The heat shock protein inhibitor KNK437 induces neurite outgrowth in PC12 cells

Neurosci Lett. 2006 Dec 27;410(3):212-7. doi: 10.1016/j.neulet.2006.10.008. Epub 2006 Oct 18.


The nervous system is highly sensitive to various environmental stresses, such as ischemia. Stress response mechanisms that result in neuroprotection, including the induction of heat shock proteins (HSP), are not well understood. We examined the effect of KNK437, a compound that inhibits the synthesis of inducible heat shock proteins, on neuronal differentiation in rat pheochromocytoma PC12 cells. KNK437 decreased the expression of HSP70, and induced the neurite outgrowth of PC12 cells in the absence of stress stimulation, although with lower efficacy than nerve growth factor (NGF). Neurite outgrowth stimulated by KNK437 and NGF was blocked by inhibitors of ERK mitogen-activated protein (MAP) kinase, p38 MAP kinase, and glycogen synthase kinase 3beta signaling pathways. NGF, and not KNK437, induced acetylcholine esterase (AChE) activity, a functional differentiation marker, indicating that KNK437 utilizes a mechanism distinct from that of NGF. KNK437 enhanced the activity of low dose NGF treatment on neurite outgrowth induction and ERK phosphorylation in PC12 cells, a finding that identifies KNK437 as a possible nerve regeneration agent. This compound may be a useful tool for the investigation of neuronal differentiation and neuroprotection against environmental stress.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation / drug effects
  • HSP70 Heat-Shock Proteins / metabolism
  • Imidazoles / pharmacology
  • Lithium Chloride / pharmacology
  • Nerve Growth Factor / pharmacology
  • Neurites / drug effects*
  • PC12 Cells / cytology
  • PC12 Cells / drug effects
  • Pyridines / pharmacology
  • Pyrrolidinones / pharmacology*
  • Rats
  • Time Factors


  • Benzhydryl Compounds
  • Enzyme Inhibitors
  • HSP70 Heat-Shock Proteins
  • Imidazoles
  • KNK 437
  • Pyridines
  • Pyrrolidinones
  • Nerve Growth Factor
  • Extracellular Signal-Regulated MAP Kinases
  • Acetylcholinesterase
  • Lithium Chloride
  • SB 203580