title: MT-Stabilizer, Dictyostatin, Exhibits Prolonged Brain Retention and Activity: Potential Therapeutic Implications.
abstract: Inclusions comprising the microtubule (MT)-stabilizing protein, tau, are found within neurons in the brains of patients with Alzheimer's disease and related neurodegenerative disorders that are broadly referred to as tauopathies. The sequestration of tau into inclusions is believed to cause a loss of tau function, such that MT structure and function are compromised, leading to neuronal damage. Recent data reveal that the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), improves cognitive function and decreases both neuron loss and tau pathology in transgenic mouse models of tauopathy. There is thus a need to identify additional MT-stabilizing compounds with blood-brain barrier (BBB) permeability and slow brain clearance, as observed with EpoD. We report here that the MT-stabilizing natural product, dictyostatin, crosses the BBB in mice and has extended brain retention. Moreover, a single administration of dictyostatin to mice causes prolonged stabilization of MTs in the brain. In contrast, the structurally related MT-stabilizer, discodermolide, shows significantly less brain exposure. Thus, dictyostatin merits further investigation as a potential tauopathy therapeutic.
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Gardner
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: James
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Yuemang
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
authors.forename: Ian
authors.initials: I
authors.lastname: Paterson
authors.affiliation: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States ; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ballatore
authors.affiliation: Department of Chemistry, School of Arts and Sciences, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
keywords: Blood−brain barrier; dictyostatin; discodermolide; microtubule; pharmacokinetics; tauopathy