GLYCATION INCREASES THE PERMEABILITY OF PROTEINS ACROSS THE BLOOD NERVE AND BLOOD-BRAIN BARRIERS

Our previous investigations have demonstrated increased permeability a cross the blood-nerve barrier of human plasma albumin after glycation with D-glucose [J.F. Podusio and G.L. Curran, Proc. Natl. Acad. Sci. U SA, 89 (1992) 2218-2222]. In the present investigation, the generality of this observation was evaluated by measuring the permeability coeff icient-surface area product (PS) after correction for the residual pla sma volume (V(p)) across the blood-nerve barrier (BNB), as well as the blood-brain barrier (BBB), for nerve growth factor (NGF) and human Ig G after in vitro glycation with D-glucose using an i.v. bolus injectio n technique in the cannulated brachial vein and artery of normal adult rats. Glycated proteins (gNGF and gIgG) had significantly decreased c irculating plasma half-lives compared to the non-glycated proteins. Th e PS across the BNB obtained for gNGF was significantly increased comp ared to NGF with a 2.0-fold increase observed after 8 weeks of glycati on and a 5.1-fold increase at 21 weeks of glycation. The V(p) measurem ent 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 glycatio n. The PS across the BBB for gNGF was about 2-fold greater than NGF wi th a glycation time of 8 weeks and 3.2-3.6-fold greater with a glycati on time of 21 weeks for six different brain regions. No changes were o bserved 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 differenc e 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 o bserved for the V(p) values. These data demonstrate that glycation can enhance the permeability across the BNB and BBB of proteins with wide ly varying molecular weight and function. Since the glycation of NGF d oes not appear to affect its neurotrophic activity, systemic deliver o f gNGF might be useful for treating a variety of neurodegenerative dis eases. Similarly, the glycation of monoclonal immunoglobulins might be a convenient procedure for delivery of a variety of antigens into the nervous system.