Discovery of a novel compound: insight into mechanisms for acrylamide-induced axonopathy and colchicine-induced apoptotic neuronal cell death

The exposure of humans and experimental animals to certain industrial toxin s such as acrylamide is known to cause nerve damage classified as axonopath y, but the mechanisms involved are poorly understood. Here we show that acr ylamide induces morphological changes and tyrosine phosphorylation of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2), a member of the FAK subfamily, in human differentiating neuroblastoma SH-SY5Y cells. Furthermore, we identified a novel molecule designated 'compound-1' that i nhibits the morphological and biochemical events. Daily oral administration s of the compound also effectively alleviated behavioral deficits in animal s elicited by acrylamide in inclined plane testing, landing foot spread tes ting and rota-rod performance testing. The, compound also effectively inhib ited the biological and biochemical responses caused by another axonopathy inducer, colchicine, including tyrosine phosphorylation of Pyk2, formation of an 85-kDa poly(ADP-ribose)polymerase (PARP) fragment and apoptosis-assoc iated induction of the NAPOR gene as well as neuronal cell death. Our findi ngs not only provide insight into FAX and Pyk2 functions in neuronal cells, but may also be important in the development of therapeutic agents for per ipheral neuropathy and neurodegeneration (C) 2001 Elsevier Science B.V. All rights reserved.