Abstract
Microtubule stabilizing agents are among the most clinically useful chemotherapeutic drugs. Mostly, they act to stabilize microtubules and inhibit cell division. While not without side effects, new generations of these compounds display improved pharmacokinetic properties and brain penetrance. Neurological disorders are intrinsically associated with microtubule defects, and efforts to reposition microtubule-targeting chemotherapeutic agents for treatment of neurodegenerative and psychiatric illnesses are underway. Here we catalog microtubule regulators that are associated with Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, schizophrenia and mood disorders. We outline the classes of microtubule stabilizing agents used for cancer treatment, their brain penetrance properties and neuropathy side effects, and describe efforts to apply these agents for treatment of brain disorders. Finally, we summarize the current state of clinical trials for microtubule stabilizing agents under evaluation for central nervous system disorders.
Highlights
Microtubule stabilizing agents are among the most clinically useful chemotherapeutic drugs
We outline the classes of microtubule stabilizing agents used for cancer treatment, their brain penetrance properties and neuropathy side effects, and describe efforts to apply these agents for treatment of brain disorders
The realization that microtubule dysfunction is associated with neuronal disorders, has fuelled efforts to reapply knowledge gained from cancer therapies, where tubulin polymerisation inhibitors have been used for over 50 years
Summary
Turku Centre for Biotechnology, Åbo Akademi University and University of Turku, Biocity, Tykistokatu, Turku, Finland. Neuronal cells are highly compartmentalized consisting of a soma, axon(s), dendrites, and synapses. These compartments develop because of particular cytoskeletal arrangements that are specific to neurons (Witte and Bradke, 2008). Axons convey long distance electrical signals leading to neurotransmitter release from nerve terminal active zones They vary in length from around 1 mm in hippocampal neurons, to 1 m in certain motor neurons; posing a long distance transport challenge. Several classes of MAPs exist in the nervous system that confer rigidity to microtubule tracks and enable motor proteins to travel long distances carrying cargo (e.g., mitochondria, proteins, and RNA granules) from soma to dendrites, synapses and axonal terminals. Cargo transport in neurons is directional, kinesin motors transport cargo toward axon terminals (anterograde) and dynein motors carry cargo away from axon tips (retrograde) (Vale, 2003)
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