Epinephrine enhances lysosomal enzyme delivery across the blood-brain barrier by up-regulation of the mannose 6-phosphate receptor

Delivering therapeutic levels of lysosomal enzymes across the blood-brain barrier (BBB) has been a pivotal issue in treating CNS storage diseases, including the mucopolysaccharidoses. An inherited deficiency of beta-glucuronidase (GUS) causes mucopolysaccharidosis type VII that is characterized by increased systemic and CNS storage of glycosaminoglycans. We previously showed that the neonate uses the mannose 6-phosphate (M6P) receptor to transport phosphorylated GUS (P-GUS) across the BBB and that this transporter is lost with maturation. Induction of expression of this BBB transporter would make enzyme replacement therapy in the adult possible. Here, we tested pharmacological manipulation with epinephrine to restore functional transport of P-GUS across the adult BBB. Epinephrine (40 nmol) coinjected i.v. with I-131-P-GUS induced the transport across the BBB in 8-week-old mice. The brain influx rate of I-131-P-GUS (0.29 mu l/g per min) returned to the level seen in neonates. Capillary depletion showed that 49% of the I-131-P-GUS in brain was in brain parenchyma. No increases of influx rate or the vascular space for I-125-albumin, a vascular marker, was observed with epinephrine (40 nmol), showing that enhanced passage was not caused by disruption of the BBB. Brain uptake of I-131-P-GUS was significantly inhibited by M6P in a dose-dependent manner, whereas epinephrine failed to increase brain uptake of nonphosphorylated GUS. Thus, the effect of epinephrine on the transport of I-131-P-GUS was ligand specific. These results indicate that epinephrine restores the M6P receptor-mediated functional transport of I-131-P-GUS across the BBB in adults to levels seen in the neonate.