Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier

• Published in: PloS one 2015-11, Vol.10 (11), p.e0142347-e0142347
• Main Authors: Urayama, Akihiko, Dohgu, Shinya, Robinson, Sandra M, Sly, William S, Grubb, Jeffery H, Banks, William A
• Format: Article
• Language: English
• Subjects: Acetylcholine; Acetylcholine - metabolism; Adrenergic Agents - metabolism; Adrenergic receptors; Adrenergics; Animals; Biochemistry; Biogenic Monoamines - metabolism; Blood-brain barrier; Blood-Brain Barrier - enzymology; Blood-Brain Barrier - metabolism; Brain - cytology; Brain - metabolism; Brain research; Care and treatment; Central nervous system; Clonidine; Clonidine - agonists; Clonidine - pharmacology; Development and progression; Diagnosis; Doisy, Edward Adelbert (1893-1986); Endothelial cells; Endothelial Cells - metabolism; Enzymes; Epinephrine - metabolism; Geriatrics; Immunohistochemistry; Inborn errors of metabolism; Kinases; L Cells (Cell Line); Laboratory animals; Lysosomal enzymes; Lysosomal storage diseases; Lysosomal Storage Diseases - enzymology; Medicine; Metabolism; Mice; Molecular biology; Monoamines; Neonates; Perfusion; Permeability; Protein Transport - drug effects; Receptors, Adrenergic, alpha - metabolism; Rodents; Stimulation; Studies; Transport
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0142347

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.