Epothilone D

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- Epothilone D -

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Observations:

Novel study offers hope for new class of Alzheimer's drugs

Washington, Oct 19 (ANI): A new Penn study has discovered and tested in an animal model of Alzheimer's disease a class of drug that is able to enter the brain, where it stabilizes degenerating neurons and improves memory and learning.In the normal brain, the protein tau plays an important role in stabilizing structures called microtubules in nerve cells, which serve as tracks upon which cellular material is transported.

In Alzheimer's disease and related disorders, tau becomes insoluble and forms clumps in the brain. One consequence of these aggregates is a depletion of normal tau, resulting in destabilization of the microtubule tracks that are critical for proper nerve-cell function.

Senior authors Virginia M.-Y. Lee, director of the Center for Neurodegenerative Disease Research (CNDR), and John Trojanowski, director of the Institute on Aging and CNDR co-director, introduced the concept of using microtubule-stabilizing drugs over 15 years ago to counteract tangles of tau and compensate for the loss of normal tau function.

Kurt Brunden, director of Drug Discovery at CNDR and Bin Zhang, senior research investigator, are the first authors on this study from the University of Pennsylvania School of Medicineand the School of Arts and Sciences.

In 2005, the CNDR researchers showed that the anti-cancer drug paclitaxel could improve spinal cord nerve function in mice with tau tangles in their brains, after the drug was absorbed at nerve termini in muscle.

"However, paclitaxel and related drugs do not cross the blood-brain barrier," notes Brunden. "So we surveyed a number of additional microtubule-stabilizing agents and discovered that the epothilone class, and in particular epothilone D, readily entered and persisted in the brain."

"The positive effect of epothilone D on the function of axons and on cognition, without the onset of side-effects offers hope that this class of microtubule-stabilizing drugs could progress to testing in Alzheimer patients in the near future," said Lee.

"There are very few tau-focused drugs in clinical trials now for Alzheimer's disease. While we and others have urged that pharmaceutical companies should not put all of their eggs in one drug basket to ensure the highest likelihood of finding disease-modifying therapies for Alzheimer's, we hope this successful mouse study of a tau drug will encourage more pharmaceutical companies to pursue programs on tau-focused drug discovery," said Trojanowski.

The study has been published this week in the Journal of Neuroscienc. (ANI)
http://news.oneindia.in/2010/10/19/novelstudy-offers-hope-for-new-class-of-alzheimersdrugs.html

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References:

Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy.
Brunden KR, Zhang B, Carroll J, Yao Y, Potuzak JS, Hogan AM, Iba M, James MJ, Xie SX, Ballatore C, Smith AB 3rd, Lee VM, Trojanowski JQ.
J Neurosci. 2010 Oct 13;30(41):13861-6.
Source: Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. kbrunden@upenn.edu
Abstract:
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 and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related "tauopathies" is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood-brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequently evaluated whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month-old male PS19 mice with low doses of EpoD once weekly 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.
PMID: 20943926 [PubMed] PMCID: PMC2958430
http://www.ncbi.nlm.nih.gov/pubmed/20943926
Full Text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958430/?tool=pubmed

The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice.
Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AM, Xie SX, Ballatore C, Smith AB 3rd, Lee VM, Brunden KR.
J Neurosci. 2012 Mar 14;32(11):3601-11.
Source: Center for Neurodegenerative Disease Research, Institute on Aging and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Abstract
Neurodegenerative tauopathies, such as Alzheimer's disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a transgenic model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.
PMID: 22423084 [PubMed] PMCID: PMC3321513 [Available on 2012/9/14]
http://www.ncbi.nlm.nih.gov/pubmed/22423084

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