Different mechanisms influencing permeation of PDGF‐AA and PDGF‐BB across the blood–brain barrier

Abstract Platelet‐derived growth factor (PDGF) exerts neurotrophic and neuromodulatory effects on the CNS. To determine the permeability of the blood–brain barrier (BBB) to PDGF, we examined the blood‐to‐brain influx of radioactively labeled PDGF isoforms (PDGF‐AA and PDGF‐BB) by multiple‐time regression analysis after intravenous (i.v.) injection and by in‐situ perfusion, and also determined the physicochemical characteristics which affect their permeation across the BBB, including lipophilicity (measured by octanol:buffer partition coefficient), hydrogen bonding (measured by differences in octanol : buffer and isooctane : buffer partition coefficients), serum protein binding (measured by capillary electrophoresis), and stability of PDGF in blood 10 min after i.v. injection (measured by HPLC). After i.v. bolus injection, neither 125 I‐PDGF‐AA nor 125 I‐PDGF‐BB crossed the BBB, their influx rates being similar to that of the vascular marker 99m Tc‐albumin. 125 I‐PDGF‐AA degraded significantly faster in blood than 125 I‐PDGF‐BB. PDGF‐BB, however, was completely bound to a large protein in serum whereas PDGF‐AA showed no binding. Thus, degradation might explain the poor blood‐to‐brain influx of PDGF‐AA, whereas protein binding could explain the poor influx of circulating PDGF‐BB. Despite their lack of permeation in the intact mouse, both 125 I‐PDGF‐AA and 125 I‐PDGF‐BB entered the brain by perfusion in blood‐free buffer, and the significantly faster rate of 125 I‐PDGF‐AA than 125 I‐PDGF‐BB may be explained by the lower hydrogen bonding potential of 125 I‐PDGF‐AA. Thus, the lack of significant distribution of PDGF from blood to brain is not because of the intrinsic barrier function of the BBB but probably because of degradation and protein binding. Information from these studies could be useful in the design of analogues for delivery of PDGF as a therapeutic agent.