title: Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier.
abstract: The impermeability of the adult blood-brain barrier (BBB) to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases. Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse) of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy.
authors.affiliation: Department of Neurology, University of Texas Medical School at Houston, Houston, TX, United States of America.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Urayama
authors.affiliation: Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Dohgu
authors.affiliation: Division of Geriatric Medicine, Department of Internal Medicine, Saint Louis University, St. Louis, MO, United States of America.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Robinson
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, United States of America.
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Jeffery H
authors.initials: JH
authors.lastname: Grubb
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States of America.|Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States of America.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D018663:Adrenergic Agents / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism; D003000:Clonidine / Q000819:agonists / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D004837:Epinephrine / Q000378:metabolism; D007739:L Cells; D016464:Lysosomal Storage Diseases / Q000201:enzymology*; D051379:Mice; D021381:Protein Transport / Q000187:drug effects; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*
chemical_list: D018663:Adrenergic Agents; D015306:Biogenic Monoamines; D011942:Receptors, Adrenergic, alpha; D003000:Clonidine; D000109:Acetylcholine; D004837:Epinephrine