Wide spectrum modulation by KP-544 in models relevant for neuronal survival.
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.
Geist
Marie A
MA
H. Lundbeck A/S, Department of Disease Biology, Valby, Denmark. maag@lundbeck.com
Volbracht
Christiane
C
Podhorna
Jana
J
Falsig
Jeppe
J
Leist
Marcel
M
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology; D003511:Cyclohexanols / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D008297:Male; D008746:Methylazoxymethanol Acetate; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins; D016716:PC12 Cells; D011247:Pregnancy; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D012559:Schizophrenia / Q000473:pathology*
C514429:2-amino-5-(4-chlorophenylethynyl)-4-(4-hydroxycyclohexylamino)pyrimidine; D003511:Cyclohexanols; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011743:Pyrimidines; D008746:Methylazoxymethanol Acetate; D020932:Nerve Growth Factor