title: Pharmacologic manipulation of lysosomal enzyme transport across the blood-brain barrier.
abstract: The adult blood-brain barrier, unlike the neonatal blood-brain barrier, does not transport lysosomal enzymes into brain, making enzyme replacement therapy ineffective in treating the central nervous system symptoms of lysosomal storage diseases. However, enzyme transport can be re-induced with alpha-adrenergics. Here, we examined agents that are known to alter the blood-brain barrier transport of large molecules or to induce lysosomal enzyme transport across the blood-brain barrier ((±)epinephrine, insulin, retinoic acid, and lipopolysaccharide) in 2-week-old and adult mice. In 2-week-old adolescent mice, all these pharmacologic agents increased brain and heart uptake of phosphorylated human β-glucuronidase. In 8-week-old adult mice, manipulations with (±)epinephrine, insulin, and retinoic acid were significantly effective on uptake by brain and heart. The increased uptake of phosphorylated human β-glucuronidase was inhibited by mannose 6-phosphate for the agents (±)epinephrine and retinoic acid and by L-NG-nitroarginine methyl ester for the agent lipopolysaccharide in neonatal and adult mice. An in situ brain perfusion study revealed that retinoic acid directly modulated the transport of phosphorylated human β-glucuronidase across the blood-brain barrier. The present study indicates that there are multiple opportunities to at least transiently induce phosphorylated human β-glucuronidase transport at the adult blood-brain barrier.
authors.affiliation: Department of Neurology, University of Texas Medical School at Houston, Houston, TX, USA Akihiko.Urayama@uth.tmc.edu.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Urayama
authors.affiliation: Lysosomal Research, Ultragenyx Pharmaceutical Inc., Novato, CA, USA Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Grubb
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism*; D005966:Glucuronidase / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D051379:Mice; D021381:Protein Transport / Q000187:drug effects*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; D014212:Tretinoin; D005966:Glucuronidase
keywords: Blood–brain barrier; brain uptake; enzyme replacement therapy; mannose 6-phosphate receptor; β-glucuronidase