs. I-131) to separately determine the PS and V-p 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 ((x) over bar +/- 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 V-p for NGF at the BNB was 1.92 +/- 0.12 mu l/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 V-p 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 systemic delivery of these proteins for practical therapeutic treatment of various neurodegenerative disorders.