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Epothilone D improves microtubule density, axonal integrity and cognition in a transgenic mouse model of tauopathy

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2010
Contact PI Name:
Kurt R. Brunden
Contact PI Affiliation:
Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Co-Authors:
Bin Zhang, Jenna Carroll, Yuemang Yao, Justin S. Potuzak, Anne-Marie L. Hogan, Michiyo Iba, Michael J. James, Sharon X. Xiec, Carlo Ballatore, Amos B. Smith III, Virginia M-Y. Lee, John Q. Trojanowski
Primary Reference (PubMED ID):
20943926
Funding Source:
National Institute on Aging (NIA)
National Institute of Neurological Disorders and Stroke (NINDS)
Study Goal and Principal Findings:

Neurons in the brains of those with Alzheimer’s disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization, axonal integrity and neuronal dysfunction. One therapeutic hypothesis posits that MT-stabilizing drugs such as the anti-cancer drug epothilone D (EpoD). In this study the authors demonstrate that EpoD is brain-penetrant and that EpoD treatment of 3-month-old male PS19 mice, for a 3 month period, significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Epothilone D
PubMed
PubChem
DrugBank
ClinicalTrials
Patents
Therapeutic Target:
Tubulin (Microtubules)
Open Targets
Pharos

Animal Model

Model Information:
Species:
Mouse
Model Type:
Tau
Model Name:
Tau P301S (Line PS19)
ALZFORUM
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Barnes Maze
Motor Function
Rotarod Test
Electron Microscopy
Dystrophic Axons
Microtubule Density
Immunochemistry
phospho-Tau
Pharmacokinetics
Drug Concentration-Plasma
Drug Concentration-Brain
Toxicology
Body Weight
Organ Weight
Hematological Analysis/Blood Cell Count
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