Microtubule stabilization by peloruside A and paclitaxel rescues degenerating neurons from okadaic acid-induced tau phosphorylation.

Many cellular organelles must travel long distances in neurons to perform their specific functions, and this transport is highly dependent on the microtubule network within the axon. Hyperphosphorylation of microtubule-associated tau protein destabilizes microtubules and leads to neuronal cell death. This destabilization can be corrected in part by treatment with microtubule-stabilizing drugs such as paclitaxel and epothilone. The phosphatase inhibitor okadaic acid inhibits the outgrowth of neurites in neuronal cell cultures by hyperphosphorylating tau protein. In this study using neuronal cultures derived from the cerebral cortex of early postnatal Sprague-Dawley rats, we examined whether stabilization of microtubules by peloruside A, a microtubule-stabilizing agent that binds to a different site on β-tubulin from paclitaxel, could counter the deleterious effects of 8 h exposure to 15 nm okadaic acid. Peloruside A reversed the decrease in axonal outgrowth and branching seen in neuronal cultures treated with okadaic acid and rescued neurons from growth cone collapse. Although peloruside A had no effect on the hyperphosphorylation of tau caused by okadaic acid, it restored the levels of acetylated tubulin, a marker of stable microtubules, and reversed the okadaic acid-induced depression of growth-associated protein-43, an axonal growth regulator. Thus, microtubule-stabilizing drugs show promise as new therapeutic agents for treating damaged microtubule networks characteristic of neurodegenerative disease.