Wide spectrum modulation by KP-544 in models relevant for neuronal survival

Neuroreport. 2007 Apr 16;18(6):571-5. doi: 10.1097/WNR.0b013e328012475c.

Abstract

Reduced neurotrophic signalling has been proposed as a part of the pathophysiology behind neuronal death and dysfunction. The small molecule KP-544 was developed with the intention to enhance nerve growth factor signalling. To characterize the actions of KP-544 pharmacologically, we used four diverse models with relevance for neuronal function and survival. We found that 300-1000 nM KP-544 enhanced the neurite outgrowth in PC12 cells in response to a suboptimal concentration of nerve growth factor. KP-544 also protected the cerebellar granule cells from excitotoxicity apoptosis induced by the mitochondrial toxin methyl-phenyl-pyridinium, and modulated inflammation by inhibiting interleukin-6 production in primary astrocytes. Chronic treatment of rats with KP-544 prevented the hyper-responsiveness to amphetamine of animals treated with methylazoxymethanol acetate, a recently described neurodevelopmental model of schizophrenia.

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Cell Death / drug effects
  • Cell Survival / drug effects
  • Cerebellum / cytology
  • Cyclohexanols / pharmacology*
  • Disease Models, Animal
  • Drug Synergism
  • Female
  • Male
  • Methylazoxymethanol Acetate
  • Nerve Growth Factor / pharmacology
  • Neurites / drug effects
  • Neurons / cytology*
  • Neurons / drug effects*
  • Neurons / ultrastructure
  • Neuroprotective Agents / pharmacology*
  • Neurotoxins
  • PC12 Cells
  • Pregnancy
  • Pyrimidines / pharmacology*
  • Rats
  • Schizophrenia / pathology*

Substances

  • 2-amino-5-(4-chlorophenylethynyl)-4-(4-hydroxycyclohexylamino)pyrimidine
  • Cyclohexanols
  • Neuroprotective Agents
  • Neurotoxins
  • Pyrimidines
  • Methylazoxymethanol Acetate
  • Nerve Growth Factor