Glycation increases the permeability of proteins across the blood-nerve and blood-brain barriers

Our previous investigations have demonstrated increased permeability across the blood-nerve barrier of human plasma albumin after glycation with d-glucose [J.F. Poduslo and G.L. Curran, Proc. Natl. Acad. Sci. USA, 89 (1992) 2218-2222]. In the present investigation, the generality of this observation was evaluated by measuring the permeability coefficient-surface area product (PS) after correction for the residual plasma volume (V_p) across the blood-nerve barrier (BNB), as well as the blood-brain barrier (BBB), for nerve growth factor (NGF) and human IgG after in vitro glycation with d-glucose using an i.v. bolus injection technique in the cannulated brachial vein and artery of normal adult rats. Glycated proteins (gNGF and gIgG) had significantly decreased circulating plasma half-lives compared to the non-glycated proteins. The PS across the BNB obtained for gNGF was significantly increased compared to NGF with a 2.0-fold increase observed after 8 weeks of glycation and a 5.1-fold increase at 21 weeks of glycation. The V_p measurement for NGF and gNGF across the BNB was not significantly different at 8 weeks of glycation but was 1.3-fold greater at 21 weeks of glycation. The PS across the BBB for gNGF was about 2-fold greater than NGF with a glycation time of 8 weeks and 3.2-3.6-fold greater with a glycation time of 21 weeks for six different brain regions. No changes were observed in the V_p for any of the brain regions for gNGF compared to NGF. The PS across the BNB for gIgG compared to IgG was significantly greater with a 4.1-fold relative increase and no significant difference in the V_p values. The PS across the BBB for gIgG ranged from a 2.8-fold increase for the thalamus to a 5.1-fold increase for the caudate putamen when compared to IgG. Again no significant differences were observed for the V_p values. These data demonstrate that glycation can enhance the permeability across the BNB and BBB of proteins with widely varying molecular weight and function. Since the glycation of NGF does not appear to affect its neurotrophic activity, systemic deliver of gNGF might be useful for treating a variety of neurodegenerative diseases. Similarly, the glycation of monoclonal immunoglobulins might be a convenient procedure for delivery of a variety of antigens into the nervous system.