title: A blood-brain barrier (BBB) disrupter is also a potent α-synuclein (α-syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD).
abstract: The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of α-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on α-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of α-synuclein from α-helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of α-synuclein aggregates in the brains of treated flies. In the mThy1-human α-synuclein transgenic mouse model, a decrease in α-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes α-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease.
authors: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv 69978, Israel.
authors: Ronit
authors: R
authors: Shaltiel-Karyo
authors: Moran
authors: M
authors: Frenkel-Pinter
authors: Edward
authors: E
authors: Rockenstein
authors: Christina
authors: C
authors: Patrick
authors: Michal
authors: M
authors: Levy-Sakin
authors: Abigail
authors: A
authors: Schiller
authors: Nirit
authors: N
authors: Egoz-Matia
authors: Eliezer
authors: E
authors: Masliah
authors: Daniel
authors: D
authors: Segal
authors: Ehud
authors: E
authors: Gazit
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry* / Q000494:pharmacology; D052160:Benzothiazoles; D001812:Blood-Brain Barrier / Q000187:drug effects*; D004330:Drosophila; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008124:Locomotion; D008297:Male; D008353:Mannitol / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy*; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D013844:Thiazoles / Q000737:chemistry; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D000978:Antiparkinson Agents; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D018840:HSP70 Heat-Shock Proteins; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; D008353:Mannitol
keywords: Alpha-Synuclein; Amyloid; Biophysics; Blood-Brain Barrier; Brain; Chemical Chaperone; Parkinson Disease
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