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NEUROPHARMACOLOGY

-Amyloid-Induced Neurodegeneration and Protection by Structurally Diverse Microtubule-Stabilizing Agents

Department of Pharmacology and Toxicology (M.L.M., S.A., Y.C., K.I.S.), Department of Medicinal Chemistry (E.R.R., G.I.G.), Department of Molecular Biosciences (R.H.H.), and Department of Pharmaceutical Chemistry (K.L.A.), University of Kansas, Lawrence, Kansas

Deposition of -amyloid peptide (A) and hyperphosphorylation of the protein are associated with neuronal dysfunction and cell death in Alzheimer's disease. Although the relationship between these two processes is not yet understood, studies have shown that both in vitro and in vivo exposure of neurons to A leads to hyperphosphorylation and neuronal dystrophy. We previously reported that the microtubule-stabilizing drug paclitaxel (Taxol) protects primary neurons against toxicity induced by the A_25-35 peptide. The studies in this report were undertaken to characterize the actions of paclitaxel more fully, to assess the effectiveness of structurally diverse microtubulestabilizing agents in protecting neurons, and to determine the time course of the protective effects of the drugs. Primary neurons were exposed to A in the presence or absence of several agents shown to interact with microtubules, and neuronal survival was monitored. Paclitaxel protected neurons against A_1-42 toxicity, and paclitaxel-treated cultures exposed to A showed enhanced survival over A-only cultures for several days. Neuronal apoptosis induced by A was blocked by paclitaxel. Other taxanes and three structurally diverse microtubule-stabilizing compounds also significantly increased survival of A-treated cultures. At concentrations below 100 nM, the drugs that protected the neurons did not produce detectable toxicity when added to the cultures alone. Although multiple mechanisms are likely to contribute to the neuronal cell death induced by oligomeric or fibrillar forms of A, low concentrations of drugs that preserve the integrity of the cytoskeletal network may help neurons survive the toxic cascades initiated by these peptides.

Address correspondence to: Dr. M. L. Michaelis, Department of Pharmacology and Toxicology, 1251 Wescoe Hall Dr., 5064 Malott Hall, University of Kansas, Lawrence KS 66045. E-mail: mlm{at}ku.edu

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