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

Brain Res. 2001 Aug 3;909(1-2):8-19. doi: 10.1016/s0006-8993(01)02608-7.

Abstract

The exposure of humans and experimental animals to certain industrial toxins such as acrylamide is known to cause nerve damage classified as axonopathy, but the mechanisms involved are poorly understood. Here we show that acrylamide 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 inhibits the morphological and biochemical events. Daily oral administrations of the compound also effectively alleviated behavioral deficits in animals elicited by acrylamide in inclined plane testing, landing foot spread testing and rota-rod performance testing. The compound also effectively inhibited 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-associated induction of the NAPOR gene as well as neuronal cell death. Our findings not only provide insight into FAK and Pyk2 functions in neuronal cells, but may also be important in the development of therapeutic agents for peripheral neuropathy and neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / toxicity*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Axons / drug effects*
  • Axons / metabolism
  • Axons / pathology
  • Benzimidazoles / pharmacology*
  • CELF Proteins
  • Colchicine / toxicity*
  • Cyclopentanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Focal Adhesion Kinase 1
  • Focal Adhesion Kinase 2
  • Focal Adhesion Protein-Tyrosine Kinases
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Movement Disorders / drug therapy
  • Movement Disorders / etiology
  • Movement Disorders / physiopathology
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / physiopathology
  • Nerve Tissue Proteins
  • Neuroprotective Agents / pharmacology*
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / physiopathology
  • Phosphorylation / drug effects
  • Poly(ADP-ribose) Polymerases / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein-Tyrosine Kinases / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / pathology

Substances

  • 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole
  • Acrylamides
  • Benzimidazoles
  • CELF Proteins
  • CELF2 protein, human
  • Cyclopentanes
  • Enzyme Inhibitors
  • Imidazoles
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • RNA, Messenger
  • RNA-Binding Proteins
  • imidazole
  • Poly(ADP-ribose) Polymerases
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Kinase 2
  • Focal Adhesion Protein-Tyrosine Kinases
  • PTK2 protein, human
  • Colchicine