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

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.

• Authors: Marie A Geist, Christiane Volbracht, Jana Podhorna, Jeppe Falsig, Marcel Leist
• Journal: Neuroreport (Neuroreport) Vol. 18 Issue 6 Pg. 571-5 (Apr 16 2007) ISSN: 0959-4965 [Print] England
• PMID: 17413659 (Publication Type: Journal Article)

Chemical References

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

Topics

• 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, drug effects, ultrastructure)
• Neuroprotective Agents (pharmacology)
• Neurotoxins
• PC12 Cells
• Pregnancy
• Pyrimidines (pharmacology)
• Rats
• Schizophrenia (pathology)